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PURPOSE: Injectable biologics have not only been described and developed to treat dermal wounds, cardiovascular disease, and cancer, but have also been reported to treat chronic pain conditions. Despite emerging evidence supporting regenerative medicine therapy for pain, many aspects remain controversial. METHODS: The American Society of Pain and Neuroscience (ASPN) identified the educational need for an evidence-based guideline on regenerative medicine therapy for chronic pain. The executive board nominated experts spanning multiple specialties including anesthesiology, physical medicine and rehabilitation, and sports medicine based on expertise, publications, research, and clinical practice. A steering committee selected preliminary questions, which were reviewed and refined. Evidence was appraised using the United States Preventive Services Task Force (USPSTF) criteria for evidence level and degree of recommendation. Using a modified Delphi approach, consensus points were distributed to all collaborators and each collaborator voted on each point. If collaborators provided a decision of disagree or abstain, they were invited to provide a rationale in a non-blinded fashion to the committee chair, who incorporated the respective comments and distributed revised versions to the committee until consensus was achieved. RESULTS: Sixteen questions were selected for guideline development. Questions that were addressed included type of injectable biologics and mechanism, evidence in treating chronic pain indications (eg, tendinopathy, muscular pathology, osteoarthritis, intervertebral disc disease, neuropathic pain), role in surgical augmentation, dosing, comparative efficacy between injectable biologics, peri-procedural practices to optimize therapeutic response and quality of injectate, federal regulations, and complications with mitigating strategies. CONCLUSION: In well-selected individuals with certain chronic pain indications, use of injectable biologics may provide superior analgesia, functionality, and/or quality of life compared to conventional medical management or placebo. Future high-quality randomized clinical trials are warranted with implementation of minimum reporting standards, standardization of preparation protocols, investigation of dose-response associations, and comparative analysis between different injectable biologics.

Understanding the intricate cellular interactions involved in bone restoration is crucial for developing effective strategies to promote bone healing and mitigate conditions such as osteoporosis and fractures. Here, we provide compelling evidence supporting the anabolic effects of a pharmacological Pyk2 inhibitor (Pyk2-Inh) in promoting bone restoration. In vitro, Pyk2 signaling inhibition markedly enhances alkaline phosphatase (ALP) activity, a hallmark of osteoblast differentiation, through activation of canonical Wnt/β-catenin signaling. Notably, analysis of human mesenchymal stem cells through RNA-seq revealed a novel candidate, SCARA5, identified through Pyk2-Inh treatment. We demonstrate that Scara5 plays a crucial role in suppressing the differentiation from stromal cells into adipocytes, and accelerates lineage commitment to osteoblasts, establishing Scara5 as a negative regulator of bone formation. Additionally, Pyk2 inhibition significantly impedes osteoclast differentiation and bone resorption. In a co-culture system comprising osteoblasts and osteoclasts, Pyk2-Inh effectively suppressed osteoclast differentiation, accompanied by a substantial increase in the transcriptional expression of Tnfrsf11b and Csf1 in osteoblasts, highlighting a dual regulatory role in osteoblast-osteoclast crosstalk. In an ovariectomized mouse model of osteoporosis, oral administration of Pyk2-Inh significantly increased bone mass by simultaneously reducing bone resorption, promoting bone formation and decreasing bone marrow fat. These results suggest Pyk2 as a potential therapeutic target for both adipogenesis and osteogenesis in bone marrow. Our findings underscore the importance of Pyk2 signaling inhibition as a key regulator of bone remodeling, offering promising prospects for the development of novel osteoporosis therapies. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem cells (MSCs) have been identified to have a unique migratory pattern toward tumor sites across diverse cancer types, playing a crucial role in cancer progression, treatment resistance, and immunosuppression. This study aims to formulate a prognostic model focused on MSC‐associated markers to efficiently predict the clinical outcomes and responses to therapy in individuals with bladder cancer (BC). Methods: Clinical and transcriptome profiling data were extracted from The Cancer Genome Atlas Urothelial Bladder Carcinoma (TCGA‐BLCA) and GSE31684 databases. Systematic quantification of MSC prevalences and stromal indices was undertaken, culminating in the discernment of genes correlated with stromal MSCs following a thorough application of weighted gene coexpression network analysis techniques. Subsequently, an exhaustive risk signature pertinent to MSC was formulated by amalgamating methods from univariate and Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression models. Drugs targeting genes associated with MSCs were screened using molecular docking. Results: The prognostic model for MSC incorporated five critical genes: ZNF165, matrix remodeling‐associated 7 (MXRA7), CEMIP, ADP‐ribosylation factor‐like 4C (ARL4C), and cerebral endothelial cell adhesion molecule (CERCAM). In the case of BC patients, stratification was performed into discrete risk categories, utilizing the median MSC risk score as a criterion. It was striking that those classified within the high‐MSC‐risk bracket demonstrated correlations with unfavorable prognostic implications. Enhanced responsiveness to immunotherapy in low‐MSC‐risk patients was delineated compared to their high‐MSC‐risk counterparts. A heightened receptivity was noted toward particular chemotherapy drugs, encompassing gemcitabine, vincristine, paclitaxel, gefitinib, and sorafenib, within this high‐risk group. Conversely, a superior reaction to cisplatin was distinctly evident among those marked by low MSC scores. The results of molecular docking demonstrated that kaempferol exhibited favorable docking with ZNF165, quercetin exhibited favorable docking with MXRA7, mairin exhibited favorable docking with CEMIP, and limonin diosphenol exhibited favorable docking with ARL4C. Conclusions: The five‐gene MSC prognostic model demonstrates substantial efficacy in prognosticating clinical outcomes and gauging responsiveness to chemotherapy and immunotherapy regimens. The genes ZNF165, MXRA7, CEMIP, ARL4C, and CERCAM are underscored as promising candidates warranting further exploration for anti‐MSC therapeutic strategies, thereby offering novel insights for personalized treatment approaches in BC. [ABSTRACT FROM AUTHOR]

The tendon-bone junction (TBJ), a critical transitional zone where tendons and bones connect, is particularly prone to injury due to the forces from muscle contractions and skeletal movements. Once tendon-bone injuries occur, the complex original tissue structure is difficult to restore, increasing the risk of re-tear. In this study, we initially established a rabbit model of tendon-bone injury and treated it using either interference screw or suture anchor. Biomechanical testing demonstrated the maximum tension and strength of TBJ with interference screw fixation were superior. However, histologic and immunohistochemical results showed more tissue regeneration and expression of cartilage markers at the site of injury with suture anchor fixation. Moreover, Gelatin Methacryloyl encapsulated with exosomes from mesenchymal stem cell (GelMA-exosomes) were prepared, showing a consistent and stable exosome release characteristic. The combined application of GelMA-exosomes with either interference screws or suture anchors further enhanced the healing of tendon-bone injuries, which may be achieved by promoting cellular proliferation as well as regulating the decreased expression of local pro-inflammatory factors IL-1β, IL-6 and TNF-α and increased expression of anti-inflammatory factors IL-10 and TGF-β. This provides a viable therapeutic strategy to enhance tendon-bone healing. [ABSTRACT FROM AUTHOR]

Exosomes derived from the stem cells of human exfoliated deciduous teeth (SHED) hold promise for tissue regeneration. Apoptotic cells release a variety of extracellular vesicles that affect intercellular communication. This study aimed to investigate the angiogenic effects of SHED-derived exosomes modified via apoptosis induction on human umbilical vein endothelial cells (HUVECs). Apoptosis was induced in SHED via serum starvation for 3 weeks and confirmed by the upregulation of the apoptotic genes, caspase 3 and 9, and via annexin V staining. The apoptotic SHED-derived exosomes were isolated, characterized, and subjected to proteomic analysis. In vitro experiments were performed to assess the effects of apoptotic SHED exosomes on the proliferation, migration, and tube formation of HUVECs. The apoptosis-induced SHED showed increased cell viability and decreased numbers of dead cells compared with those of conventional cultures while retaining their identity as mesenchymal stem cells positive for CD44, CD73, and CD90. The apoptotic SHED-derived exosomes exhibited characteristic features, such as standard size, cup-shaped morphology, and positive staining, for exosomal markers CD9, CD63, and CD81. Proteins associated with apoptosis, programmed cell death, and cellular senescence were downregulated in the apoptotic SHED exosomes, whereas those associated with extracellular matrix organization were upregulated, indicating positive angiogenesis. HUVECs treated with apoptotic SHED exosomes exhibited significantly enhanced proliferation and migration compared with those treated with normal SHED exosomes. The mesh-like structures in the apoptotic SHED exosomes exhibited significantly increased signs of angiogenesis. The findings of this study provide new insights into the potential use of apoptotic SHED-derived exosomes in regenerative medicine. [ABSTRACT FROM AUTHOR]

