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The immunomodulatory function of mesenchymal stem cells (MSCs) is plastic and susceptible to resident microenvironment in vivo or inflammatory factors in vitro. We propose a unique method to enhance the immunoregulatory functions of mesenchymal stem cells (MSCs) through an artificially controllable in vivo inflammatory microenvironment generated by biomaterials loaded with BMP-2 that induce bone development. MSCs activated through this method effectively induce M1 macrophage polarization toward the M2 phenotype, promote differentiation of naïve T cells into regulatory T cells, and inhibit the proliferation of activated T cells via prostaglandin E2 (PGE2) secretion. This in vivo licensing not only preserves the immunogenicity of MSCs but also alters DNA methylation patterns, enabling MSCs to exhibit immunoregulatory effects with epigenetic memory. Validation in a mouse colitis model demonstrated their therapeutic efficacy and long-term viability. Furthermore, we found that the material composition influences the inflammatory response during development, with polysaccharide-based biomaterials proving advantageous over protein-based materials in establishing an inflammatory niche conducive to MSC activity. These findings underscore the potential of tissue engineering to create in vivo environments that license MSCs, offering a strategic avenue to enhance MSC-based therapies for addressing significant immune disorders., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Knee osteoarthritis (OA) is a leading cause of disability, with current treatment options often falling short of providing satisfactory outcomes. Autologous-cultured adipose-derived mesenchymal stem cells (ADMSCs) and stromal vascular fractions (SVFs) have emerged as potential regenerative therapies., Methods: A comprehensive search was conducted among multiple databases for studies up to June 2023. The risk of bias was assessed in randomized and non-randomized studies, adhering to PRISMA guidelines. The study has been registered with PROSPERO (CRD 42023433160)., Results: Our analysis encompassed 31 studies involving 1,406 patients, of which, 19 studies with 958 patients were included in a meta-analysis, examining both SVF and autologous-cultured ADMSC methods. Significant pain reduction was observed with autologous-cultured ADMSCs starting at 3 months (MD = -2.43, 95% CI, -3.99, -0.86), whereas significant pain mitigation in response to SVF therapy was found to start at 12 months (MD = -2.13, 95% CI, -3.06, -1.21). Both autologous-cultured ADMSCs and SVF provided significant improvement in knee function starting at 12 months (MD = -9.19, 95% CI, -12.48, -5.90 vs. MD = -9.09, 95% CI, -12.67, -5.51, respectively). We found no evidence of severe adverse events linked directly to ADMSC therapy., Conclusion: Autologous-cultured ADMSCs offer a promising alternative for more rapid pain relief in knee OA, with both ADMSCs and SVF demonstrating substantial long-term benefits in joint function and cartilage regeneration, in the absence of any severe ADMSC-related adverse events., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: The aim of this study was to assess the safety and efficacy of human umbilical cord mesenchymal stromal cells (hUC-MSCs) patch used as an adjuvant therapy in fetal myelomeningocele (MMC) surgery in the ovine model., Methods: hUC-MSCs were isolated from human umbilical cords (UC) using the explant method, cultured and characterized. hUC-MSCs were then embedded in a fibrin patch. MMC were surgically created at 75 days of gestation and repaired at 89 days of gestation in sheep fetuses. Two groups were compared: the hUC-MSCs group in which MMC was repaired using a cellular patch and the control group, in which MMC was repaired using an acellular patch. Safety was evaluated by clinical ewes' monitoring during gestation, and clinical and histological examinations of lambs after birth. Efficacy was assessed by clinical neurological evaluation at 2 and 24 h of life using the sheep locomotor rating scale and by histological analyses., Results: Among the 17 operated lambs, nine were born alive: six in the hUC-MSCs group and three in the control group. Overall fetal loss was 47% (8/17) without differences between the two groups. No fever was reported in ewes. No tumors were detected in clinical and histological examinations in the lambs. At 24 h of life, mean Sheep Locomotor Rating score was higher in the hUC-MSCs group than in the control group: 15.0 versus 2.0 (p = 0.07). Histological analyses showed a higher large neurons density in the hUC-MSCs group in comparison with the control group: 9.9 versus 6.3/mm 2 of gray matter (p = 0.04). Lambs in the hUC-MSCs group had lower fibrosis around the spinal cord and at the level of the MMC scar: 70.9 versus 253.7 μm (p = 0.10) and 691.3 versus 1684.4 μm (p = 0,18), respectively., Conclusions: Ovine fetal repair of MMC using human UC-MSCs seems to be an effective and safe procedure., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved the 6th of July, 2020, by the French National Committee on Animal Research (APAFIS#25589-2020052810367317 v4). Title: “Myéloméningocèle: évaluation du bénéfice d’un patch de cellules souches mésenchymateuses dans le traitement anténatal”. Women gave written consent for the use of their umbilical cord for research. Consent for publication: All authors confirm their consent for publication. Competing interests: The authors declare that they have no competing interests. Disclosure of AI: The authors declare that they have not used Artificial Intelligence in this study., (© 2024. The Author(s).)

Background: The use of mesenchymal stem cells (MSCs) is recognized as a promising strategy for the treatment of androgenetic alopecia (AGA). However, the underlying mechanism remains to be explored. Here, we evaluated the therapeutic effects and potential mechanisms of the use of human umbilical cord mesenchymal stem cells (hUCMSCs) in dihydrotestosterone (DHT)-induced AGA models in vivo and in vitro., Methods: Intradermal transplantation of hUCMSCs was performed in AGA model mice and therapeutic effects were evaluated using histological and immunofluorescence staining. Transwell assays were used for co-culture of hUCMSCs and dermal papilla cells (DPCs), and communication was assessed using RT-qPCR, immunofluorescence, and apoptosis analysis. Interactions between DPCs and hair follicle stem cells (HFSCs) were investigated using RT-qPCR, EdU assays, and cell cycle analysis., Results: Treatment of AGA mice with hUCMSCs promoted hair growth, HFs density, skin thickness, and anagen phase activation, while inhibiting DPCs apoptosis, and promoting HFSCs proliferation. In vitro, hUCMSCs activated Wnt/β-catenin signaling in DPCs via Wntless (Wls), while stimulating growth factor secretion and HFSCs proliferation. Blocking β-catenin degradation with MSAB increased DPCs apoptosis, reduced growth factor secretion, and retarded HFSCs proliferation., Conclusion: hUCMSCs promoted hair regeneration in AGA model mice. This was found to be dependent on reducing DPCs apoptosis, thereby relieving the inhibitory effects of DPCs on the growth of HFSCs. The activation of the Wnt/β-catenin signaling pathway was shown to play a crucial role in the promotion of hair growth by hUCMSCs in AGA mice., Competing Interests: Declarations Ethics approval and consent to participate hUCMSCs are provided by Jiangsu Cell Tech Medical Research Institute Co., Ltd. The product was registered and reviewed by the China Clinical Trial Center (Registration No. ChiCTR2000031494) [48]. All animal procedures were performed in accordance with the guidelines for the Care and Use of Laboratory Animals and the Animal Welfare Act in China and approved by the Committee of Ethics on Experimentation of China pharmaceutical University (Project title: The therapeutic effect and mechanism of human umbilical cord-derived mesenchymal stem cells on androgenetic alopecia; Approval date: 2023.06.01; Approval number: 2023-06-028). The ethical approval permits the use of human umbilical cord-derived mesenchymal stem cells for animal experiments. Consent for publication All authors confirm their consent for publication. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: The underlying mechanism of human umbilical-derived mesenchymal stem cells (hUC-MSCs) therapy for renal senescence in post-acute kidney injury (post-AKI) remains unclear. Unopposed mitochondrial fusion-based mitochondrial elongation is required for cellular senescence. This study attempted to dissect the role of hUC-MSCs therapy in modulating mitochondrial elongation-related senescence by hUC-MSCs therapy in post-AKI., Methods: Initially, a unilateral renal ischemia-reperfusion (uIRI) model was established in C57 mice. Subsequently, lentivirus-transfected hUC-MSCs were given by subcapsular injection. Two weeks after transplantation, histochemical staining, and transmission electron microscopy were used to assess the efficacy of hUC-MSCs in treating renal senescence, fibrosis, and mitochondrial function. To further investigate the mitochondrial regulation of hUC-MSCs secretion, hypoxic HK-2 cells were built. Finally, antibodies of HGF and its receptor were used within the hUC-MSCs supernatant., Results: Unopposed mitochondrial fusion, renal senescence, and renal interstitial fibrosis were successively identified after uIRI in mice. Then, the efficacy of hUC-MSCs after uIRI was confirmed. Subsequently, inhibiting hUC-MSCs-derived HGF significantly compromises the efficacy of hUC-MSCs and leads to ineffectively curbing mitochondrial elongation, accompanying insufficient control of elevated PKA and inhibitory phosphorylation of drp1 (Drp1pSer637). As a result, the treatment efficacy of renal senescence and fibrosis alleviation was also weakened. Furthermore, similar results were obtained with antibodies blocking HGF or cMet in hypoxic HK-2 cells treated with hUC-MSCs-condition medium for further proving. Uncurbed mitochondrial elongation induced by PKA and Drp1pSer637 was inhibited by hUC-MSCs derived HGF but reversed in the activation or overexpression of PKA., Conclusions: The research concluded that hUC-MSCs-derived HGF can inhibit PKA-Drp1pSer637-mitochondrial elongation via its receptor cMet to alleviate renal senescence and fibrosis in post-AKI., Competing Interests: Declarations Ethics approval and consent to participate hUC-MSCs used in this study were donated by Vcanbio Cell & Gene Engineering Corp. Ltd, which had confimmed that there was initial ethical approval for collection of human cells, and that informed consent was duly signed by the donors. The animal experiments were conducted in line with the ARRIVE guidelines 2.0. All animal experiments were performed under ethical supervision and approved by the Institutional Animal Care and Use Committee of the Chinese PLA General Hospital in 2022 (Title research: Study on stem cell therapy for acute kidney injury. No. 2022-X18-39). This ethics approval also permitted performing experiments using the aforementioned hUC-MSCs. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: Deep partial-thickness burns have a significant impact on both the physical and mental health of patients. Our previous study demonstrated human Umbilical Cord Mesenchymal stem cells (hUCMSCs) could enhance the healing of severe burns in small animal burn models, such as rats. Furthermore, our team has developed a deep partial-thickness burn model in Bama miniature pigs, which can be utilized for assessing drug efficacy in preclinical trials for wound healing. Therefore, this study further determine the optimal dosage of hUCMSCs in future clinical practice by comparing the efficacy of low-to-high doses of hUCMSCs on deep partial-thickness burn wounds in Bama miniature pigs., Materials and Methods: The male Bama miniature pigs (N = 8, weight: 23-28 kg and length: 71-75 cm) were used to establish deep partial-thickness burn models, which used a continuous pressure of 1 kg and contact times of 35 s by the invented electronic burn instrument at 100℃ to prepare 10 round burn wounds with diameter of 5 cm according to our previous report. And then, 0 × 10^7, 1 × 10^7, 2 × 10^7, 5 × 10^7 and 1 × 10^8 doses of hUCMSCs were respectively injected into burn wounds of their corresponding groups. After treatment for 7, 14 and 21 days, the burned wound tissues were obtained for histological evaluation, including HE staining for histopathological changes, immunohistochemistry for neutrophil (MPO+) infiltration and microvessel (CD31+) quantity, as well as Masson staining for collagen deposition. The levels of inflammatory factors TNF-α, IL-1β, IL-10 and angiogenesis factors angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF), as well as collagen type-I/type-III of the wound tissues were quantified by ELISA., Results: All of doses hUCMSCs can significantly increase wound healing rate and shorten healing time of the deep partial-thickness burn pigs in a dose-dependent manner. Furthermore, all of doses hUCMSCs can significantly promote epithelialization and decreased inflammatory reaction of wound, including infiltration of inflammatory cells and levels inflammatory factors. Meanwhile, the amounts of microvessel were increased in all of doses hUCMSCs group than those in the burn group. Furthermore, the collagen structure was disordered and partially necrotized, and ratios of collagen type-I and type-III were significantly decreased in burn group (4:1 in normal skin tissue), and those of all hUCMSCs groups were significantly improved in a dose-dependent manner. In a word, 1 × 10^8 dose of hUCMSCs could regenerate the deep partial-thickness burn wounds most efficaciously compared to other dosages groups and the burn group., Conclusion: This regenerative cell therapy study using hUCMSCs demonstrates the best efficacy toward a high dose, that is dose of 1 × 10^8 of hUCMSCs was used as a reference therapeutic dose for treating 20 cm 2 deep partial-thickness burns wound in future clinical practice., Competing Interests: Declarations Ethics approval and consent to participate The project “An application study of new materials and techniques in the treatment of burns with different depths” was approved by the Institutional Animal Care and Use Committee at The Fourth Medical Center of PLA General Hospital (the ethics approval ID 2021KY033-KS001, Date approval: Nov. 29th, 2021 ), and the application of human umbilical cord mesenchymal stem cells (hUCMSCs) is one of the new techniques. Consent for publication The manuscript did not contain any individual person’s data. Competing interests The authors declare that they have no competing interests., (© 2024. The Author(s).)