Senescence of bone marrow mesenchymal stem cells (BMSCs) impairs their stemness and osteogenic differentiation, which is the principal cause of senile osteoporosis (SOP). Imbalances in nicotinamide phosphoribosyltransferase (NAMPT) homeostasis have been linked to aging and various diseases. Herein, reduction of NAMPT and impaired osteogenesis were observed in BMSCs from aged human and mouse. Knockdown of Nampt in BMSCs promotes lipogenic differentiation and increases age‐related bone loss. Overexpression of Nampt ameliorates the senescence‐associated (SA) phenotypes in BMSCs derived from aged mice, as well as promoting osteogenic potential. Mechanistically, NAMPT inhibits BMSCs senescence by facilitating OPA1 expression, which is essential for mitochondrial dynamics. The defect of NAMPT reduced mitochondrial membrane potential, interfered with mitochondrial fusion，and increased SA protein and phenotypes. More importantly, we have confirmed that P7C3, the NAMPT activator, is a novel strategy for reducing SOP bone loss. P7C3 treatment significantly prevents BMSCs senescence by improving mitochondrial function through the NAMPT‐OPA1 signaling axis. Taken together, these results reveal that NAMPT is a regulator of BMSCs senescence and osteogenic differentiation. P7C3 is a novel molecule drug to prevent the pathological progression of SOP. [ABSTRACT FROM AUTHOR]

Most high grade serous ovarian cancers (HGSOC) originate in the fallopian tube but spread to the ovary and peritoneal cavity, highlighting the need to understand antitumor immunity across HGSOC sites. Using spatial analyses, we discover that tertiary lymphoid structures (TLSs) within ovarian tumors are less developed compared with TLSs in fallopian tube or omental tumors. We reveal transcriptional differences across a spectrum of lymphoid structures, demonstrating that immune cell activity increases when residing in more developed TLSs and produce a prognostic, spatially derived TLS signature from HGSOC tumors. We interrogate TLS-adjacent stroma and assess how normal mesenchymal stem cells MSCs (nMSCs) may support B cell function and TLS, contrary to cancer-educated MSCs (CA-MSCs) which negate the prognostic benefit of our TLS signature, suggesting that pro-tumorigenic stroma could limit TLS formation. [Display omitted] • TLS activity varies by HGSOC anatomical site • An in situ -derived TLS signature from ovarian tumors is prognostic • TLS state governs B cell immunity • Cancer reprogrammed stroma blunts B cell function and is implicated in TLS regulation Therapies that harness the immune response are lacking for ovarian cancer patients. MacFawn et al. utilize spatial transcriptomics to understand how tumor site, stroma, and cellular interactions govern the activity of tertiary lymphoid structures. These studies reveal how we may promote development of these prognostic structures to bolster adaptive antitumor immunity. [ABSTRACT FROM AUTHOR]

Introduction: Our study aims to provide a comprehensive overview of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in drug delivery research, focusing on the period between 2013 and 2023. Given the increasing global interest in this field, we utilized bibliometric tools to explore publication trends, key contributors, and thematic research clusters. Methods: Data was collected from the Web of Science (WoS) database, and an in-depth bibliometric analysis was conducted using VOSviewer. The analysis encompassed bibliographic coupling, co-citation, co-authorship, and co-occurrence trends, offering a structured insight into global research activity. We also employed Citespace to further analyze thematic clusters in this domain. Results: Our analysis revealed a total of 1,045 publications related to MSC-EVs in drug delivery over the past decade, showing a steady increase in research output. China led in publication count, H-index, prolific authors, and research funding, while the United States ranked highest in total citations, average citation counts, and H-index performance. Pharmaceutics emerged as the leading journal by publication volume, with the Journal of Controlled Release having the strongest total link strength. Top institutions driving research included Shanghai Jiao Tong University, Zhejiang University, and Harvard University. VOSviewer analysis identified four major research clusters: tissue engineering, cancer, neurological diseases, and targeted delivery. Citespace analysis refined this further into ten thematic areas, including differentiation, tissue regeneration, and drug resistance. Discussion: This bibliometric assessment provides a holistic visualization of the research landscape for MSC-EVs in drug delivery, underlining the significant contributions of China and the United States. Our findings underscore the increasing global importance of MSC-EV research and highlight emerging themes that will likely guide future research directions. The insights from this study offer a foundational framework for identifying nascent frontiers in MSC-EV-based drug delivery. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

BACKGROUND: In the co-culture environment of mesenchymal stem cells and macrophages, mesenchymal stem cells can promote the polarization of macrophages into anti-inflammatory macrophages to reduce inflammation, and macrophages can promote the osteogenic differentiation of mesenchymal stem cells. The co-culture of both plays an important role in regulating the immune system and promoting tissue regeneration. OBJECTIVE: To summarize the methods, influencing factors and possible mechanisms of co-culture between mesenchymal stem cells and macrophages, and to provide theoretical basis and experimental methods for the application of co-culture of mesenchymal stem cells and macrophages in tissue engineering. METHODS: The first author searched the relevant articles published from January 1970 to September 2023 in PubMed and CNK by computer from January to September 2023. The Chinese and English key words were “mesenchymal stem cells, macrophages, co-culture”. Finally, 63 articles were included and analyzed. RESULTS AND CONCLUSION: (1) In vitro co-culture of mesenchymal stem cells and macrophages can be divided into direct contact co-culture and indirect contact co-culture according to the model, and two-dimensional cell co-culture and three-dimensional cell co-culture according to the dimension. (2) The coculture of mesenchymal stem cells and macrophages can promote the polarization of macrophages towards M2 type and enhance the osteogenic effect of mesenchymal stem cells. (3) In the co-culture model, the methods of co-culture, the proportion and time of co-culture, the phenotype of macrophages, and the cell source and conditions all affected the immune regulation of macrophages and the osteogenesis of mesenchymal stem cells. (4) Cell interaction in coculture may regulate the immune function of macrophages, proliferation, migration and osteogenesis of mesenchymal stem cells through cell-secreted soluble factors, extracellular vesicles, cell-cell contact, and metabolic pathways. (5) Mesenchymal stem cells and macrophages can enhance cardiac function after acute myocardial infarction, promote epithelial wound healing, reduce lung inflammation, improve renal function, and accelerate bone repair. (6) There are still some problems in co-culture of mesenchymal stem cells and macrophages, such as the selection of co-culture conditions, the maintenance of good cell state and interaction of co-cultured cells. (7) The co-culture of mesenchymal stem cells and macrophages can improve the local inflammatory microenvironment and promote tissue regeneration and repair, so it will have a broad application prospect in tissue engineering. [ABSTRACT FROM AUTHOR]

BACKGROUND: Mesenchymal stem cells possess characteristics such as rapid renewal, targeted homing, tissue repair, and immune regulation, which provide potential for the treatment of inflammatory diseases. In most inflammatory diseases, interleukin-1β is highly expressed. Both exogenous and endogenous mesenchymal stem cells unavoidably exist in an environment with high interleukin -1β concentration. OBJECTIVE: To study the interaction of interleukin-1β with mesenchymal stem cells in inflammatory environment and the mechanism of its influence on the migration and adhesion of mesenchymal stem cells to provide a theoretical basis for adjusting stem cell therapy strategies. METHODS: The first author searched for studies involving interleukin-1β enhancing migration and adhesion of mesenchymal stem cells by computer on CNKI, WanFang, VIP, PubMed, and Web of Science using search terms “interleukin-1β, mesenchymal stem cell, nuclear factor-κB, MAPK, ERK, p38, migration, adhesion” in Chinese and English. The literature tracing method was also used to search for some of the literature. Finally, 65 articles were included in the review analysis. RESULTS AND CONCLUSION: (1) In the inflammatory environment, interleukin-1β can regulate the migration and adhesion ability of mesenchymal stem cells. This effect may be achieved by recruiting IRAK1 through interleukin-1RI and then activating TAK1 and IKK in turn. After IKK phosphorylation, nuclear factor-κB and ERK signaling pathways are activated or CXCR expression is upregulated through the p38 pathway to promote mesenchymal stem cell migration and adhesion. However, further standardized research needs to be carried out based on the genetic background of mesenchymal stem cells, the dose and processing time of interleukin-1β. (2) In vitro experiments using pre-stimulated mesenchymal stem cells with interleukin-1β can change the survival environment of mesenchymal stem cells and alter their secretion factors to make them develop towards a more anti-inflammatory direction. On the other hand, under the premise of producing higher levels of anti-inflammatory and pro-nutrient factors, extracted mesenchymal stem cell exosomes can exert antiinflammatory effects. (3) It has been observed in various animal disease models that pre-stimulating mesenchymal stem cells with interleukin-1β regulates their immune regulation ability, thereby affecting the development and outcome of inflammation. However, this is limited to preclinical basic research only; further verification on efficacy and safety of stem cell therapy with interleukin-1β pre-treated mesenchymal stem cells is required in clinical settings. [ABSTRACT FROM AUTHOR]