Objective: To assess the efficacy and safety of stem cell therapy in human studies for diabetic peripheral neuropathy (DPN)., Methods: A comprehensive literature review was performed across multiple databases, including Ovid MEDLINE ALL, Embase via Ovid SP, Scopus, Web of Science Core Collection, and Cochrane CENTRAL, up to January 31, 2024. Keywords and controlled vocabularies related to diabetic neuropathy and stem cell therapy were used. Inclusion criteria encompassed all controlled trials examining stem cell therapy for DPN, excluding animal or in vitro studies, review papers, conference abstracts, and editor letters. Data extraction and risk of bias assessment were independently performed by multiple reviewers using standardized tools., Results: Out of 5431 initial entries, seven were included. Stem cell therapies included bone marrow-derived mononuclear cells and umbilical cord-derived mesenchymal stem cells, administered mainly via intramuscular transplantation. Meta-analysis indicated significant improvements in motor nerve conduction velocity (weighted mean differences (WMD): 2.2, 95% CI 1.6-2.8) and sensory nerve conduction velocity (WMD: 1.9, 95% CI 1.1-2.6). Vibration perception threshold and Toronto Clinical Scoring System scores decreased significantly (WMD: - 2.9, 95% CI - 4.0, - 1.8, and WMD: - 3.6, 95% CI - 5.0, - 2.2, respectively). Sensitivity analysis and subgroup analysis confirmed the robustness and specificity of these findings. The complications were pain and swelling at the injection sites, which disappeared in a few days., Conclusion: Stem cell therapy shows significant promise in improving clinical outcomes for DPN, with evident benefits in nerve conduction and sensory parameters. Further research is needed to consolidate these findings and optimize therapeutic protocols., Competing Interests: Declarations Ethics approval and consent to participate All gathered data was maintained in confidentiality and analyzed without any identifying names included. The study adhered to Helsinki's ethical principles. The Ethics Committee of Tehran University of Medical Sciences approved the study (Title of the approved project: Human Studies of the Efficacy and Safety of Stem Cells in the Treatment of Diabetic Peripheral Neuropathy: A Systematic Review and Meta-Analysis; Name of the institutional approval committee or unit: Research Ethics Committees of Sina Hospital; Approval number: IR.TUMS.SINAHOSPITAL.REC.1403.046; Date of approval: 2024-07-06). Consent for publication All authors have agreed to publish the paper in Stem Cell Research and Therapy (SCRT). Competing interest The authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: Systemic lupus erythematosus (SLE) is an incurable chronic autoimmune disease of unknown etiology. Therefore, the development of new treatments is urgently needed. This study aimed to investigate the therapeutic effects of extracellular vesicles (EV) derived from immortalized mesenchymal stem cells (iMSCs) primed with conditioned media obtained from disease-conditioned immune cells (CM-EV) and iMSC-derived EV (ASC-EV) in a murine model of SLE., Methods: Female NZB/W F1 mice were divided into the control (C, n = 15), ASC-EV (E, n = 15), and CM-EV (CM, n = 15) groups. Mice in the C, E, and CM groups were intravenously administered saline, ASC-EV, and CM-EV, respectively, once weekly from 6 to 42 weeks of age., Results: Compared to the ASC-EV, the CM-EV showed a significant increase in TGF-β1 production and miR-155-5p and miR-142-3p expression. CM-EV treatment increased survival, decreased anti-dsDNA antibody levels, and ameliorated renal histopathology. Although ASC-EV treatment significantly reduced the incidence of severe proteinuria and improved renal histopathology, it did not significantly improve survival rate. ASC-EV or CM-EV treatment significantly decreased the proportion of pro-inflammatory macrophages (CD11c + CD206-; M1) and M1:M2 ratio. Additionally, CM-EV treatment significantly increased the expression of anti-inflammatory macrophages (CD11c-CD206 + ; M2). Moreover, CM-EV treatment significantly decreased the expression of lupus-specific miRNAs (miR-182-5p and miR-183-5p) in the spleen., Conclusions: EV derived from iMSCs primed with conditioned media obtained from disease-conditioned immune cells exert immunomodulatory effects and ameliorate SLE in a murine model., Competing Interests: Declarations Ethics approval and consent to participate This study, using de-identified human iMSCs, was reviewed by the institutional review board (IRB) (KWNUIRB-2021–04-009–002): (1) Title of the approved project: Development of next-generation therapeutic agents for autoimmune diseases using advanced mesenchymal stem cell-derived materials; (2) Name of the institutional approval committee: IRB of Kangwon National University; (3) Approval number: KWNUIRB-2021–04-009–002; (4) Date of approval: May 17, 2022. The animal studies were reviewed and approved (KW-211020–1) by the IACUC of Kangwon National University and the IACUC of GenNBio (GN-IACUC-22–05-07) as follows: Experiment to obtain splenocytes from a murine model of SLE: (1) Title of the approved project: The effects of advanced mesenchymal stem cell-derived materials on SLE; (2) Name of the institutional approval committee: IACUC of Kangwon National University; (3) Approval number: KW-211020–1; (4) Date of approval: October 26, 2021; In vivo study: (1) Title of the approved project: The therapeutic effect of advanced exosome in a murine model of SLE; (2) Name of the institutional approval committee: IACUC of GenNBio; (3) Approval number: GN-IACUC-22–05-07; (4) Date of approval: May 11, 2022. Consent for publication Not applicable. Competing interests EWC is listed as an inventor on a pending patent that describes the “Mesenchymal stem cells primed with disease-condition-immune cells and uses thereof.” Since EWC and her institute stand to profit from this work, EWC has a conflict of interest in this capacity, which has hereby been officially disclosed. JL, BC, and SK are employees of GenNBio Inc. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Background: Mesenchymal stromal cell (MSC) therapy commonly involves systemic infusion of MSCs, which undergo apoptosis in the lung and induce immunoregulatory macrophages that reduce disease. The relevance of this mode of action, however, is yet to be determined for MSCs administered via other routes. Here, we administered MSCs via subcutaneous (SC) injection into inflamed tissue and investigated the immunomodulatory effects on the local lymph node (LN), which is a major site for the initiation and regulation of immune responses., Methods: A mouse model of localised skin inflammation was established with low-dose lipopolysaccharide (LPS) to in vivo prime adipose-derived MSCs delivered via SC injection. We then analysed the immunomodulatory changes in the LN draining the inflamed tissue, as well as the neutrophil TNF response to LPS re-exposure., Results: When administered directly into the inflamed skin tissue, SC MSC injection induced an expansion of IL-10-producing MerTK + subcapsular sinus macrophages and T cell zone macrophages, as well as activated CD44 + regulatory T cells (Tregs), in the draining LN, which was not observed in the non-draining LN. SC injection of viable, but not apoptotic, MSCs dampened TNF production by inflammatory cells in the draining LN when re-exposed to the inflammatory stimulus. SC injection of MSCs remote to the site of inflammation also did not attenuate the LN response to subsequent inflammatory challenge., Conclusions: MSCs delivered directly into inflamed skin activated immunoregulatory cells in the local LN and inhibited LN responsiveness to subsequent inflammatory challenge. The immunoregulatory effects of SC-injected MSCs in the LN require priming by inflammatory cytokines in the local milieu. Furthermore, SC-injected MSCs exert anti-inflammatory effects in the draining LN prior to their apoptosis, in contrast to intravenously delivered MSCs, where anti-inflammatory effects are linked to their apoptosis., Competing Interests: Declarations Ethics approval and consent to participate All animal experiments received approval from Monash University Animal Ethics Committee (Project title: Mesenchymal stromal cells and the innate immune system; Approval number: 23407; Date of approval: 01/04/2020) and were performed in accordance with the guidelines of the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes. Human MSCs were isolated from healthy donor lipoaspirate, performed with informed patient consent in accordance with Monash University Human Research Ethics Committee (Project title: Immunomodulatory properties of different stem cell types; Approval number: 2007/1798; Date of approval: 10/10/2007). Consent for publication Not applicable. Competing interests TSPH had received funding from Regeneus Ltd. MRH had also undertaken other related funded research for Regeneus Ltd. FM, CM and GV were employees of Regeneus Ltd. The funders were not involved in the study design, collection, analysis or interpretation of data, the writing of this article or the decision to submit it for publication. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Spinal cord injury (SCI) represents a severe trauma to the central nervous system, resulting in significant disability and imposing heavy burdens on families and society. Pathophysiological changes following SCI often trigger secondary injuries that complicate treatment. Bone marrow mesenchymal stem cells (BM-MSCs) have become a focal point of research due to their multifunctionality and self-renewal capabilities; however, their survival and neuroprotective functions are compromised in inflammatory environments. Resveratrol, known for its anti-inflammatory, anti-aging, and anti-oxidative stress properties, has been extensively studied. This research focuses on the anti-inflammatory effects of resveratrol post-SCI and its combined application with BM-MSCs to treat rat spinal cord injuries, exploring both efficacy and mechanisms. In vivo experiments investigated changes in the Sirt-1 signaling pathway post-SCI, while in vitro studies examined the effects of resveratrol on BM-MSCs under inflammatory conditions. The assessment included recovery of motor function, neuronal survival, and apoptosis in SCI rats treated with resveratrol alone or in combination with BM-MSCs. Findings reveal a correlation between Sirt-1 and inflammation signaling pathways post-injury. Resveratrol significantly enhanced the survival and efficacy of BM-MSCs in inflammatory environments by upregulating Sirt-1 and downregulating NF-κB and other inflammatory markers, thereby reducing apoptosis. Combined treatment with resveratrol and BM-MSCs showed superior outcomes in motor function recovery and neuronal survival compared to treatment with BM-MSCs alone. This study offers a novel therapeutic strategy for SCI, enhancing stem cell survival and function through modulation of the Sirt-1/NF-κB pathway, providing a theoretical and experimental foundation for clinical applications., Competing Interests: Declarations Competing Interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: This study aimed to evaluate the effects of umbilical cord mesenchymal stem cells (UC-MSCs) in the treatment of knee osteoarthritis., Methods: PubMed, Web of Science, Cochrane Library, Embase, Chinese National Knowledge Infrastructure and Wanfang databases were searched from inception to March 31, 2024. RevMan 5.3 was used to conduct meta-analyses of the final included studies., Results: Three randomized controlled studies were conducted. Western Ontario and McMaster Universities Osteoarthritis Index was reduced in the UC-MSCs group compared that in to the control group (mean difference: -25.85; 95% confidence interval: -41.50, -10.20; P = .001). Knee Lysholm Score was improved in the UC-MSCs group compared with the control group (mean difference: 18.33; 95% confidence interval: 12.89, 23.77; P < .00001). Egger test showed P = .583, indicating no publication bias. Sensitivity analysis indicated that the results were stable., Conclusion: Intra-articular injection of UC-MSCs improved function and reduced pain in patients with knee osteoarthritis. However, the number of included studies was small and more studies are needed to confirm this., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To review the research progress on bone repair biomaterials with the function of recruiting endogenous mesenchymal stem cells (MSCs)., Methods: An extensive review of the relevant literature on bone repair biomaterials, particularly those designed to recruit endogenous MSCs, was conducted, encompassing both domestic and international studies from recent years. The construction methods and optimization strategies for these biomaterials were summarized. Additionally, future research directions and focal points concerning this material were proposed., Results: With the advancement of tissue engineering technology, bone repair biomaterials have increasingly emerged as an ideal solution for addressing bone defects. MSCs serve as the most critical "seed cells" in bone tissue engineering. Historically, both MSCs and their derived exosomes have been utilized in bone repair biomaterials; however, challenges such as limited sources of MSCs and exosomes, low survival rates, and various other issues have persisted. To address these challenges, researchers are combining growth factors, bioactive peptides, specific aptamers, and other substances with biomaterials to develop constructs that facilitate stem cell recruitment. By optimizing mechanical properties, promoting vascular regeneration, and regulating the microenvironment, it is possible to create effective bone repair biomaterials that enhance stem cell recruitment., Conclusion: In comparison to cytokines, phages, and metal ions, bioactive peptides and aptamers obtained through screening exhibit more specific and targeted recruitment functions. Future development directions for bone repair biomaterials will involve the modification of peptides and aptamers with targeted recruitment capabilities in biological materials, as well as the optimization of the mechanical properties of these materials to enhance vascular regeneration and adjust the microenvironment.