BACKGROUND: Stem cell therapy has become an emerging method of treating pathological scars. miRNAs are involved in scarring mechanisms, and the targeted action of some stem cell sources of miRNA is mediated by exosomes. OBJECTIVE: To review the biological properties of miRNA derived from mesenchymal stem cells and its derivatives, the mechanism of treatment of scarring through anti-inflammation, suppression of excessive tissue reconstruction and antioxidation. METHODS: The first author used a computer in September 2023 to retrieve the relevant literature published from January 2000 to September 2023, searching for “stem cell, exosome, miRNA, keloid” in English, and “stem cells, exosome, keloid” in Chinese, eventually incorporating 74 papers for analysis. RESULTS AND CONCLUSION: (1) miRNAs with high expression of exosomes derived from mesenchymal stem cells increase the proportion of M2-type macrophages by promoting the polarization of macrophages, target the regulation of transforming growth factor β, transforming growth factor β receptors or related signaling pathways, inhibit the expression of pro-inflammatory factors, promote the expression of anti-inflammatory factors and other mechanisms to inhibit inflammation and thus suppress scar lesions. (2) miRNAs with high expression of exosomes derived from mesenchymal stem cells can reduce the secretion of matrix metalloproteinases, regulate the balance between matrix metalloproteinase inhibitors and matrix metalloproteinases, inhibit the proliferation and migration of fibroblasts and myofibroblasts, directly reduce the production of collagen and other mechanisms, and ultimately lead to the normal degradation of extracellular matrix, thereby inhibiting excessive tissue remodeling and cicatricial lesions. (3) miRNAs with high expression of exosomes from mesenchymal stem cells can improve the resistance of scar fibroblasts to oxidative stress by regulating reactive oxygen species and hypoxia-inducing factors, and then regulate the proliferation and apoptosis of scar fibroblasts to inhibit scar lesions. (4) Exosomes derived from mesenchymal stem cells have good prospects for scar treatment. Studies on this aspect can find mirnas that regulate inflammatory cells, inflammatory factors, signaling pathways, matrix metalloproteinases, fibroblasts, reactive oxygen species, hypoxia-inducing factors and other key factors from the three aspects of inflammation, tissue remodeling and oxidative stress. Then, by inducing mesenchymal stem cells with high expression of the above miRNA, exosomes were extracted, and finally verified and clinical trials were carried out. [ABSTRACT FROM AUTHOR]

BACKGROUND: The osteogenic differentiation of mesenchymal stem cells is regulated by a variety of molecules. Long non-coding RNA (lncRNA) has attracted much attention because they can participate in regulating a variety of biological processes, but the regulatory role of lncRNA on osteogenic differentiation of mesenchymal stem cells has not been fully explored. OBJECTIVE: To explore the effect of lncRNA Gm16104 on osteogenic differentiation of C3H10T1/2 mesenchymal stem cells. METHODS: The C3H10T1/2 mesenchymal stem cells were induced into osteogenic differentiation by bone morphogenetic protein-2. Alkaline phosphatase staining was performed to identify the osteogenic differentiation of the cells 5 days after osteogenic induction. Expression levels of alkaline phosphatase and lncRNA Gm16104 were detected by qRT-PCR after 0, 1, 3, and 5 days of osteogenic differentiation. After transfection of the overexpression plasmid of pcDNA-Gm16104, the osteogenic differentiation was identified by alkaline phosphatase staining and qRT-PCR 4 days after osteogenic induction. The expression levels of osteogenesis-related signalling pathway proteins were detected by western blot assay. RESULTS AND CONCLUSION: (1) After 5 days of osteogenic induction, alkaline phosphatase activity was significantly increased. (2) Compared with 0 days, expression levels of the osteogenic marker gene alkaline phosphatase increased and expression levels of Gm16104 decreased after 1, 3, and 5 days of osteogenic induction. (3) Transfection of C3H10T1/2 cells with pcDNA-Gm16104 plasmid significantly increased the expression level of Gm16104. (4) Overexpression of Gm16104 inhibited alkaline phosphatase activity, the expression levels of the osteogenic marker gene alkaline phosphatase and the osteogenesis-related transcription factor Osterix. (5) Overexpression of Gm16104 inhibited phosphorylated protein expression of PI3K and Akt. (6) The above results suggest that overexpression of Gm16104 may inhibit osteogenic differentiation of C3H10T1/2 mesenchymal stem cells through the PI3K/Akt signaling pathway. [ABSTRACT FROM AUTHOR]

Aim: To use autofluorescence multispectral imaging (AFMI) to develop a non-invasive assay for the in-depth characterisation of human bone marrow derived mesenchymal stromal cells (hBM-MSCs). Methods: hBM-MSCs were imaged by AFMI on gridded dishes, stained for endpoints of interest (STRO-1 positivity, alkaline phosphatase, beta galactosidase, DNA content) then relocated and results correlated. Intensity, texture and morphological features were used to characterise the colour distribution of regions of interest, and canonical discriminant analysis was used to separate groups. Additionally, hBM-MSC lines were cultured to arrest, with AFMI images taken after each passage to investigate whether an assay could be developed for growth potential. Results: STRO-1 positivity could be predicted with a receiver operator characteristic area under the curve (AUC) of 0.67. For spontaneous differentiation this was 0.66, for entry to the cell-cycle it was 0.77 and for senescence it was 0.77. Growth potential (population doublings remaining) was estimated with an RMSPE = 2.296. The Mean Absolute Error of the final prediction model indicated that growth potential could be predicted with an error of ± 1.86 doublings remaining. Conclusions: This non-invasive methodology enabled the in-depth characterisation of hBM-MSCs from a single assay. This approach is advantageous for clinical applications as well as research and stands out for the characterisation of both present status as well as future behaviour. The use of data from five MSC lines with heterogenous AFMI profiles supports potential generalisability. [ABSTRACT FROM AUTHOR]

Some oxysterols were shown to promote osteogenic differentiation of mesenchymal stem cells (MSCs). Little is known about the effects of 7-ketocholesterol (7-KC) in this process. We describe its impact on human adipose tissue-derived MSC (ATMSC) osteogenic differentiation. ATMSCs were incubated with 7-KC in osteogenic or adipogenic media. Osteogenic and adipogenic differentiation was evaluated by Alizarin red and Oil Red O staining, respectively. Osteogenic (ALPL, RUNX2, BGLAP) and adipogenic markers (PPARƔ, C/EBPα) were determined by RT-PCR. Differentiation signaling pathways (SHh, Smo, Gli-3, β-catenin) were determined by indirect immunofluorescence. ATMSCs treated with 7-KC in osteogenic media stained positively for Alizarin Red. 7-KC in adipogenic media decreased the number of adipocytes. 7-KC increased ALPL and RUNX2 but not BGLAP expressions. 7-KC decreased expression of PPARƔ and C/EBPα, did not change SHh, Smo, and Gli-3 expression, and increased the expression of β-catenin. In conclusion, 7-KC favors osteogenic differentiation of ATMSCs through the expression of early osteogenic genes (matrix maturation phase) by activating the Wnt/β-catenin signaling pathway, while inhibiting adipogenic differentiation. This knowledge can be potentially useful in regenerative medicine, in treatments for bone diseases. [ABSTRACT FROM AUTHOR]

Pemphigus is an IgG-mediated autoimmune condition characterized by autoantibodies targeting desmogleins, leading to acantholysis. Current treatments, including systemic corticosteroids and immunosuppressive drugs, are associated with significant adverse effects. Mesenchymal stem cells (MSCs) offer a promising alternative due to their immunomodulatory properties and low immunogenicity. This study evaluates the immunomodulatory effects of dental follicle mesenchymal stem cells (DF-MSCs) obtained from healthy donors on Pemphigus vulgaris (PV) patients and healthy controls by examining T-cell proliferation, apoptosis, cytokine levels, and anti-desmoglein 1/3 IgG profiles. Peripheral blood mononuclear cells (PBMCs) were isolated from twenty-one symptomatic PV patients and eleven healthy volunteers. DF-MSCs were characterized and differentiated into osteocytes, adipocytes, and chondrocytes. Peripheral blood mononuclear cells (PBMCs) were co-cultured with DF-MSCs, and various assays were conducted to evaluate T-cell proliferation, apoptosis, regulatory T cells, cytokine expression, and autoantibody levels. Results showed that DF-MSC co-cultures significantly reduced lymphocyte proliferation (43.58–16.27%), IL-4 (38.06 ng/L to 32.26 ng/L), TNF-α (32.45 ng/L to 29.41 ng/L), and DSG1 (3.29 ng/ml to 3.00 ng/ml) and DSG3 (262.40 ng/ml to 245.08 ng/ml) levels in PV patients. An increase in regulatory T cells (1.22–3.75%), IL-10 (47.46 pg/ml to 54.94 pg/ml), and IFN-γ (12.39 ng/ml to 19.70 ng/ml) was also observed. No significant changes were noted in healthy controls. These findings suggest that DF-MSCs could potentially offer a curative approach for treating pemphigus by restoring immune balance. However, further clinical trials are necessary to confirm their efficacy. [ABSTRACT FROM AUTHOR]

Purpose of Review: The purpose of this narrative review is to evaluate the efficacy of the most commonly studied intradiscal biologics used for the treatment and alleviation of chronic intractable discogenic low back pain. Additionally, it explores the therapeutic potential and durability of these novel treatment options. Recent Findings: Recently published literature highlights the therapeutic potential of intradiscal biologics, such as mesenchymal stem cells, platelet-rich plasma, and alpha-2-macroglobulin, in promoting chondrogenesis within the lumbar intervertebral discs to treat discogenic low back pain. Studies demonstrate significant improvements in pain relief, physical function, and quality of life post-treatment. Summary: A comprehensive review of the literature evaluating the efficacy of intradiscal biologics suggests some evidence supporting its efficacy in treating discogenic low back pain. However, more rigorous studies into mechanistic modulation and large-scale randomized trials as well as a more thorough understanding of adverse events will be instrumental for including these therapies into clinical practice paradigms. [ABSTRACT FROM AUTHOR]