Alzheimer's disease (AD) is a severe neurodegenerative disorder, and the current treatment options are limited. Mesenchymal stem cell-derived exosomes (MSC-Exos) have garnered significant attention due to their unique biological properties, showcasing tremendous potential as an acellular alternative therapy for AD. MSC-Exos exhibit excellent biocompatibility and low immunogenicity, enabling them to effectively cross the blood-brain barrier (BBB) and deliver therapeutic molecules directly to target cells. They are highly efficacious in delivering nucleic acid-based drugs. Moreover, the production process of MSC-Exos benefits from a high proliferation capacity and multilineage differentiation potential, allowing for production while maintaining a stable composition. Despite the significant theoretical advantages of MSC-Exos, their clinical use still faces multiple challenges, including cross-contamination during isolation and purification processes, the complexity of their components, and the presence of potential adverse paracrine factors. Future research needs to focus on optimizing separation and purification techniques, enhancing delivery methods to improve therapeutic efficacy, and performing detailed analyses of the components of MSC-Exos. In summary, MSC-Exos hold promise as an effective option for the treatment of AD and other neurodegenerative diseases, driving their clinical research and use in related fields.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of preterm infants, with its incidence rising due to improved survival rates of these infants. BPD results from a combination of prenatal and postnatal factors, such as mechanical ventilation, oxygen toxicity, and infections, all of which significantly impact the prognosis and growth of affected infants. Current treatment options for BPD are largely supportive and do not address the underlying pathology. Exosomes are cell-derived bilayer-enclosed membrane structures enclosing proteins, lipids, RNAs, growth factors, cytokines and metabolites. They have become recognized as crucial regulators of intercellular communication in various physiological and pathological processes. Previous studies have revealed the therapeutic potential of human umbilical cord mesenchymal stem cells-derived exosomes (HUCMSCs-Exos) in promoting tissue repair and regeneration. Therefore, HUCMSCs-Exos maybe a promising and effective therapeutic modality for BPD. In this review, we firstly provide a comprehensive overview of BPD, including its etiology and the mechanisms of lung injury. Then we detail the isolation, characterization, and contents of HUCMSCs-Exos, and discuss their potential mechanisms of HUCMSCs-Exos in BPD treatment. Additionally, we summarize current clinical trials and discuss the challenges in translating these findings from bench to bedside. This review aims to lay the groundwork for future clinical applications of HUCMSCs-Exos in treating BPD., Competing Interests: Declaration of competing interest HL and XL are co-corresponding authors. The other authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Although mesenchymal stem cells (MSCs) have been proven to be appropriate candidates for the treatment of AKI-CKD, their efficacy is limited and variable. Astilbin (AST) had a protective effect on MSCs from oxidative stress via ROS-scavenging, however, whether it can improve MSCs' renoprotection and the underlying mechanism need to be elucidated., Methods: AST-pretreated MSCs were administered intravenously into the ischemia-reperfusion injury mice models and the renal function, pathological changes and inflammation. Were evaluated. In addition, DARTS, molecular docking, surface plasma resonance(SPR), dual-luciferase reporter gene assay and the ChIP-PCR were utilized to explore the potential signaling pathways through which AST exert renal protective effects on MSCs., Results: AST-pretreated MSCs markedly improved kidney function, reduced kidney pathological injury and inflammation in AKI and AKI-CKD mice. RNA-seq results showed that PTGS2 related pathway was significantly up-regulated in MSCs after AST pretreatment. DARTS assay, molecular docking and SPR assay revealed that AST could bind with the transcriptional factor of Kruppel-Like Factor 4(KLF4) protein. The promoter of PTGS2 had the binding and transcriptional activation by KLF4. Furthermore, AST pretreatment promoted the secretion of PGE2 in MSCs. And then the westren blot results showed that the protein levels of CD163 and CD206 were upregulated after coculture in AST-pretreated MSCs, indicating that the polarization of RAW264.7 cells towards M2-like macrophages was induced. Knockdown of PTGS2 reversed the ability of AST-pretreated MSCs in converting macrophages to M2 phenotype and reducing their therapeutic effects on AKI-CKD mice., Conclusion: AST pretreatment enhances the efficacy of MSCs on AKI and AKI-CKD mice by inducing of M2-like phenotype polarization in macrophages through the PTGS2-mediated pathway. This approach not only provides a novel strategy to strengthen the capability of MSCs but also helps elucidate the beneficial effects of the Chinese herbal medicine AST., Competing Interests: Declarations Ethics approval and consent to participate All animal experiments were conducted in accordance with the ARRIVE guidelines 2.0 (Animal Research: Reporting of In Vivo Experiments) and approved by the by the Ethics Committee for the Use of Animals of PLA General Hospital. (Approval No. 2022-X18-36, “Astilbin improves the therapeutic effects of mesenchymal stem cells in AKI-CKD mice by regulating macrophage polarization through PTGS2-mediated pathway” approved on November 5, 2022). Human bone marrow MSCs were obtained from Cyagen Company (Guangzhou, China). Cyagen Company has confirmed that there was initial ethical approval for collection of human cells, and that the donors had signed informed consent. Consent for publication All authors confirm their consent for publication. Competing interests The authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: The efficiency of mesenchymal stem cells (MSCs) in treating myocardial infarction (MI) remains inconsistent, which limits their therapeutic applications. Therefore, exploring the mechanism for the inconsistent efficacy of MSCs and identification the criteria for screening MSCs are important for improving the efficiency of MSCs., Methods: Mouse model after MI was utilized to test the role of MSCs from different donors and the functional subpopulation in improving cardiac function. Heterogeneity of MSCs was identified using single-cell RNA sequencing (scRNA-seq) of MSC-GY. GSEA and Scissor analyses were used to find the functional subpopulations of MSCs that promote angiogenesis. The role of functional subpopulations in promoting angiogenesis was verified by detecting the secretory proteins, the ratio of N-CADHERIN + /CD168 - subpopulations in MSCs, and the tube formation, migration, and proliferation of HUVECs after treatment with conditional medium (CM) derived from different MSCs., Results: We found that umbilical cord-derived MSCs (UC-MSCs) from different donors have varied therapeutic efficacy in MI mice and UC-MSCs with higher therapeutic effectiveness exhibited the most potent pro-angiogenic effects by secreting elevated levels of angiogenesis-related proteins, such as MYDGF, VEGFA, and FGF2. ScRNA-seq of 10,463 UC-MSCs revealed that the N-CADHERIN + /CD168 - subpopulation was closely associated with pro-angiogenic effects, and the ratio of this cell subpopulation was positively correlated with the angiogenic potential of MSCs. We also found that the N-CADHERIN + /CD168 - subpopulation was the functional subpopulation of MSCs in improving cardiac function of MI mice., Conclusions: Our study identified that the N-CADHERIN + /CD168 - subpopulation was the functional subpopulation of MSCs in treating MI, which was essential for the development and utilization of MSCs in MI treatment., Competing Interests: Declarations Ethical approval and consent to participate This study was approved by the Animal Experimentation Ethics Committee, Tongji University [TJABO4523102 (title: The functions and mechanisms of N-CADHERIN+/CD168− umbilical cord mesenchymal stem cell subpopulation in the treatment of myocardial infarction; date:28 th Feb, 2023)] and approved by the Institutional Animal Care and Use Committee of Tongji University. Human umbilical cord mesenchymal stem cells were obtained following signed informed consent and approved for the project: The preparation and construction of clinical human umbilical cord and umbilical cord blood stem cells, the Ethics Committee of Shanghai East Hospital (No: 2017 Preliminary Review No. (001)). 18th Oct. 2019. Consent for publication Not applicable. Competing interests Authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: Although stem cell transplantation is a promising approach for the treatment of myocardial infarction (MI), there are still some problems faced such as the low survival rate of stem cells. Here, we investigated the role of Notoginsenoside R1 (NGR1) pretreatment in improving the effects of neonatal rat bone marrow mesenchymal stem cell (MSC) transplantation for treatment of MI., Methods: Cardiac functions were detected by echocardiography and the myocardial infarct size was determined by Masson's trichrome staining in a rat model of MI. The cardioprotective effects of NGR1/LY294002 co-pretreated MSCs was evaluated to explore the underlying mechanism. The angiogenesis was determined by vWF and α-SMA immunofluorescence staining and cell apoptosis was detected by TUNEL. In vitro, the effects of NGR1 on stem cell proliferation was examined by CCK-8 and levels of P-Akt, P-CREB, P-FoxO1 were detected by western blot. Apoptosis, ROS content, and cytokine levels were examined by DAPI and TUNEL staining, a ROS assay kit, and ELISA, respectively., Results: NGR1 elevated the therapeutic effect of MSC transplantation on infarction by preserving cardiac function, increasing angiogenesis and expressions of IGF-1, VEGF, and SDF-1, and reducing cell apoptosis, whereas the addition of LY294002 prior to NGR1 treatment significantly counteracted the foregoing effects of NGR1. NGR1 pretreatment and SC79 pretreatment were similar in that both significantly increased P-Akt and P-FoxO1 levels in MSC and did not affect P-CREB levels. Besides, both NGR1 and SC79 promoted VEGF, SCF and bFGF levels in MSC cultures, and significantly reduced ROS accumulation and the attenuated cell apoptosis in MSC triggered by H 2 O 2 . Similarly, addition of LY294002 before NGR1 treatment significantly counteracted the aforementioned effects of NGR1 in vitro., Conclusions: NGR1 pretreatment enhances the effect of MSC transplantation for treatment of MI through paracrine signaling, and the mechanism underlying this effect may be associated with PI3K/Akt/FoxO1 signaling pathways., Competing Interests: Declarations Ethics approval and consent to participate This study was approved by the Animal Ethics Committee of Shanghai University of TCM (No. PZSHUTCM190628003, approved on June 30, 2019). The title of the approved project was ‘Mechanism of optimizing microenvironment in induced pluripotent stem cell transplantation for myocardial infarction by qi replenishing and blood activating traditional Chinese medicine’. Consent for publication Not applicable. Competing interests The authors declare that they have no conflicts of interest., (© 2024. The Author(s).)

Background: Congenital heart defects can lead to right ventricular (RV) pressure-overload and heart failure. Cell-based therapies, including mesenchymal stromal cells (MSCs) and c-kit positive cells (CPCs) have been studied clinically as options to restore heart function in disease states. Many studies have indicated these cells act through paracrine mechanisms to prevent apoptosis, promote cellular function, and regulate gene/protein expression. We aimed to determine the proteomic response of diseased hearts to cell therapy., Methods: We utilized a juvenile rat model of RV pressure overload created by banding the pulmonary artery (PAB). Two weeks post-banding, bone marrow-derived mesenchymal stromal cells (MSCs) and 3 populations of CPCs (nCPCs, cCPCs, ES-CPCs) were delivered to the RV free wall. RV function and cellular retention were measured for four weeks post-injection, at which point hearts were extracted and the RV was excised for liquid chromatography and tandem mass spectrometry. Resulting RV proteomes were compared and analyzed using systems biology and bioinformatics., Results: Proteomic profiling identified 1156 total proteins from the RV, of which 5.97% were significantly changed after PAB. This disease-altered proteome was responsive to cellular therapy, with 72% of the PAB-altered proteome being fully or partially reversed by MSC therapy. This was followed by nCPCs (54%), ES-CPCs (52%), and cCPCs (39%). Systems biology and bioinformatics analysis showed MSC, nCPC, or ES-CPC cell therapy is associated with a decrease in predicted adverse cardiac effects. We also observed an effect of cell therapy on the non-altered RV proteome, however, this was associated with minor predicted pathological endpoints., Conclusions: Our data indicate MSCs, ES-CPCs, and nCPCs significantly reverse the PAB-altered proteome towards a pre-disease state in our animal model. These results indicate cell-based therapies show promise in improving RV function after pressure overload through partial restoration of the disease-altered cardiac proteome., Competing Interests: Declarations Ethics approval and consent to participate This study was approved by the Institutional Review Board at Children’s Healthcare of Atlanta and Emory University for the isolation of human c-kit positive cells from patients (Protocol title: Molecular and Cellular Characterization of Cardiac Tissue in Postnatal Development; Protocol number: IRB00005500; approved on 08/15/2017). The patients or their guardians/legally authorized representatives provided written informed consent for participation in the study and the use of samples. All animal experiments were performed with the approval of the Institutional Animal Care and Use Committee of Emory University (Protocol title: Development of novel therapies for right heart failure; Protocol number: DAR-4000044-ENTRPR-N; approved on 09/12/2017) and conform to the guidelines from the NIH Guide for the Care and Use of Laboratory Animals. Consent for publication Not applicable. Competing interests The authors declare they have no competing interests., (© 2024. The Author(s).)

Myocardial infarction (MI) is a leading cause of heart failure, disability and mortality worldwide. In this study, the effects of intramyocardial injection of human platelet lysate (HPL), bone marrow mesenchymal stem cells pretreated with HPL (PMSCs), and PMSC lysate (lys), alone and in combination were investigated on MI-induced by LAD ligation in male Wistar rats. The experiment was carried out on sham, vehicle (Veh), HPL, PMSCs, PMSC lysate (PMSC lys), HPL + PMSCs, and HPL + PMSC lys groups. SBP, DBP, and ± dp/dt max were monitored by the PowerLab physiograph. The MSC characteristics and CD31, NKX2.5, and cardiac troponin I (cTnI) contents were determined by flow cytometry, immunohistochemistry, and immunofluorescence, respectively. SBP, DBP, and ± dp/dt max that decreased in the MI group were recovered by HPL, PMSC, PMSC lys, HPL + PMSC, and HPL + PMSC lys treatments. CD31 density was higher in all treated groups compared to the Veh group. CD31 density in the HPL + PMSCs and HPL + PMSC lys groups was higher than in the PMSCs group. The number of Dil+/NKX2.5 + and Dil+/cTnI + cells was higher in the HPL + PMSCs group compared to the PMSCs group. The HPL and PMSCs mitigates heart injuries and cardiac dysfunction after MI. HPL provides an appropriate environment for cardiomyocyte differentiation from PMSCs., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Preemptive regenerative medicine using mesenchymal stem cells (MSCs) may provide a novel therapeutic approach to prevent the progression from organ damage to organ failure. Although immunosuppressive drugs are often used in patients with organ disorder, their impact on MSC therapy remains unclear. We investigated the effects of immunosuppressive drugs on the therapeutic efficacy of MSCs. We created unilateral ureteral obstruction models, as a well-established model of renal fibrosis, a preliminary stage of organ failure. Three immunosuppressive drugs (methylprednisolone, cyclosporine, and cyclophosphamide) were intraperitoneally administered 3 days after surgery, and MSCs were injected via tail vein the following day. Preadministration of methylprednisolone or cyclophosphamide interfered with MSC activation by reducing expression of interferon-gamma (IFN-γ) and high-mobility group box-1 protein, thus significantly attenuating the therapeutic efficacy of MSCs. Preadministration of cyclophosphamide downregulated the expression of stromal cell-derived factor-1/C-X-C motif ligand 12, which is a potent migration factor for MSCs, resulting in reduced MSC engraftment in the renal cortex. IFN-γ-preconditioned activated MSCs were unaffected by these drugs and maintained their beneficial therapeutic effects. Cyclosporine preadministration had no effect on the therapeutic efficacy of MSCs. Our study demonstrated that the administration of certain immunosuppressive drugs interfered with MSC activation and engraftment at the site of injury, resulting in a significant attenuation of their therapeutic efficacy. These findings provide crucial information for selecting patients suitable for MSC therapy. Use of MSCs preactivated with IFN-γ or other means is preferred for patients on methylprednisolone or cyclophosphamide., (© The Author(s) 2024. Published by Oxford University Press.)