The challenges associated with animal testing in pharmaceutical development have driven the search for alternative in vitro models that mimic human tissues more accurately. In this study, we present a simple and cost-effective method for generating 3D cell sheets and spheroids using curvature-controlled paraffin wax films, which are easily accessible laboratory materials that eliminate the need for extracellular matrix (ECM) components or thermo-responsive polymers. By adjusting the curvature of the paraffin wax film, we successfully generated human periodontal ligament fibroblast (HPdLF) cell sheets and bone marrow-derived mesenchymal stem cell (hBMSC) spheroids. Key parameters, such as cell density, substrate curvature, and incubation time, were identified as critical factors for optimizing the formation of these 3D structures. In addition, the use of quantum dots (QDs) for cell tracking enabled long-term visualization and distinction between different cell types within complex tissue-like structures. We further demonstrated that wrapping the hBMSC spheroids with HPdLF cell sheets partially replicated the connective tissue structure of the periodontal ligament surrounding the tooth root. This highlights the potential of this platform for the construction of more sophisticated tissue-mimicking assemblies. In conclusion, curvature-controlled paraffin wax films provide a versatile and practical approach for 3D cell cultures. This simplifies the generation of both cell sheets and spheroids, offering a promising tool for tissue engineering and regenerative medicine applications, where precise cell-to-cell interactions are essential. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a degenerative disease of the joints, prevalent worldwide. Polydeoxyribonucleotide (PDRN) is used for treating knee OA. However, the role of PDRN in IL-1β-induced inflammatory responses in human bone marrow-derived mesenchymal stem cells (hBMSCs) remains unknown. Here, we investigated the role of PDRN in IL-1β-induced impairment of chondrogenic differentiation in hBMSCs. hBMSCs treated with PDRN showed a large micromass, enhanced safranin O and alcian blue staining intensity, and increased expression of chondrogenic genes in IL-1β-induced inflammatory responses, in addition to regulation of catabolic and anabolic genes. In addition, PDRN treatment suppressed the expression of inflammatory cytokines and mitigated IL-1β-induced apoptosis in hBMSCs. Mechanistically, PDRN treatment increased the formation of cyclic adenosine monophosphate (cAMP) and upregulated the phosphorylation of cAMP-dependent protein kinase A (PKA)/cAMP response element binding protein (CREB) through the adenosine A2A receptor in hBMSCs and thus blocked the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling pathway. Thus, IL-1β-induced expression of inflammatory cytokines in hBMSCs was directly reduced by adenosine A2A receptor activation. Based on our results, we suggest that PDRN may be a promising MSC-based therapeutic agent for OA. [ABSTRACT FROM AUTHOR]

Microfluidics cell encapsulation offers a way to mimic a 3D microenvironment that supports cell growth and proliferation, while also protecting cells from environmental stress. This technique has found extensive applications in tissue engineering and cell therapies. Several studies have demonstrated the advantages of graphene oxide (GO) as an osteogenic inducer; however, the significance of GO on stem cell fate in the single-cell state is still unclear. Here, a microfluidics-based approach is developed for continuous encapsulation of mesenchymal stem cells (MSCs) at the single-cell level using alginate microgels. So, single-layer graphene oxide (slGO) nanosheet is used to be encapsulated inside the alginate droplets. The results of AFM and SEM show that slGO can increase the roughness and reduce the stiffness of alginate hydrogels. The Young's modulus of the alginate and alginate-slGO was obtained as 1414 kPa and 985.9 kPa, respectively. Live/dead assay and fluorescence microscopy images illustrate that slGO can maintain the viability and proliferation of microencapsulated hBMSCs. The obtained results show that slGO increases the mineralization of the encapsulated hBMSCs, so that microgels containing hBMSCs gradually became opaque during 21 days of culture. RT-qPCR results indicate that the expression of OCN, Runx2, and ALP in the alginate-slGO microgels is significantly higher than in the alginate microgels. The expression of OCN and Runx2 in the alginate-slGO microgels is 4.27 and 5.87-fold higher than in the alginate microgels, respectively. It can be concluded that low doses of slGO nanosheets have the potential to be utilized in the development of tissue engineering and bone regeneration. This finding offers a new method for creating injectable tissue transplants that are minimally invasive. [ABSTRACT FROM AUTHOR]

Objective: The safety, feasibility, and potential functional improvement following the intravenous infusion of mesenchymal stem cells (MSCs) were investigated in patients with chronic severe spinal cord injury (SCI). Methods: The intravenous infusion of autologous MSCs cultured in auto-serum under Good Manufacturing Practices (GMP) was administered to seven patients with chronic SCI (ranging from 1.3 years to 27 years after the onset of SCI). In addition to evaluating feasibility and safety, neurological function was evaluated using the American Spinal Injury Association Impairment Scale (AIS), International Standards for Neurological Classification of Spinal Cord Injury (ISCSCI-92), and Spinal Cord Independence Measure III (SCIM-III). Results: No serious adverse events occurred. Neither CNS tumors, abnormal cell growth, nor neurological deterioration occurred in any patients. While this initial case series was not blinded, significant functional improvements and increased quality of life (QOL) were observed at 90 and 180 days post-MSC infusion compared to pre-infusion status. One patient who had an AIS grade C improved to grade D within six months after MSC infusion. Conclusions: This case series suggests that the intravenous infusion of autologous MSCs is a safe and feasible therapeutic approach for chronic SCI patients. Furthermore, our data showed significant functional improvements and better QOL after MSC infusion in patients with chronic SCI. A blind large-scale study will be necessary to fully evaluate this possibility. [ABSTRACT FROM AUTHOR]

Background: Restoring the function of the ovary is important for chemotherapy-induced ovarian failure (COF) patients. Stem cell and extracellular vesicles (EVs) therapy show promise but need further improvement. Methods: Human umbilical cord mesenchymal stem cells (hUC-MSCs) were primarily cultured and further three-dimensional (3D) cultured using an ultra-low attachment surface method. The expression levels of nutritional cytokines and immunomodulatory and stemness-related genes of 3D-cultured hUC-MSCs were analyzed. EVs were isolated by ultracentrifugation and characterized. Ovaries were decellularized with sodium dodecyl sulfate to obtain extracellular matrix (ECM). Lyophilized EVs from three-dimensional (2D) or 3D hUC-MSCs were mixed with ECM to prepare the 2D/3D-MSC-EVs-ECM gels. The therapeutic effect of the MSC-EVs-ECM gel on cyclophosphamide (CTX) -treated rats was analyzed through various tests. RNA sequencing was used to analyze the expression changes of genes before and after treatment. Results: After culturing in ultra-low attachment dishes, hUC-MSCs aggregated into spheroids and significantly upregulated the expression levels of immunomodulatory and stemness-related genes. The total EVs yield was also upregulated (5.6-fold) after 3D culture. The cell viability of CTX-treated ovarian granulosa cells (OGCs) was significantly rescued by coculture with the 3D-MSC-EVs-ECM gel. Hormones indicative of ovarian function, AMH, E2, and FSH, were recovered in both the CTX + 2D-MSC-EVs-ECM gel group and the CTX + 3D-MSC-EVs-ECM gel group, while the apoptosis-related protein Bax was significantly downregulated. The 3D-MSC-EVs-ECM gel was more effective than the 2D-MSC-EVs-ECM gel. Significantly differentially expressed genes, such as Hbb-b1, Gpd1, and Sirpa, were detected by RNA sequencing. Hbb-b1 was increased in the ovaries of CTX-treated rats, and this increase was attenuated by injecting the 2D/3D-MSC-EVs-ECM gel. Gpd1 was increased after CTX treatment, and this increase was reversed by the 3D-MSC-EVs-ECM gel. Sirpa was decreased in the ovaries of CTX-treated rats, and this decrease was attenuated by injecting the 3D-MSC-EVs-ECM gel. Conclusions: Our study demonstrated that the 3D-MSC-EVs-ECM gel is an efficient strategy for the recovery of ovarian function in CTX-induced ovarian failure. [ABSTRACT FROM AUTHOR]

Background: Salivary hypofunction leads to debilitating oral symptoms and has major complications for overall quality of life. Two of the most frequent causes of xerostomia are radiotherapy in the head and neck and Sjögren's syndrome. Only symptomatic treatment is available today. An increasing number of both preclinical and clinical studies have suggested that mesenchymal stem cell (MSC) transplantation treatment can increase the salivary flow rate and ameliorate symptoms of xerostomia. However, both adipose-derived and bone marrow–derived MSCs are used, although they differ in important ways. The primary objective of this study is an indirect comparison of the change in the unstimulated salivary flow rate after intervention between patients treated with adipose-derived or bone marrow–derived MSCs. Methods: This systematic review and network meta-analysis will search for eligible studies in the MEDLINE, EMBASE, and Cochrane CENTRAL register of Controlled Trials. Eligible studies are as follows: clinical studies including human patients with salivary hypofunction due to either radiotherapy or Sjogren's syndrome who were subsequently treated with either adipose-derived MSCs or bone marrow–derived MSCs. Studies with no control group will be excluded. The search phrase has been peer-reviewed following the PRESS guidelines. The primary outcome is the change in the unstimulated salivary flow rate after treatment with either adipose-derived or bone marrow–derived MSCs. Secondary outcomes are as follows: change in patient reported outcomes, methods of intervention administration, number of injected MSCs, and safety. Data from included studies will be pooled and compared with a fixed-effects or random effects model dependent on signs of heterogeneity, presented with a forest plot, and indirectly compared with a meta-regression in a network meta-analysis. Risk of bias will be assessed with the tools ROBINS-I or RoB-2 depending on type of study. Discussion: Both adipose-derived and bone marrow–derived MSCs are used today for experimental treatment of salivary hypofunction in humans as no direct or indirect comparisons have been made. Therefore, an evaluation of the effect of adipose-derived vs bone marrow–derived MSC treatment is needed to support future decision-making on the type of MSC used in a clinical trial. Systematic review registration: PROSPERO ID CRD42024527183. [ABSTRACT FROM AUTHOR]