Over the years, the neuroprotective potential of bone marrow mesenchymal stem cells (BMSCs) in acute ischemic stroke has attracted significant attention. However, BMSCs face challenges like short metabolic cycles and low survival rates post-transplant. Polypyrimidine tract-binding protein 1 (PTBP1) is an immunomodulatory RNA-binding protein that regulates the cell cycle and increases cell viability. This study investigated the protective effects and underlying mechanism of PTBP1 knockdown in BMSCs (PTBP1KD-BMSCs) following ischemia-reperfusion injury (IRI) in neurons. BMSCs were isolated from Sprague-Dawley rat femurs and characterized through flow cytometry and differentiation induction. PTBP1 knockdown inhibited BMSCs proliferation. Co-culture with PTBP1KD-BMSCs decreased reactive oxygen species (ROS) and malondialdehyde (MDA) levels, while increasing glutathione (GSH) production in oxygen and glucose deprivation/reperfusion-induced PC12 cells. Transcriptome sequencing analysis of PC12 cells suggested that the protective effect of PTBP1KD-BMSCs against injury may involve ferroptosis. Furthermore, western blotting showed upregulation of glutathione synthetase (GSS), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11) in PTBP1KD-BMSCs, known negative regulators of ferroptosis. Moreover, PTBP1KD-BMSCs inhibited p38MAPK and JNK activation. In addition, PTBP1KD-BMSCs transplantation into middle cerebral artery occlusion/reperfusion (MCAO/R) rats reduced cerebral infarction volume and improved neurological function. Immunofluorescence analysis confirmed the upregulation of GSS expression in neurons of the ischemic cortex, while immunohistochemistry indicated a downregulation of p-P38. These result suggest that PTBP1KD-BMSCs can alleviate neuronal IRI by reducing oxidative stress, inhibiting ferroptosis, and modulating the MAPK pathway, providing a theoretical basis for potential treatment strategies for cerebral IRI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

After prolonged space operations, astronauts showed maladaptive atrophy within mostly left-ventricular myocardium, resulting in cardiac dysfunction. However, the mechanism of cardiac dysfunction under microgravity conditions is unclear, and the relevant prevention and treatment measures also need to be explored. Through simulating the microgravity environment with a tail suspension (TS) model, we found that long-term exposure to microgravity promotes aging of mouse hearts, which is closely related to cardiac dysfunction. The intravenous administration of adipose-derived mesenchymal stem cells (ADSCs) emerged preventive and therapeutic effect against myocardial senescence and the decline in cardiac function. Plasma metabolomics analysis suggests the loss of NAD+ in TS mice and motivated myocardial NAD + metabolism and utilization in ADSCs-treated mice, likely accounting for ADSCs' function. Oral administration of nicotinamide mononucleotide (NMN, a NAD + precursor) showed similar therapeutic effect to ADSCs treatment. Collectively, these data implicate the effect of ADSCs in microgravity-induced cardiac dysfunction and provide new therapeutic ideas for aging-related maladaptive cardiac remodeling., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Mesenchymal stem cells (MSCs) are widely dispersed in vivo and are isolated from several tissues, including bone marrow, heart, body fluids, skin, and perinatal tissues. Bone marrow MSCs have a multidirectional differentiation potential, which can be induced to differentiate the medium in a specific direction or by adding specific regulatory factors. MSCs repair damaged tissues through lineage differentiation, and the ex vivo transplantation of bone marrow MSCs can heal injured sites. MSCs have different propensities for lineage differentiation and pathological evolution for different diseases, which are crucial in disease progression. In this study, we describe various lineage analysis methods to explore lineage ontology in vitro and in vivo, elucidate the impact of MSC lineage differentiation on diseases, advance our understanding of the role of MSC differentiation in physiological and pathological states, and explore new targets and ideas associated with disease diagnosis and treatment., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests., (© 2024. The Author(s).)

This study aimed to investigate the healing effect of a polylactic- co -glycolic acid (PLGA) scaffold containing nanohydroxyapatite (NHA) along with curcumin (CCM), loaded with adipose-derived mesenchymal stem cells (AD-MSCs), on mandibular bone defects. The designed PLGA scaffolds containing NHA were evaluated for their mechanical and structural properties. Forty rats were divided into five groups ( n = 8) based on the treatment: Sham, PLGA scaffolds containing NHA, PLGA scaffolds containing NHA + CCM, PLGA scaffolds containing NHA + AD-MSCs, and PLGA scaffolds containing NHA + CCM + AD-MSCs. After 8 weeks' follow-up, mandible bones were isolated for histomorphometry evaluation. Data were analyzed using SPSS version 21, with p -values <0.05 considered statistically significant. SEM evaluation showed that the designed nanocomposite scaffold had 80% porosity. Histomorphometry results indicated a significant difference in osteocyte, osteoblast, bone area, and vascular area parameters in the group treated with scaffolds loaded with AD-MSCs + CCM compared to the other groups ( p < 0.05). The PLGA-containing NHA-CCM nanocomposite scaffold demonstrated good porosity and dispersion, suitable for treating bone defects. Rats treated with scaffolds containing AD-MSCs and CCM showed better therapeutic results than the other groups. Further research is needed to evaluate its anti-inflammatory, antioxidant properties, osteogenesis, and therapeutic effects in larger animal models.

Background: The clinical application of mesenchymal stem cells (MSCs) in myocardial infarction (MI) is severely hampered by their poor survival. Pretreatment is a key strategy that has been adopted to promote their therapeutic efficacy. This study aimed to investigate the benefit of growth differentiation factor 15-pretreated MSCs (GDF15-MSCs) in enhancing cardiac repair following MI and to determine the underlying mechanisms., Methods: MSCs with or without GDF15 pretreatment were exposed to serum deprivation and hypoxia (SD/H) challenge. Apoptosis of MSCs was assessed by TUNEL staining. The conditioned media (CM) of MSCs and GDF15-MSCs was collected by centrifugation. MSCs and GDF15-MSCs were transplanted into the peri-infarct region in a mouse model of MI. Cardiac function, fibrosis and MSC survival were examined 4 weeks after MSC transplantation., Results: Pretreatment with GDF15 greatly reduced SD/H-induced apoptosis of MSCs via inhibition of reactive oxygen species (ROS) generation by attenuating mitochondrial fission. Mechanistically, GDF15 pretreatment ameliorated mitochondrial fission of MSCs under SD/H challenge by activating the AMPK pathway. These effects were partially abrogated by AMPK inhibitor. Pretreatment with GDF15 also promoted paracrine effects of MSCs in vitro, evidenced by improving tube formation of HUVECs, and inhibited the apoptosis of cardiomyocytes induced by SD/H. At 4 weeks after transplantation, compared with MSCs, GDF15 pretreatment strongly promoted the survival of MSCs in the ischemic heart with consequent enhanced cardiac function, reduced cardiac fibrosis and increased angiogenesis., Conclusions: Our study showed that pretreatment with GDF15 promoted the cardioprotective effects of MSCs in MI via regulation of pro-survival signaling and paracrine actions. GDF15 pretreatment is an effective approach to enhance the therapeutic efficacy of MSCs in ischemic heart disease., Competing Interests: Declarations Ethics approval and consent to participate All cell cultures in this study were reviewed and approved by the Ethics Committees of Tongji University (Approved project: mesenchymal stem cell-based therapy for myocardial infarction, Approval No. 2016-050, Date of approval: Sep 18, 2016). Written informed consents were obtained from patients and their families for participation in the study and the use of samples. All animal procedures were performed in accordance with the ARRIVE guidelines and approved by approved by the Committee on the Use of Live Animals in Teaching and Research of Tongji University for Laboratory Animal Medicine (Approved project: The therapeutic effects of growth differentiation factor 15 pretreated mesenchymal Stem Cells on myocardial infarction, Approval No. TJBB04724101, Date of approval: Feb 28, 2024). Consent for publication All authors have read and approved the final version of the manuscript. Competing interests The authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: Inflammatory bowel disease (IBD) poses a significant and growing global health challenge, affecting both humans and domestic cats. Research on feline IBD has not kept pace with its widespread prevalence in human populations. This study aimed to develop a model of feline IBD by incorporating dextran sulfate sodium (DSS) to evaluate the therapeutic potential of MSCs and to elucidate the mechanisms that enhance their action., Methods: We conducted a comprehensive clinical assessment, including magnetic resonance imaging (MRI), endoscopy, and histopathological examination. Additionally, alterations in intestinal microbiota were characterized by 16 S rDNA sequencing, and the influence of MSCs on IBD-related gene expression was investigated through transcriptome analysis., Results: According to our findings, MSC treatment significantly mitigated DSS-induced clinical manifestations, reduced inflammatory cell infiltration, decreased the production of inflammatory mediators, and promoted mucosal repair. Regarding the intestinal microbiota, MSC intervention effectively corrected the DSS-induced dysbiosis, increasing the presence of beneficial bacteria and suppressing the proliferation of harmful bacteria. Transcriptome analysis revealed the ability of MSCs to modulate various inflammatory and immune-related signaling pathways, including cytokine-cytokine receptor interactions, TLR signaling pathways, and NF-κB pathways., Conclusion: The collective findings indicate that MSCs exert multifaceted therapeutic effects on IBD, including the regulation of intestinal microbiota balance, suppression of inflammatory responses, enhancement of intestinal barrier repair, and modulation of immune responses. These insights provide a solid scientific foundation for employing MSCs as an innovative therapeutic strategy for IBD and pave the way for future clinical explorations., (© 2024. The Author(s).)

Since wound healing is one of the most important medical challenges and common dressings have not been able to manage this challenge well today, efforts have been increased to achieve an advanced dressing. Mesenchymal stem cells and exosomes derived from them have shown high potential in healing and regenerating wounds due to their immunomodulatory, anti-inflammatory, immunosuppressive, and high regenerative capacities. However, challenges such as the short life of these cells, the low durability of these cells in the wound area, and the low stability of exosomes derived from them have resulted in limitations in their use for wound healing. Nowadays, different scaffolds are considered suitable biomaterials for wound healing. These scaffolds are made of natural or synthetic polymers and have shown promising potential for an ideal dressing that does not have the disadvantages of common dressings. One of the strategies that has attracted much attention today is using these scaffolds for seeding and delivering MSCs and their exosomes. This combined strategy has shown a high potential in enhancing the shelf life of cells and increasing the stability of exosomes. In this review, the combination of different scaffolds with different MSCs or their exosomes for wound healing has been comprehensively discussed., (© 2024. The Author(s).)

Background: Defects in the ataxin-2 (ATXN-2) protein and CAG trinucleotide repeat expansion in its coding gene, Atxn-2, cause the neurodegenerative disorder spinocerebellar ataxia type 2 (SCA2). While clinical studies suggest potential benefits of human-derived mesenchymal stem cells (hMSCs) for treating various ataxias, the exact mechanisms underlying their therapeutic effects and interaction with host tissue to stimulate neurotrophin expression remain unclear specifically in the context of SCA2., Methods: Human bone marrow-derived MSCs (hMSCs) were injected into the cisterna magna of 26-week-old wild-type and SCA2 mice. Mice were assessed for impaired motor coordination using the accelerating rotarod, open field test, and composite phenotype scoring. At 50 weeks, the cerebellum vermis was harvested for protein assessment and immunohistochemical analysis., Results: Significant loss of NeuN and calbindin was observed in 25-week-old SCA2 mice. However, after receiving multiple injections of hMSCs starting at 26 weeks of age, these mice exhibited a significant improvement in abnormal motor performance and a protective effect on Purkinje cells. This beneficial effect persisted until the mice reached 50 weeks of age, at which point they were sacrificed to study further mechanistic events triggered by the administration of hMSCs. Calbindin-positive cells in the Purkinje cell layer expressed bone-derived neurotrophic factor after hMSC administration, contributing to the protection of cerebellar neurons from cell death., Conclusion: In conclusion, repeated administration of hMSCs shows promise in alleviating SCA2 symptoms by preserving Purkinje cells, improving neurotrophic support, and reducing inflammation, ultimately leading to the preservation of locomotor function in SCA2 mice., (© 2024. The Author(s).)

Rationale: Nonhealing ulcers are difficult to manage because they deviate from the normal wound healing process. Conventional therapy cannot achieve satisfactory therapeutic effects. To verify the effectiveness of combined treatment with human umbilical cord mesenchymal stem cells (hUMSCs) and platelet-rich plasma (PRP) for nonhealing ulcers, we studied a patient with left lower limb venous ulcer (LEVU) treated with combined injection therapy., Patient Concerns: We present the case of a LEVU patient who has not healed for a long period of time (up to 1 year)., Diagnoses: LEVU was diagnosed with clinical symptoms., Interventions: The hUMSCs plus PRP were injected into the wound edge and base (1 µL of cells/cm2 of wound surface), 0.5 mL at each point, with a distance of approximately 1 to 3 cm between points. The injection point was determined according to the extent of wound involvement., Outcomes: Seven days after hUMSC + PRP application, the wound area decreased by nearly 50%. The ulcers had almost completely healed by day 62, and no serious treatment-related toxic side effects were observed., Lessons: hUMSCs can improve wound healing through re-epithelialization, increased angiogenesis, and granulation tissue formation. PRP has also been suggested to promote wound healing through the secretion of various nutritional factors. The combination of hUMSCs and PRP has a mutually reinforcing effect, which may achieve a 1 + 1 > 2 effect. Therefore, the combination of hUMSCs and PRP may be a safe and effective treatment option for LEVU., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Mesenchymal stem cells (MSCs) have shown potential in repairing chemotherapy-induced premature ovarian failure (POF). However, challenges such as stem cell loss and immune phagocytosis post-transplantation hinder their application. Due to easy and safe handling, in vitro ovarian culture is widely available for drug screening, pathophysiological research, and in vitro fertilization. MSCs could exhibit therapeutic capacity for ovarian injury, and avoid stem cell loss and immune phagocytosis in vitro tissue culture system. Therefore, this study utilizes an in vitro ovarian culture system to investigate the reparative potential of human umbilical cord mesenchymal stem cells (hUCMSCs) and their mechanism., Methods: In this study, a chemotherapy-induced POF model was established by introducing cisplatin in vitro ovarian culture system. The reparative effects of hUCMSCs on damaged ovarian tissue were validated through Transwell chambers. Tissue histology examination, immunohistochemical staining, Western blotting, and RT-PCR were employed to evaluate the expression effects of hUCMSCs on ferroptosis and fibrosis-related genes during the process of repairing cisplatin-induced POF., Results: Cisplatin was found to activate ovarian follicles in vitro POF model. Transcriptomic sequencing analysis revealed that cisplatin could activate genes associated with ferroptosis. hUCMSCs alleviated cisplatin-induced POF by suppressing the expression of ferroptosis. Moreover, inhibiting ferroptosis by hUCMSCs also ameliorated ovarian hormone levels and reduced the expression of fibrosis-related factors α-SMA and COL-I in the ovaries., Conclusions: This study confirms that cisplatin-induced ovarian damage via ferroptosis in vitro POF model, and hUCMSCs repair ovarian injury by inhibiting the ferroptosis pathway and suppressing fibrosis. This research contributes to evaluating the effectiveness of hUCMSCs in treating chemotherapy-induced POF by inhibiting ferroptosis in an in vitro ovarian culture system and provides a potential therapeutic strategy for chemotherapy-induced POF., (© 2024. The Author(s).)

A major challenge for stem cell therapies, such as using mesenchymal stem cells to treat skin injuries, is the stable engraftment of exogenous cells and the maintenance of their regenerative capacities in the wound areas. DNA-based self-assembly strategies can be used for artificial and multifunctional cell surface engineering to stabilize and enhance their functions for therapeutic applications. Here, we developed DNA nanofiber-decorated stem cells, in which DNA-based, multivalent fiber-like structures were self-assembled in situ on the cell surfaces. These engineered stem cells have demonstrated robust reactive oxygen species (ROS) scavenging effects, specific adhesion to damaged vascular endothelial cells, and the ability to enhance angiogenesis, which were effective and safe for acute or chronic wound healing in a mouse model with excisional skin injury. This DNA nanostructure-engineered stem cell provides a novel therapeutic platform for the treatment of tissue damage.

Peripheral arterial disease (PAD) is associated with lower-extremity muscle wasting. Hallmark features of PAD-associated skeletal muscle pathology include loss of skeletal muscle mass, reduced strength and physical performance, increased inflammation, fibrosis, and adipocyte infiltration. At the molecular level, skeletal muscle ischemia has also been associated with gene and microRNA (miRNA) dysregulation. Mesenchymal stromal cells (MSCs) have been shown to enhance muscle regeneration and improve muscle function in various skeletal muscle injuries. This study aimed to evaluate the effects of intramuscularly delivered human umbilical cord-derived MSCs (hUC-MSCs) on skeletal muscle ischemia. Herein, we report an hUC-MSC-mediated amelioration of ischemia-induced skeletal muscle atrophy and function via enhancement of myofiber regeneration, reduction of tissue inflammation, adipocyte accumulation, and tissue fibrosis. These changes were observed in the absence of cell-mediated enhancement of blood flow recovery as measured by laser Doppler imaging. Furthermore, reduced tissue fibrosis in the hUC-MSC-treated group was associated with upregulation of miR-1, miR-133a, and miR-29b and downregulation of targeted pro-fibrotic genes such as Col1a1 and Fn1. Our results support the use of hUC-MSCs as a novel approach to reduce fibrosis and promote skeletal muscle regeneration after ischemic injury in patients with PAD., (© The Author(s) 2024. Published by Oxford University Press.)

Transplanted mesenchymal stem cells (MSCs) can significantly aid in repairing spinal cord injuries (SCIs) by migrating to and settling at the injury site. However, this process is typically inefficient, as only a small fraction of MSCs successfully reach the target lesion area. During SCI, the increased expression and secretion of hepatocyte growth factor (HGF) act as a chemoattractant that guides MSC migration. Nonetheless, the precise mechanisms by which HGF influences MSC migration are not fully understood. This study focused on unraveling the molecular pathways that drive MSC migration toward the SCI site in response to HGF. It was found that HGF can activate β-catenin signaling in MSCs by either phosphorylating LRP6, suppressing GSK3β phosphorylation through the AKT and ERK1/2 pathways, or enhancing the expression and nuclear translocation of TCF4. This activation leads to elevated Nedd9 expression, which promotes focal adhesion formation and F-actin polymerization, facilitating chemotactic migration. Transplanting MSCs during peak HGF expression in injured tissues substantially improves nerve regeneration, reduces scarring, and enhances hind limb mobility. Additionally, prolonging HGF release can further boost MSC migration and engraftment, thereby amplifying regenerative outcomes. However, inhibiting HGF/Met or interfering with β-catenin or Nedd9 signaling significantly impairs MSC engraftment, obstructing tissue repair and functional recovery. Together, these findings provide a theoretical basis and practical strategy for MSC transplantation therapy in SCI, highlighting the specific molecular mechanisms by which HGF regulates β-catenin signaling in MSCs, ultimately triggering their chemotactic migration., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Osteoporosis is characterized by low systemic bone mineral content and destruction of bone microarchitecture. Promoting bone regeneration and reversing its loss by infusion of exogenous bone marrow mesenchymal stem cells (BMSCs) is a potentially effective treatment for osteoporosis. However, their limited migration to target organs reduces the therapeutic effect of the cells. Stromal cell-derived factor 1 (SDF1) is a chemokine that induces targeted cell migration through the SDF1/CXCR4 (C-X-C chemokine receptor 4) axis and can induce migration of exogenous mesenchymal stem cells to sites of high SDF1 concentration. There are no studies on BMSCs overexpressing SDF1 (SDF1-BMSCs) in osteoporotic mice in vivo. We aimed to investigate if the increased SDF1 concentration facilitated cell migration to the bone., Methods: We used lentivirus to construct BMSCs overexpressing SDF1 or knocking down CXCR4. We verified the proliferation ability of the cells in vitro using Cell Counting Kit-8 (CCK8) and 5-Bromodeoxyuridinc (BrdU), the migration ability of the cells using Transwell, and the osteogenic and lipogenic ability of the cells using osteogenic and lipogenic induction solutions. In in vivo experiments, we induced osteoporosis in 72 female mice by ovariectomy and injected different groups of cells via the tail vein. Femoral tissue samples were collected for a fixed time, and the osteogenic and homing abilities of the cells were verified by MicroCT and tissue section staining., Results: We successfully demonstrated that high expression of SDF1 promoted cell proliferation and migration in vitro, without affecting their cell differentiation ability. In an ovariectomized mouse model, SDF1-BMSCs were more likely to be home to the femur than the BMSCs, had a better pro-osteogenic ability, and had higher expression of Wnt-1. Blocking the SDF1/CXCR4 axis reduced the homing of exogenous mesenchymal stem cells (MSCs) to the femur and their osteogenic capacity., Conclusions: SDF1-BMSCs can further promote bone formation by increasing the number of cells homing to the femur in osteoporotic mice. Our study shows that stem cells can promote their proliferation and home to the femur via the SDF1/CXCR4 axis and further help bone formation via Wnt-1 signaling., (© 2024. The Author(s).)