Introduction: This study explored the potential efficacy and safety of therapy with mesenchymal stem cells (MSC) derived from gonadal tissue to address the early stage of myxomatous mitral valve disease (MMVD), the predominant cardiac condition in dogs. Methods: Sixteen dogs diagnosed with MMVD B1 were enrolled in this trial and assigned to either a control group (control group, n = 10) or a group that received MSC derived from gonadal tissue (treatment group, n = 6). In the treatment group, allogeneic MSC derived from gonadal tissue (1 × 106 cells/kg) were intravenously administered at monthly intervals for five or more sessions. Data were compared at baseline and at the endpoint 1-year intervals. The efficacy was assessed using echocardiography, thoracic radiography, NT-proBNP, and the duration from B1 diagnosis to B2 transition to evaluate its effect on MMVD stage progression. Safety was evaluated through physical examinations, blood tests, imaging studies, and monitoring of adverse events. Results: After 1 year of observation, the control group exhibited deteriorating echocardiographic parameters, whereas the treatment group displayed no substantial differences between baseline and endpoint measurements. Notably, a statistically significant disparity was noted in the left atrial diameter (p < 0.05) and E-wave velocity (p < 0.05) between the two groups, indicating a favorable impact of MSC derived from the gonadal tissue on left atrial pressure. Additionally, in contrast to the control group, the treatment group demonstrated delayed progression to MMVD stage B2, enabling them to prolong their disease duration without requiring cardiac medication (p = 0.038). In quality of life (QoL) metrics following MSC treatment, appetite showed a statistically significant improvement, increasing from 4 to 4.83 (p < 0.05). Discussion: Treatment with gonadal tissue-derived MSCs significantly delayed MMVD stage progression, highlighting the broad potential of MSC derived from gonadal tissue for treating complex veterinary conditions. [ABSTRACT FROM AUTHOR]

Background: The metabolic patterns of human placental-derived mesenchymal stem cell (hP-MSC) treatment for primary sclerosing cholangitis (PSC) remain unclear, and therapeutic effects significantly vary due to individual differences. Therefore, it is crucial to investigate the serological response to hP-MSC transplantation through small molecular metabolites and identify easily detectable markers for efficacy evaluation. Methods: Using Mdr2−/− mice as a PSC model and Mdr2+/+ mice as controls, the efficacy of hP-MSC treatment was assessed based on liver pathology, liver enzymes, and inflammatory factors. Serum samples were collected for 12C-/13C-dansylation and DmPA labeling LC–MS analysis to investigate changes in metabolic pathways after hP-MSC treatment. Key metabolites and regulatory enzymes were validated by qRT-PCR and Western blotting. Potential biomarkers of hP-MSC efficacy were identified through correlation analysis and machine learning. Results: Collectively, the results of the liver histology, serum liver enzyme levels, and inflammatory factors supported the therapeutic efficacy of hP-MSC treatment. Based on significant differences, 41 differentially expressed metabolites were initially identified; these were enriched in bile acid, lipid, and hydroxyproline metabolism. After treatment, bile acid transport was accelerated, whereas bile acid production was reduced; unsaturated fatty acid synthesis was upregulated overall, with increased FADS2 and elongase expression and enhanced fatty acid β-oxidation; hepatic proline 4-hydroxylase expression was decreased, leading to reduced hydroxyproline production. Correlation analysis of liver enzymes and metabolites, combined with time trends, identified eight potential biomarkers: 2-aminomuconate semialdehyde, l-1-pyrroline-3-hydroxy-5-carboxylic acid, l-isoglutamine, and maleamic acid were more abundant in model mice but decreased after hP-MSC treatment. Conversely, 15-methylpalmitic, eicosenoic, nonadecanoic, and octadecanoic acids were less abundant in model mice but increased after hP-MSC treatment. Conclusions: This study revealed metabolic regulatory changes in PSC model mice after hP-MSC treatment and identified eight promising biomarkers, providing preclinical evidence to support therapeutic applications of hP-MSC. [ABSTRACT FROM AUTHOR]

Aortic dissection (AD) is a devastating disease with a high mortality rate. Exosomes derived from mesenchymal stem cells (exo-MSCs) offer a promising strategy to restore aortic medial degeneration and combat ferroptosis in AD. However, their rapid degradation in the circulatory system and low treatment efficiency limit their clinical application. Methylacrylated gelatin (Gelma) was reported as a matrix material to achieve controlled release of exosomes. Herein, exo-MSCs-embedded in Gelma hydrogels (Gelma-exos) using ultraviolet light and three-dimensional (3D) printing technology. These Gelma-exos provide a sustained release of exo-MSCs as Gelma gradually degrades, helping to restore aortic medial degeneration and prevent ferroptosis. The sustained release of exosomes can inhibit the phenotypic switch of vascular smooth muscle cells (VSMCs) to a proliferative state, and curb their proliferation and migration. Additionally, the 3D-printed Gelma-exos demonstrated the ability to inhibit ferroptosis in vitro, in vivo and ex vivo experiments. In conclusion, our Gelma-exos, combined with 3D-printed technology, offer an alternative treatment approach for repairing aortic medial degeneration and ferroptosis in AD, potentially reducing the incidence of aortic dissection rupture. [ABSTRACT FROM AUTHOR]

Sulfur mustard (SM) is an established chemical weapon that can result in severe damage to parts of the body. Currently, there are no effective treatments available for SM-caused damage. We aimed to investigate the therapeutic potential of adipose-derived mesenchymal stromal cells (AD-MSCs) and conditioned medium (CM-MSCs) in acute and chronic pulmonary mouse models caused by 2- chloroethyl ethyl sulfide (CEES), an SM analog. The mice were divided into 4 experimental groups:(1) CEES+AD-MSCs, (2) CEES+CMMSCs, (3) CEES, and (4) control. The model observation time was divided into 7 days for the short and 6 months for the long term. AD-MSCs were injected into mice via intraperitoneal injection 24 hours after CEES exposure. The therapeutic effects of AD-MSCs on pulmonary tissue damage were assessed using a histopathologic assay, measuring the neutrophil count, and bronchial alveolar lavage fluid (BALF) protein level. The levels of inflammatory and anti-inflammatory cytokines were evaluated using the enzyme-linked immunosorbent assay as the outcomes of interest. Lung damage progression was reduced by AD-MSC treatment in mice after CEES injection into the peritoneum. The proportion of CD11b+F4/80+ macrophages in the peritoneum was significantly lowered by AD-MSC treatment following CEES exposure. AD-MSC administration also reduced the level of pro-inflammatory cytokines, BALF protein, and nitric oxide levels in the peritoneal cavity. By reducing inflammation and enhancing tissue healing, AD-MSCs and CM-MSC help prevent acute lung damage caused by CEES. The current study supports the use of a mouse model as a solid experimental foundation and indicates potential use for future cell treatment. [ABSTRACT FROM AUTHOR]

Conventional treatments for degenerative disc disease have limitations in regenerating the intervertebral disc because of its anatomical characteristics. Hence, researchers are investigating biological therapies for degenerative disc disease. The advances in genetic engineering and fields, such as tissue engineering, are accelerating the development of biological treatments for degenerative discs. Biological treatments for degenerative discs focus on inhibiting cell apoptosis and maintaining cell populations within the disc. Current biological therapies studied include gene therapy, cell therapy, and growth factor therapy. Gene therapy involves the use of RiboNucleic Acid (RNA) interference, such as small interfering RNA (siRNA), to inhibit genes related to cell apoptosis and to explore therapeutic targets. Cell therapy, which involves a direct injection of stem cells into the disc, has attracted considerable attention. Mesenchymal stem cells and notochordal cells are commonly used, with mesenchymal stromal/stem cells (MSCs) being preferred because of their ease of production and anti-inflammatory effects. Several clinical trials using MSCs have reported favorable clinical outcomes, such as alleviating lower back pain, but disc height was not restored. These results were not from randomized trials, and double-blind clinical trials using MSCs are currently underway. Research is ongoing to promote anabolic processes within the nucleus pulposus by injecting growth factors into the disc. Preclinical studies have shown that a biglycan fragment targeting transforming growth factor (TGF)-β can inhibit degenerative changes in the disc, and clinical trials using growth/differentiation factor (GDF)-5 are currently in progress. Research on biological treatments for degenerative discs is being conducted in three main areas: gene therapy, cell-based therapy, and growth factor-based therapy. Although cell therapy using MSCs has shown symptomatic improvement in clinical trials, a double-blind clinical trial is still needed to confirm the therapeutic effects. [ABSTRACT FROM AUTHOR]