Objective: As research into preclinical rheumatoid arthritis (pre-RA) has advanced, a growing body of evidence suggests that abnormalities in RA-affected joint cartilage precede the onset of arthritis. Thus, early prevention and treatment strategies are imperative. In this study, we aimed to explore the protective effects of mesenchymal stem cell (MSC)-derived microvesicles (MVs) on cartilage degradation in a collagen-induced arthritis (CIA) mouse model., Methods: A CIA mouse model was established to observe early pathological changes in cartilage (days 21-25) through histological and radiological examinations. On day 22, MSCs-MVs were intravenously injected into the mice with CIA. Radiological, histological, and flow cytometric examinations were conducted to observe inflammation and cartilage changes in these mice compared to the mice with CIA and the control mice. In vitro, chondrocytes were cultured with inflammatory factors such as IL-1β and TNFα to simulate inflammatory damage to cartilage. After the addition of MVs, changes in inflammatory levels and collagen expression were measured via Western blotting, immunofluorescence, enzyme-linked immunosorbent assays (ELISAs), and quantitative PCR to determine the role of MVs in maintaining chondrocytes., Results: MSC-MVs expressed vesicular membrane proteins (CD63 and Annexin V) and surface markers characteristic of MSCs (CD44, CD73, CD90, and CD105). In the early stages of CIA in mice, a notable decrease in collagen content was observed in the joint cartilage. In mice with CIA, injection of MSCs-MVs resulted in a significant reduction in the peripheral blood levels of IL-1β, TNFα, and IL-6, along with a decrease in the ratio of proinflammatory T and B cells. Additionally, MSC-MVs downregulated the expression of IL-1β, TNFα, MMP-13, and ADAMTS-5 in cartilage while maintaining the stability of type I and type II collagen. These MVs also attenuated the destruction of cartilage, which was evident on imaging. In vitro experiments demonstrated that MSC-MVs effectively suppressed the secretion of the inflammatory factors IL-1β, TNFα, and IL-6 in stimulated peripheral blood mononuclear cells (PBMCs)., Conclusions: MSCs-MVs can inhibit the decomposition of the inflammation-induced cartilage matrix by regulating immune cell inflammatory factors to attenuate cartilage destruction. MSC-MVs are promising effective treatments for the early stages of RA., (© 2024. The Author(s).)

Background: Acetaminophen (APAP) overdose is a significant cause of drug-induced liver injury (DILI). N-acetylcysteine (NAC) is the first-line agent used in the clinic. However, it rarely benefits patients with advanced APAP toxicity. Mesenchymal stromal cells (MSCs) have demonstrated potential in treating DILI. However, the specific mechanism by which MSCs protect against APAP-induced liver injury remains unclear., Methods: APAP was injected intraperitoneally to induce a liver injury model. We then detected histopathology, biochemical indices, and inflammatory cytokine levels to assess the efficacy of MSCs and MSC extracellular vesicles (MSC-EVs). Flow cytometry was performed to reveal the immunoregulatory effects of MSCs and MSC-EVs on the neutrophils. RNA sequencing (RNA-Seq) of liver tissues was used to identify critical target genes for MSC treatment., Results: MSC and MSC-EV treatment effectively alleviated APAP-induced liver injury and inhibited neutrophil infiltration. RNA-Seq analysis and ELISA data indicated that C-X-C motif chemokine 1 (CXCL1), a chemoattractant for neutrophils, was a key molecule in the MSC-mediated amelioration of APAP-induced liver damage. In addition, neutralization of CXCL1 reduced APAP-induced liver damage, which was accompanied by decreased neutrophil infiltration. Importantly, we verified that MSC-EV-derived miR-186-5p directly binds to the 3'-UTR of Cxcl1 to inhibit its expression in hepatocytes. The agomir miR-186-5p showed excellent potential for the treatment of DILI., Conclusions: Our findings suggest that MSCs and MSC-EVs are an effective approach to mitigate DILI. Targeting the miR-186-5p/CXCL1 axis is a promising approach to improve the efficacy of MSCs and MSC-EVs in the treatment of DILI., (© 2024. The Author(s).)

This study was performed to: detect the histological, immunohistochemical, and biochemical alterations that may occur in the testes of adult rats in induced hypothyroidism. And to investigate which one, ozone or MSCs-MVs have better therapeutic effect on testicular changes after hypothyroidism. Eighty-four male adult rats were separated into: control group, hypothyroidism group: rats will be given carbimazole for 30 days, ozone group: rats treated as hypothyroidism group then will be injected with ozone intraperitoneal for 7 days. MSC-MVs group: rats treated as hypothyroidism group then will be injected with a single intravenous dose MSC-MVs. Specimens of testes were handled for light, electron microscope, and immunohistochemical of vimentin and S100. Biochemical analysis for; MDA and TNFα; serum testosterone, TSH, T3, and T4 was done, also, sperm count and morphology assay. Morphometric and statistical analysis were performed. Hypothyroidism group showed disorganized seminiferous tubules. A noticeable gap was between the basement membrane and the germinal epithelium. Wide interstitium had congested vessels and acidophilic homogenous material. Vacuolated germinal epithelium and few germ cells had dark nuclei with noticeable separation of between the basement membrane and the germinal epithelium. Ozone and MSCs-MVs induced improvement in all the previous parameters and restoration of spermatogenesis. In Conclusion MSCs-MVs has better ameliorative effect than ozone on hypothyroidism-exposed testes.

Ulcerative colitis (UC) is a chronic relapsing intestinal inflammation that is becoming of increasing incidence worldwide and has insufficient treatment. Therefore, finding effective therapies remains a priority. A dextran sodium sulfate colitis model was established to elucidate colonic layers alterations and compare adipose mesenchymal stem cell-derived microvesicles (MSC-MVs) versus infliximab (IFX) efficacy through biochemical, light, and electron microscope studies. Fifty-four rats were allocated to 4 groups: Control (Con), UC, UC+IFX, and UC+MSC-MVs groups. End body weights (BW) and serum malondialdehyde (MDA) levels were recorded. Colitis severity was estimated by disease activity index (DAI). Colonic specimens were processed to evaluate the histological structure, collagen content, surface mucous and goblet cells, CD44, TNF-α, and GFAP immune expression. Morphometric and statistical analyses were performed. The UC group revealed congested, stenosed colons, a significant decline in end BW, and a significant increase in serum MDA and DAI. Furthermore, disturbed histoarchitecture, inflammatory infiltration, depletion of surface mucous and goblet cells, increased collagen, and TNF-α expression and decreased GFAP expression were observed. Alterations were partially attenuated by IFX therapy, whereas MSC-MVs significantly improved all parameters. In conclusion, MSC-MVs were a superior therapeutic option, via attenuating oxidative stress and inflammatory infiltration, in addition to restoring intestinal epithelial integrity and mucosal barrier.

Aim: This study aims to assess the effectiveness of therapy of human synovial membrane-derived MSCs (SM-MSC) from OA grade IV patients in treating knee OA., Methods: SM-MSC were isolated from patients undergoing total knee replacement surgery, cultured to the fourth passage, and characterized using flow cytometry. Differentiation potential was assessed through lineage-specific staining. Osteoarthritis was induced in 24 Wistar rats via monosodium iodoacetate (MIA). The rats were divided into three groups: negative control, OA control, and OA treated with SM-MSC. Radiological, histopathological, and molecular analyses were conducted to evaluate cartilage repair and gene expression., Results: Flow cytometry confirmed the MSC phenotype of SM-MSC, and successful differentiation was observed. Radiological and histopathological analyses showed significant improvement in the SM-MSC treated group, with reduced cartilage damage and higher Safranin O staining compared to the OA control group. Gene expression analysis indicated increased type-2 collagen (COL-2) expression in the SM-MSC treated group, although MMP-13 levels remained unchanged across all groups., Conclusion: Human SM-MSCs from OA grade IV patients significantly improved cartilage repair in an OA rat model, demonstrating their potential as a therapeutic option for OA. To enhance long-term efficacy and anti-inflammatory effects, further studies are needed to optimize treatment protocols, including injection frequency and dosage., (© 2024. The Author(s).)