Traumatic heterotopic ossification is a condition in which extraskeletal bone formation occurs in soft tissues after injury. It most commonly occurs in patients who had major orthopedic surgery and in those with severe extremity injuries. The lesion causes local pain and can impair motor function of the affected limb, but there is currently no established prophylaxis or treatment for this condition. In this study, we show that immobilization at an early stage of the inflammatory response after injury can attenuate ossification formation in a murine Achilles tenotomy model. Gene expression analysis revealed a decrease in the expression of Tnf and an increase in the expression of Mkx, which encodes one of the master regulators of tendon differentiation, Mohawk. Notably, we found that TNF‐α suppressed the expression of Mkx transcripts and accelerated the osteogenic differentiation of tendon‐derived mesenchymal stem cells (MSCs), suggesting that TNF‐α acts as a negative regulator of Mkx transcription. Consistent with these findings, pharmaceutical inhibition of TNF‐α increased the expression of Mkx transcripts and suppressed bone formation in this mouse model. These findings reveal the previously unrecognized involvement of TNF‐α in regulating tendon MSC fate through suppression of Mkx expression and suggest that TNF‐α is a potential target for preventing traumatic heterotopic ossification. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD), which severely affects the quality of patients' lives. However, the current therapeutic approaches can only postpone its progression to ESRD. It is therefore imperative to develop a novel therapeutic strategy for renal injury in DKD, with the objective of restoring renal function and reversing the process of ESRD. In recent years, the potential of mesenchymal stem cell (MSC) therapy for DKD has garnered increasing attention within the scientific community. Preclinical research on MSC therapy has yielded promising results, and the safety of MSC treatment in vivo has been substantiated in clinical studies. An increasing body of evidence suggests that MSC therapy has significant potential for the treatment of DKD. This article reviews the existing research on MSCs and their derived exosomes in treating DKD and analyzes the underlying mechanism of MSC-based therapy for DKD. Additionally, we discuss the potential of combining MSC therapy with conventional pharmacological treatments, along with the constraints and prospects of MSC therapy for DKD. We hope this review can provide a precise and comprehensive understanding of MSCs for the treatment of DKD. [ABSTRACT FROM AUTHOR]

Searching for biomarkers of senescence remains necessary and challenging. Reliable and detectable biomarkers can indicate the senescence condition of individuals, the need for intervention in a population, and the effectiveness of that intervention in controlling or delaying senescence progression and senescence‐associated diseases. Therefore, it is of great importance to fulfill the unmet requisites of senescence biomarkers especially when faced with the growing global senescence nowadays. Here, we established that DNA G‐quadruplex (G4) in mitochondrial genome was a reliable hallmark for mesenchymal senescence. Via developing a versatile and efficient mitochondrial G4 (mtG4) probe we revealed that in multiple types of senescence, including chronologically healthy senescence, progeria, and replicative senescence, mtG4 hallmarked aged mesenchymal stem cells. Furthermore, we revealed the underlying mechanisms by which accumulated mtG4, specifically within respiratory chain complex (RCC) I and IV loci, repressed mitochondrial genome transcription, finally impairing mitochondrial respiration and causing mitochondrial dysfunction. Our findings endowed researchers with the visible senescence biomarker based on mitochondrial genome and furthermore revealed the role of mtG4 in inhibiting RCC genes transcription to induce senescence‐associated mitochondrial dysfunction. These findings depicted the crucial roles of mtG4 in predicting and controlling mesenchymal senescence. [ABSTRACT FROM AUTHOR]

Identifying specific markers of adipose stem and progenitor cells (ASPCs) in vivo is crucial for understanding the biology of white adipose tissues (WAT). PDGFRα‐positive perivascular stromal cells represent the best candidates for ASPCs. This cell lineage differentiates into myofibroblasts that contribute to the impairment of WAT function. However, ASPC marker protein(s) that are functionally crucial for maintaining WAT homeostasis are unknown. We previously identified Meflin as a marker of mesenchymal stem cells (MSCs) in bone marrow and tissue‐resident perivascular fibroblasts in various tissues. We also demonstrated that Meflin maintains the undifferentiated status of MSCs/fibroblasts. Here, we show that Meflin is expressed in WAT ASPCs. A lineage‐tracing experiment showed that Meflin+ ASPCs proliferate in the WAT of obese mice induced by a high‐fat diet (HFD), while some of them differentiate into myofibroblasts or mature adipocytes. Meflin knockout mice fed an HFD exhibited a significant fibrotic response as well as increases in adipocyte cell size and the number of crown‐like structures in WAT, accompanied by impaired glucose tolerance. These data suggested that Meflin expressed by ASPCs may have a role in reducing disease progression associated with WAT dysfunction. [ABSTRACT FROM AUTHOR]

Primary sclerosing cholangitis (PSC) is a challenging cholestatic liver disease marked by progressive bile duct inflammation and fibrosis that has no FDA-approved therapy. Although obeticholic acid (OCA) has been sanctioned for PSC, its clinical utility in PSC is constrained by its potential hepatotoxicity. Here, we introduce a novel therapeutic construct consisting of OCA encapsulated within a reactive oxygen species (ROS)-responsive, biodegradable polymer, further cloaked with human placenta-derived mesenchymal stem cell (hP-MSC) membrane (MPPFTU@OCA). Using PSC patient-derived organoid models, we assessed its cellular uptake and cytotoxicity. Moreover, using a PSC mouse model induced by 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC), we demonstrated that intravenous administration of MPPFTU@OCA not only improved cholestasis via the FXR-SHP pathway but also reduced macrophage infiltration and the accumulation of intracellular ROS, and alleviated mitochondria-induced apoptosis. Finally, we verified the ability of MPPFTU@OCA to inhibit mitochondrial ROS thereby alleviating apoptosis by measuring the mitochondrial adenosine triphosphate (ATP) concentration, ROS levels, and membrane potential (ΔΨm) using H 2 O 2 -stimulated PSC-derived organoids. These results illuminate the synergistic benefits of integrating an ROS-responsive biomimetic platform with OCA, offering a promising therapeutic avenue for PSC. ROS-responsive and self-positioning biomimetic nanoparticle delivery of obeticholic acid mitigates primary sclerosing cholangitis via mitochondria-induced apoptosis. [Display omitted] • ROS-responsive PPFTU material loaded with OCA alleviated hepatobiliary damage. • MSC membrane encapsulation enables powerful targeting of the liver and inflammation. • Organoids and animal models reveal that MPPFTU@OCA mitigates disease progression via mitochondrial-induced apoptosis. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cell (MSC)-based therapies have emerged as promising methods for regenerative medicine; however, how to precisely enhance their tissue repair effects is still a major question in the field. Circulating extracellular vesicles (EVs) from diseased states carry diverse pathological information and affect the functions of recipient cells. Based on this unique property, we report that disease-derived circulating EV (disease-EV) preconditioning is a potent strategy for precisely enhancing the tissue repair potency of MSCs in diverse disease models. Briefly, plasma EVs from lung or kidney tissue injuries were shown to contain distinctly enriched molecules and were shown to induce tissue injury-specific gene expression responses in cultured MSCs. Disease-EV preconditioning improved the performance (including proliferation, migration, and growth factor production) of MSCs through metabolic reprogramming (such as via enhanced oxidative phosphorylation and lipid metabolism) without inducing an adverse immune response. Consequently, compared with normal MSCs, disease-EV-preconditioned MSCs exhibited superior tissue repair effects (including anti-inflammatory and antiapoptotic effects) in diverse types of tissue injury (such as acute lung or kidney injury). Disease-derived EVs may serve as a type of "off-the-shelf" product due to multiple advantages, such as flexibility, stability, long-term storage, and ease of shipment and use. This study highlights the idea that disease-EV preconditioning is a robust strategy for precisely enhancing the regenerative capacity of MSC-based therapies. Disease-derived circulating extracellular vesicles preconditioning enables the transferring of various disease-specific information to mesenchymal stem cells (MSCs) and thus precisely enhances their therapeutic effects. [Display omitted] [ABSTRACT FROM AUTHOR]

To assess the effectiveness of mesenchymal stem cells (MSCs) for chronic knee pain secondary to osteoarthritis (OA). We searched MEDLINE, EMBASE, CINAHL, and Cochrane Central to September 2023 for trials that (1) enrolled patients with chronic pain associated with knee OA, and (2) randomized them to MSC therapy vs. placebo or usual care. We performed random-effects meta-analysis and used Grading of Recommendations, Assessment, Development, and Evaluation to assess the certainty of evidence. We included 16 trials (807 participants). At 3–6 months, MSC therapy probably results in little to no difference in pain relief (weighted mean difference [WMD] −0.74 cm on a 10 cm visual analog scale [VAS], 95% confidence interval [95%CI] −1.16 to −0.33; minimally important difference [MID] 1.5 cm) or physical functioning (WMD 2.23 points on 100-point 36-item Short Form Survey (SF-36) physical functioning subscale, 95%CI −0.97 to 5.43; MID 10-points; both moderate certainty). At 12 months, injection of MSCs probably results in little to no difference in pain (WMD −0.73 cm on a 10 cm VAS, 95%CI −1.69 to 0.24; moderate certainty) and may improve physical functioning (WMD 19.36 points on 100-point SF-36 PF subscale, 95%CI −0.19 to 38.9; low certainty). MSC therapy may increase risk of any adverse events (risk ratio [RR] 2.67, 95%CI 1.19 to 5.99; low certainty) and pain and swelling of the knee joint (RR 1.58, 95%CI 1.04 to 2.38; low certainty). Intra-articular injection of MSCs for chronic knee pain associated with OA probably provides little to no improvement in pain or physical function. [ABSTRACT FROM AUTHOR]

Introduction: Spinal cord injury (SCI) leads to severe disabilities and remains a significant social and economic challenge. Despite advances in medical research, there are still no effective treatments for SCI. Human amnion-derived mesenchymal stem cells (hAMSCs) have shown potential due to their antiinflammatory and neuroprotective effects. This study evaluates the therapeutic potential of intravenously administered hAMSCs in SCI models. Methods: Three days after induction of SCI with forceps calibrated with a 0.2mm gap, hAMSCs or vehicle were administered intravenously. Up to 4 weeks of SCI induction, motor function was assessed by scores on the Basso Mouse Locomotor Scale (BMS) and the Basso-Beattie-Bresnahan Scale (BBB), and sensory function by hindlimb withdrawal reflex using von Frey filaments. Six weeks after SCI induction, gait function was assessed using three-dimensional motion analysis. Immunohistochemistry, polymerase chain reaction (PCR), flow cytometry, and ELISA assay were performed to clarify the mechanisms of functional improvement. Results: The hAMSC treatment significantly improved sensory response and gait function. In the SCI site, immunohistochemistry showed a reduction in Iba1-positive cells and PCR revealed decreased TNFa and increased BDNF levels in the hAMSC-treated group. In assessing the systemic inflammatory response, hAMSC treatment reduced monocytic bone marrow-derived suppressor cells (MMDSCs) and Ly6C-positive inflammatory macrophages in the bone marrow by flow cytometry and serum NO levels by ELISA assay. Discussion: This study demonstrates the therapeutic potential of the hAMSC in SCI, with improvements in gait and sensory functions and reduced inflammation both locally and systemically. The findings support further investigation of the hAMSC as a potential treatment for SCI, focusing on their ability to modulate inflammation and promote neuroprotection. [ABSTRACT FROM AUTHOR]

BACKGROUND: Mouse osteogenic potential is regulated by the JAK-STAT signaling pathway, and interleukin-9 can regulate multiple cellular functions through the JAK-STAT pathway, which has the potential to be a novel cytokine that regulates osteogenic potential. OBJECTIVE: To investigate the effect of interleukin-9 deficiency on osteogenic potential in mice METHODS: The femurs collected from 2-month-old wild-type and interleukin-9 knockout mice were subjected to Micro-CT scanning to analyze the changes in bone mass. Then, hematoxylin-eosin staining, Masson staining, and immunohistochemical staining of type I collagen were performed on the slices of the femurs of mice. Bone marrow cells from 2-month-old wild-type and interleukin-9 knockout mice were extracted for colony-forming assay and detection of osteogenic gene expression in bone marrow mesenchymal stem cells. To further verify whether interleukin-9 worked through the JAK-STAT pathway, the expression of STAT3 protein was detected by western blot. RESULTS AND CONCLUSION: Micro-CT results showed the bone mass of interleukin-9 knockout mice decreased significantly compared with that of wild-type mice. In addition, the bone mineral density, bone volume fraction, trabecular number significantly decreased and trabecular separation markedly escalated in interleukin-9 knockout mice. The findings of hematoxylin-eosin staining were consistent with Micro-CT results. Interleukin-9 knockout mice had lower bone trabecular density. Type I collagen immunohistochemistry staining and Masson staining indicated the number of type I collagen positive osteoblasts was significantly reduced and the capacity of collagen formation was damaged in interleukin-9 knockout mice. The results of colony-forming assay indicated that the mineralization capacity of osteoblast in interleukin-9 knockout mice were significantly lower than that in wild-type mice. Western blot results showed that osteogenesis induction activated STAT3 signaling, and the pSTAT3 level in wild-type mice with osteogenic induction was significantly higher than that in interleukin-9 knockout mice with osteogenic induction. These findings suggest that interleukin-9 regulates osteogenesis through the JAK-STAT3 pathway and interleukin-9 deficiency inhibits osteoblast differentiation and function, which may lead to reduced bone mass in interleukin-9 knockout mice. [ABSTRACT FROM AUTHOR]

Chronic liver injuries and their complications are leading causes of death, especially in developing countries (Sharma and Nagalli in Sex/Gender-Specific Medicine in the Gastrointestinal Diseases, StatPearls Publishing, 2023). The available and effective treatment plans are limited, implicating the need for innovative treatment approaches (Tsuchiya et al. in Inflamm Regener, 2019;Sharma and Nagalli in Sex/Gender-Specific Medicine in the Gastrointestinal Diseases, StatPearls Publishing, 2023;Younossi et al. in Clin Gastroenterol Hepatol 21:1978–1991, 2023;). This paper aims to summarize the effects and mechanisms of hUC-MSC-exo on liver injuries and its complications; it also suggests future directions for future research. The outcomes of interest are the morphology and histology of the liver, pathology score, liver function enzyme, glucose and lipid metabolism, and the effect hUC-MSC-exo had on gene regulation regarding liver diseases. A comprehensive review of nineteen studies was conducted to assess the effectiveness of the implementation of the hUC-MSC-Exo, instilling confidence in the validity of the findings. Regarding the morphology and histology of the liver and pathology score, hUC-MSC-exo treatment resulted in improved liver morphology post-treatment, as indicated by the reduction in pathology scores. However, these observed improvements in the liver surface are not directly attributed to the hUC-MSC-Exo itself but to the overall healing processes stimulated by the treatment. In physiological outcomes, hUC-MSC-exo also improves glucose and lipid metabolism, especially in diet-induced liver injury and its complications. In gene regulation, one interesting gene in this intervention is the fat mass and obesity-associated (FTO), in which hUC-MSC-exo combined with miRNAs can suppress FTO. HUC-MSC-Exo can improve by utilizing several possible pathways, targeting pinpoints in the pathogenesis of liver disease or glucose and lipid metabolism. This study presents hUC-MSC-exo better in all outcomes of interest compared to the control or sham group. Further specification of indications of the hUC-MSC-exo method may be beneficial and essential to be analyzed in future reviews to better understand the effectiveness of each hUC-MSC-exo dose, duration, and medium. [ABSTRACT FROM AUTHOR]

Simple Summary: Equine laminitis is a serious condition causing severe pain and lameness in horses, often leading to euthanasia. This study developed a lab model to better understand laminitis using keratinocytes which were exposed to conditions simulating the disease. This research showed that adding muscle-derived stem cells helped protect and restore the keratinocytes' metabolism. These results highlight the potential of stem cell therapy in treating laminitis, offering new hope for managing this debilitating disease in horses. Laminitis in horses is a crippling condition marked by the deterioration of the dermal–epidermal interface, leading to intense lameness and discomfort, often necessitating euthanasia. This study aimed to establish an in vitro model of laminitis using a continuous keratinocyte cell line exposed to anoxia–reoxygenation and an activated neutrophil supernatant. A significant decrease in the keratinocytes' metabolism was noted during the reoxygenation period, indicative of cellular stress. Adding muscle-derived mesenchymal stem/stromal cells during the reoxygenation demonstrated a protective effect, restoring the keratinocytes' metabolic activity. Moreover, the incubation of the keratinocytes with either an activated neutrophil supernatant or myeloperoxidase alone induced increased keratinocyte myeloperoxidase activity, which was modulated by stem cells. These findings underscore the potential of muscle-derived mesenchymal stem/stromal cells in mitigating inflammation and restoring keratinocyte metabolism, offering insights for future cell therapy research in laminitis treatment. [ABSTRACT FROM AUTHOR]

Intrauterine adhesion (IUA), a prevalent etiology of female infertility, is attributed to endometrial damage. However, conventional therapeutic interventions for IUA are plagued by high recurrence rates. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUCMSC-EVs) demonstrate the promising therapeutic effects on IUA, but the current efficacy of extracellular vesicles (EVs) is hindered by lower retention and bioavailability. In this study, a thermosensitive hydrogel was utilized as a prolonged release carrier to improve the retention and bioavailability of hUCMSC-EVs in IUA treatment. The hydrogel-EVs complex effectively prolonged EVs retention in human endometrial stromal cells and an IUA mouse model. The complex exhibited superior protection against cellular injury, significantly alleviated endometrial damage, inhibited fibrosis, suppressed inflammation, and improved fertility compared to EVs alone. The results indicated that thermosensitive hydrogel enhanced the therapeutic capacity of EVs for IUA by prolonging their retention in the uterine environment. The hydrogel-EVs complex provides a novel strategy for the sustained release of hUCMSC-EVs in the treatment of IUA. [ABSTRACT FROM AUTHOR]