Background/aim: In the pursuit of translating stem cell therapy technology into clinical practice, ensuring the safety and efficacy of treatments is paramount. Despite advancements, the effectiveness of stem cell applications often falls short of clinical requirements. This study aimed to address the challenge of limited efficacy by investigating the safety and effectiveness of canine adipose tissue-derived mesenchymal stem cells (cATMSCs) preconditioned with deferoxamine (DFO)., Materials and Methods: Different concentrations of DFO were used to evaluate its impact on cATMSC activity. The therapeutic potential of these preconditioned cells was validated using a mouse model of systemic inflammation. Comprehensive evaluations, including clinical hematological and radiological assessments before and after intravenous injection of preconditioned cells were conducted., Results: The study showed a notable reduction in inflammatory markers and an overall decrease in the inflammatory response in the mouse model. The data collected from the clinical hematological and radiological assessments provided essential insights., Conclusion: This study lays the groundwork for the future clinical deployment of DFO-preconditioned cATMSCs, demonstrating their potential to improve the efficacy and safety of stem cell therapies., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Pelvic floor dysfunctions (PFDs), which encompass pelvic organ prolapse (POP), stress urinary incontinence (SUI), and anal incontinence (AI), are common degenerative diseases in women. Bone marrow mesenchymal stem cells (BMSCs) hold promise for the treatment of PFDs. Extracellular vesicles (EVs) derived from BMSCs, have displayed an extensive role in intercellular communication and tissue repair. However, efficacy of the treatment using EVs originated from BMSCs on mouse models of PFD remains unknown. This study investigated the therapeutic potential of BMSC-derived EVs in a female PFD mouse model induced by vaginal distension (VD)., Materials and Methods/results: Flow cytometry analysis confirmed the positive expression of BMSC-related markers, and successful induction of multilineage differentiation further validated their characteristics. As expected, the EVs extracted from BMSCs exhibited typical cup-shaped and circular-shaped structures. In the PFD model, BMSC-derived EVs significantly reduced the levels of inflammatory cytokines (p<0.05), improved tissue repair, and mitigated neutrophil infiltration. Furthermore, EVs promoted cell proliferation, decreased expression of relaxin receptors, increased expression of elastin, and elevated collagen content in the anterior vaginal wall tissue (p<0.05), suggesting beneficial effects on tissue regeneration and connective tissue restoration in PFD., Conclusion: BMSC-derived EVs effectively reduce tissue inflammation, promote tissue regeneration and connective tissue reconstruction, and improve pelvic support deficiency, thereby alleviating PFD induced by vaginal distension (VD) in vivo., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The quest for scarless wound healing is imperative in healthcare, aiming to diminish the challenges of conventional wound treatment. Hyaluronic acid (HA), a key component of the skin's extracellular matrix, plays a pivotal role in wound healing and skin rejuvenation. Leveraging the advantages of HA hydrogels, this research focuses first on tuning the physicochemical and mechanical properties of photo-crosslinkable methacrylated HA (MAHA) by varying the methacrylation degree, polymer concentration, photo-crosslinker concentration, and UV exposure time. The optimized hydrogel, featuring suitable porosity, swelling ratio, degradability, and mechanical properties, was then used for the combined delivery of tannic acid (TA), known for its hemostatic, antibacterial, and antioxidant properties, and Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) cultured on the MAHA-TA hydrogel to enhance skin regeneration. The composite MAHA-TA-MSC hydrogel demonstrated favorable pores and biocompatibility, evidenced by cell viability, and promoted cell proliferation. When applied to dorsal wounds in rats, this composite hydrogel accelerated wound healing and reduced scarring. Additionally, molecular and histopathological analyses revealed increased expression of IL-10, the TGF-β3/TGF-β1 ratio, and the Collagen III/Collagen I ratio. These findings suggest that the MAHA-TA-MSC hydrogel is a promising candidate for scarless acute wound healing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Mesenchymal stromal cells (MSCs) exhibit significant potential in the context of cell therapy because of their capacity to perform a range of interconnected functions in damaged tissues, including immune modulation, hematopoietic support, and tissue regeneration. MSCs are hypoimmunogenic because of their diminished expression of major histocompatibility molecules, absence of costimulatory molecules, and presence of coinhibitory molecules. While autologous MSCs reduce the risk of rejection and infection, variability in cell numbers and proliferation limits their potential applications. Conversely, allogeneic MSCs (allo-MSCs) possess broad clinical applications unconstrained by donor physiology. Nonetheless, preclinical and clinical investigations highlight that transplanted allo-MSCs are subject to immune attack from recipients. These cells exhibit anti-inflammatory and proinflammatory phenotypes contingent on the microenvironment. Notably, the proinflammatory phenotype features enhanced immunogenicity and diminished immunosuppression, potentially triggering allogeneic immune reactions that impede long-term clinical efficacy. Consequently, preserving the low immunogenicity of allo-MSCs in vivo and mitigating immune rejection in diverse microenvironments represent crucial challenges for the widespread clinical application of MSCs. In this review, we elucidate the immune regulation of allo-MSCs, specifically focusing on two distinct subgroups, MSC1 and MSC2, that exhibit varying polarization states and immunogenicity. We discuss the factors and underlying mechanisms that induce MSC immunogenicity and polarization, highlighting the crucial role of major histocompatibility complex class I/II molecules in rejection post-transplantation. Additionally, we summarize the immunogenic regulatory targets and applications of allo-MSCs and outline strategies to address challenges in this promising field, aiming to enhance allo-MSC therapeutic efficacy for patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Mesenchymal stem cells (MSCs), characterized by their undifferentiated and multipotent nature, can be derived from various sources, including bone marrow, adipose, and dental tissues. Among these, dental MSCs (DSCs) exhibit universal MSC characteristics and are attracting considerable attention for regenerating oral and craniofacial tissues. This review provides a contemporary overview of recently published clinical studies using DSCs for various orodental and maxillofacial regenerative applications, including bone, periodontal, and endodontic regeneration. It also explores the utilization of DSCs in treating systemic conditions, exemplified by their application in managing conditions such as COVID-19 and osteoarthritis. The available evidence underscores the potential of DSCs and their secretome as efficacious tools in regenerative medicine for both dental and nondental clinical applications, supporting the continued promise of stem cell-based therapies. It is nevertheless evident that there are a number of important challenges that restrict the widespread utilization of DSCs, namely, difficulty in standardizing autologous preparations, insufficient cell surface marker characterization, high production costs, and regulatory compliance requirements. Further, the unique requirements of dental applications, especially complex structures such as the periodontium, where temporospatial control over the healing process is required, necessitate the combination of stem cells with appropriate scaffolds according to the principles of tissue engineering. There is currently insufficient evidence to support the clinical translation of DSCs into clinical practice, and phase 3 clinical trials with standardized protocols for cell sourcing, propagation, dosing, and delivery are required to move the field forward. In summary, this review provides a contemporary overview of the evolving landscape of stem cell therapy, offering insights into the latest developments and trends as well as the challenges that need to be addressed for the widespread application of DSC-based cell therapies., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are accompanied by high mortality rates and few effective treatments. Transplantation of human placental mesenchymal stem cells (hPMSCs) may attenuate ALI and the mechanism is still unclear. Our study aimed to elucidate the potential protective effect and therapeutic mechanism of hPMSCs against lipopolysaccharide (LPS)-induced ALI, An ALI model was induced by tracheal instillation of LPS into wild-type (WT) and angiotensin-converting enzyme 2 (ACE2) knockout (KO) male mice, followed by injection of hPMSCs by tail vein. Treatment with hPMSCs improved pulmonary histopathological injury, reduced pulmonary injury scores, decreased leukocyte count and protein levels in bronchoalveolar lavage fluid(BALF), protected the damaged alveolar epithelial barrier, and reversed LPS-induced upregulation of pro-inflammatory factors Interleukin-6 (IL-6) and Tumor necrosis factor-α(TNF-α) and downregulation of anti-inflammatory factor Interleukin-6(IL-10) in BALF. Moreover, administration of hPMSCs inhibited Angiotensin (Ang)II activation and promoted the expression levels of ACE2 and Ang (1-7) in ALI mice. Pathological damage, inflammation levels, and disruption of alveolar epithelial barrier in ALI mice were elevated after the deletion of ACE2 gene, and the Renin angiotensin system (RAS) imbalance was exacerbated. The therapeutic effect of hPMSCs was significantly reduced in ACE2 KO mice. Our findings suggest that ACE2 plays a key role in hPMSCs repairing the alveolar epithelial barrier to protect against ALI, laying a new foundation for the clinical treatment of ALI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Myasthenia gravis (MG) is an autoimmune disorder. Microvesicle-derived miRNAs have been implicated in autoimmune diseases. However, the role of microvesicle-derived miR-29a-3p in MG remains poorly understood. This study aimed to investigate the therapeutic effect and mechanism of miR-29a-3p derived from stem cell microvesicles (MVs) on experimental autoimmune myasthenia gravis (EAMG) rats., Methods: EAMG was induced in rats by injection of the subunit of the rat nicotinic anti-acetylcholine receptor (AChR) R97-116 peptide.Besides the control group, EAMG rats were randomly allocated into the EAMG model group, MV group, MV-NC-agomir group, and MV- miR-29a-3p-agomir group., Results: Our results found that BMSCs-MV promoted miR-29a-3p expression in gastrocnemius of EAMG rats. Bone marrow mesenchymal stem cells (BMSCs) derived microvesicle miR-29a-3p improved the hanging ability and swimming time of EMGA rats and weakened the degree of muscle fiber atrophy. Furthermore, microvesicles from miR-29a-3p overexpressing BMSCs reduced the content of AchR-Ab in the serum of EAMG rats. BMSC-derived microvesicle miR-29a-3p further suppressed the expression of IFN-γ and enhanced the IL-4 and IL-10 in the serum of EAMG rats by restoring the Th17/Treg cells balance., Discussion: BMSCs-derived microvesicle miR-29a-3p improved the stability of rat myasthenia gravis by regulating Treg/Th17 cells. It may be an effective treatment for MG.

A thermosensitive and injectable hydrogel composed of chitosan (CS), chitosan biguanide hydrochloride (CSG) and collagen (CO) could embed umbilical cord mesenchymal stem cells (UC-MSCs), then was applied for the type 2 diabetes mellitus (T2DM) treatment in vivo. UC-MSCs could adhere well on CS/CSG/CO hydrogel surface and cell division could be clearly observed. Especially, UC-MSCs maintained alive till they grew in CS/CSG/CO hydrogel for 8 days, while the amount of UC-MSCs was limited due to the steric hindrance in hydrogel. To T2DM mice contrastive treatment by intraperitoneal injection for thirteen weeks, UC-MSCs + Hydrogel group could improve the impaired glucose tolerance, maintain glucose homeostasis in vivo, and restore islet morphology for T2DM mice. The immunofluorescence staining and western blot experiments further displayed that both the nuclear antigen Ki67 for cell proliferation and pancreatic duodenal homeobox-1 (Pdx1) expression in UC-MSCs + Hydrogel group were significantly higher than the expressions in untreated T2DM group and treated UC-MSCs + PBS group, which indicated that UC-MSCs + Hydrogel elevated β cell transcriptional activity. Moreover, the positivity rates of iNOS and CD163 in UC-MSCs + Hydrogel group were generally decreased and increased, respectively, compared to those in untreated T2DM group and treated UC-MSCs + PBS group. It displayed that UC-MSCs + Hydrogel could reduce M1 macrophage expression and increase M2 macrophage polarization in T2DM mice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Spinal cord injury (SCI) is incurable and raises growing concerns. The main barrier to nerve repair is the complicated inhibitory microenvironment, where single-targeted strategies are largely frustrated. Despite the progress in combinatory therapeutic systems, the development and translation of effective therapies remain a challenge with extremely limited clinical materials. In this study, mesenchymal stem cells are transplanted in combination with sustained release of methylprednisolone through delivery in one composite matrix of a microsphere-enveloped adhesive hydrogel. All the materials used, including the stem cells, drug, and the matrix polymers gelatin and hyaluronan, are clinically approved. The therapeutic effects and safety issues are evaluated on rat and canine SCI models. The implantation significantly promotes functional restoration and nerve repair in a severe long-span rat spinal cord transection model. Distant spinal cord segments and the urinary system are effectively protected against pathologic damage. Moreover, the local sustained drug delivery mitigates the inflammatory microenvironment when overcoming the clinical issue of systemic side effects. The study presents an innovative strategy to achieve safe and efficient combinatory treatment of SCI., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Sepsis‑induced myopathy (SIM) is one of the leading causes of death in critically ill patients. SIM mainly involves the respiratory and skeletal muscles of patients, resulting in an increased risk of lung infection, aggravated respiratory failure, and prolonged mechanical ventilation and hospital stay. SIM is also an independent risk factor associated with increased mortality in critically ill patients. At present, no effective treatment for SIM has yet been established. However, mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach and have been utilized in the treatment of various clinical conditions. A significant body of basic and clinical research supports the efficacy of MSCs in managing sepsis and muscle‑related diseases. This literature review aims to explore the relationship between MSCs and sepsis, as well as their impact on skeletal muscle‑associated diseases. Additionally, the present review discusses the potential mechanisms and therapeutic benefits of MSCs in the context of SIM.

Mesenchymal stem cells based therapy has been used in clinic for almost 20 years and has shown encouraging effects in treating a wide range of diseases. However, the underlying mechanism is far more complicated than it was previously assumed. Mitochondria transfer is one way that recently found to be employed by mesenchymal stem cells to exert its biological effects. As one way of exchanging mitochondrial components, mitochondria transfer determines both mesenchymal stem cells and recipient cell fates. In this review, we describe the factors that contribute to MSCs-MT. Then, the routes and mechanisms of MSCs-MT are summarized to provide a theoretical basis for MSCs therapy. Besides, the advantages and disadvantages of MSCs-MT in clinical application are analyzed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)