Background: Eosinophilic granulomatosis with polyangiitis (EGPA), a rare but life-threatening systemic vasculitis, is distinguished by marked eosinophilia and presents with diverse symptoms, including asthma, cutaneous purpura, ecchymosis, skin necrosis, cardiac lesions, peripheral neuropathy, and necrotizing vasculitis. The etiology of EGPA involves a complex interaction among humoral, adaptive, innate, and allergic immune responses. Standard treatment employs prolonged high-dose glucocorticoid therapy, which is critical for survival; however, some patients' symptoms cannot be relieved. Case report: This case report details the medical management of an 11-year-old patient with EGPA, who was at risk of bilateral lower limb amputation due to differential arterial occlusion and severe, necrotizing vasculitis-induced gangrene in both feet. Treatment modalities administered included systemic infusion of Umbilical Cord Mesenchymal Stem Cells (UC-MSCs), targeted gastrocnemius muscle injections, and application of a Placenta-Derived Mesenchymal Stem Cells (PD-MSCs) hydrogel. Results: After receiving a four-month regimen of allogeneic mesenchymal stem cell therapy via intravenous and local administration, the patient showed normalized eosinophil counts, reestablished blood flow in the dorsal arteries, and marked improvement in foot ulcerations. Conclusion: Mesenchymal stem cell therapy is a promising option for severe EGPA cases refractory to glucocorticoids. [ABSTRACT FROM AUTHOR]

Aims: Mesenchymal stem cells (MSCs) are key components in promoting glioblastoma (GBM) progression. This study aimed to explore new therapeutic targets and related pathogenic mechanisms based on different MSCs infiltration levels in GBM patients. Methods: We estimated the relationship between cell infiltration and prognosis of GBM. Subsequently, key risk genes were identified and prognostic models were constructed by LASSO-Cox analysis. The risk genes were validated by five independent external cohorts, single-cell RNA analysis, and immunohistochemistry of human GBM tissues. TIDE analysis predicted responsiveness to immune checkpoint inhibitors in different risk groups. Results: The MSCs infiltration level was negatively associated with survival in GBM patients. LOXL1, LOXL4, and GUCA1A are key risk genes that promote GBM progression and may act through complex intercellular communication. Conclusion: This research has provided a comprehensive study for exploring the MSCs infiltration environment on GBM progression, which could shed light on novel biomarkers and mechanisms involved in GBM progression. [ABSTRACT FROM AUTHOR]

[Display omitted] • Alzheimer's disease is the most pervasive neurodegenerative disease. • Current drugs for Alzheimer's disease provide symptomatic relief but do not cure or stop disease progression. • Stem cells, due to their robust properties, appear to be the most reliable treatment approach. • Among various stem cells, Mesenchymal Stem Cell (MSCs) are the most novel method of treatment. • MSCs have several properties that make them promising for therapeutic applications. Alzheimer's disease (AD) is one of the most progressive and prevalent types of neurodegenerative diseases in the aging population (aged >65 years) and is considered a major factor for dementia, affecting 55 million people worldwide. In the current scenario, drug-based therapies have been employed for the treatment of Alzheimer's disease but are only able to provide symptomatic relief to patients rather than a permanent solution from Alzheimer's. Recent advancements in stem cell research unlock new horizons for developing effective and highly potential therapeutic approaches due to their self-renewal, self-replicating, regenerative, and high differentiation capabilities. Stem cells come in multiple lineages such as embryonic, neural, and induced pluripotent, among others. Among different kinds of stem cells, mesenchymal stem cells are the most investigated for Alzheimer's treatment due to their multipotent nature, low immunogenicity, ability to penetrate the blood–brain barrier, and low risk of tumorigenesis, immune & inflammatory modulation, etc. They have been seen to substantially promote neurogenesis, synaptogenesis by secreting neurotrophic growth factors, as well as in ameliorating the Aβ and tau-mediated toxicity. This review covers the pathophysiology of AD, new medications, and therapies. Further, it will focus on the advancements and benefits of Mesenchymal Stem Cell therapies, their administration methods, clinical trials concerning AD progression, along with their future prospective. [ABSTRACT FROM AUTHOR]

BACKGROUND: Amyotrophic lateral sclerosis is a progressive neurodegenerative disease, which often leads to the death of neurons in the brain and spinal cord. The pathogenesis of amyotrophic lateral sclerosis is extremely complex, with high refractory rate and mortality rate. There are only two kinds of drugs for its treatment, so it is urgent to develop new treatment methods to improve the prognosis of patients. OBJECTIVE: To review the mechanism of Chinese medicine and mesenchymal stem cells regulating the immune response in the treatment of amyotrophic lateral sclerosis. METHODS: “Traditional Chinese medicine, medical stem cells, ALS, immune response” were Chinese and English search terms. Articles were retrieved from WanFang, CNKI, PubMed, Web of Science and other databases from 2010 to 2023. Finally, 69 articles were included for review. RESULTS AND CONCLUSION: (1) The article summarizes in detail the five mechanisms of traditional Chinese medicine regulating the immune response in the treatment of amyotrophic lateral sclerosis: mainly including the promotion of expression of closed zone protein-1 and closed protein-5 by traditional Chinese medicine such as borneol and astragaloside IV to rebuild the integrity of the blood central nervous system barrier. Fufangteng Mixture can regulate the receptor molecules on the surface of the natural killer cells to inhibit their autotoxicity. The complement system factors such as Scutellaria barbata and patchouli can inhibit their abnormal activation. Tripterygium wilfordii and Uncaria rhynchophylla inhibit the activation of microglia by mediating the production of extracellular signal-regulated kinase 1/2 attenuated inducible nitric oxide synthase. Zuogui Pill and Trichosanthes kirilowii Root promote the expression of interleukin-10 and regulate T cells to improve the immune environment. (2) Through existing research, five mechanisms of mesenchymal stem cells regulating the immune response in the treatment of amyotrophic lateral sclerosis have been summarized, mainly including reducing the expression of aquaporin 4 and reducing endothelial nitric oxide synthase signal transduction to repair the integrity of the immune barrier; releasing indoleamine 2,3-dioxygenase, prostaglandin E2 and other factors to resist natural killer cell toxicity; secretion factor H interferes with the activity of invertase and inhibits abnormal activation of the complement system; regulating the CX3CL1/CX3CR1 system axis or secreting transforming growth factors β, which can change the phenotype of microglia and inhibit its activity by other ways; increasing the expression of interleukin-10 or activating the STATS phosphorylation pathway to restore T cell function. (3) At present, there are few studies on the combination of traditional Chinese medicine and mesenchymal stem cells in the treatment of amyotrophic lateral sclerosis. Relevant research reports have shown that Jiweiling Injection can promote stem cell proliferation and differentiation and that Buyang Huanwu decoction combined with bone marrow mesenchymal stem cells can significantly improve the integrity of the blood-brain barrier. In the future, further exploration is needed to explore the synergistic treatment effect of both on refractory amyotrophic lateral sclerosis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Despite a series of clinical treatment measures, the treatment of pulmonary fibrosis still faces challenges. In recent years, mesenchymal stem cells and their extracellular vesicles have attracted extensive attention as an emerging therapeutic strategy and are considered to be a promising means of treating pulmonary fibrosis. OBJECTIVE: To systematically review the application of mesenchymal stem cells and their extracellular vesicles in the treatment of pulmonary fibrosis, to comprehensively understand their therapeutic mechanism, efficacy evaluation and problems, and provide reference and guidance for further research and clinical application in the future. METHODS: Using Chinese and English search terms “mesenchymal stem cells”, “ mesenchymal stem cell extracellular vesicles”, “pulmonary fibrosis”, we searched the CNKI and PubMed electronic journal databases. By means of manual reading and eliminating duplicate articles, 112 articles were selected, but 58 Chinese and English articles were finally included for summary. RESULTS AND CONCLUSION: (1) Mesenchymal stem cells and their extracellular vesicles have shown great potential in the treatment of pulmonary fibrosis, such as regulating inflammatory responses, inhibiting fibroblast proliferation, and promoting damaged tissue repair. Preliminary results from clinical trials have also shown some effects of the treatment, including improved lung function and quality of life in patients. (2) However, mesenchymal stem cells and extracellular vesicles in the treatment of pulmonary fibrosis still face some challenges. During treatment, technical challenges such as cell migration and intrachistological localization need to be addressed for it to accurately reach the damaged lung tissue. Furthermore, its long-term safety also needs to be further studied and improved. For translational medicine development, standardized procedures such as cell collection, cell isolation, cell culture, cell harvesting, and cell identification need to be refined. (3) Despite these challenges, through the joint efforts of scientific researchers and medical personnel, these problems are expected to be gradually solved. In the future, we can further improve treatment outcomes by optimizing treatment regimens and exploring individualized treatments. At the same time, in-depth research on the therapeutic mechanism of stem cells and their extracellular vesicles is expected to develop more efficient and safe therapeutic strategies. [ABSTRACT FROM AUTHOR]

BACKGROUND: Mesenchymal stem cells are used in flap ischemia-reperfusion injury due to their antioxidant and inflammatory inhibition, and angiogenesis induction. OBJECTIVE: To review the mechanism and latest treatment progress of mesenchymal stem cells in the treatment of flap ischemia-reperfusion injury, and to provide a basis for further theoretical research and clinical rational application. METHODS: We searched the relevant articles indexed in CNKI, WanFang and PubMed databases. Chinese and English search terms were “mesenchymal stem cells; flap ischemia reperfusion injury; conditioned medium; exosomes; oxidative stress; inflammatory reactions; angiogenesis”. Relevant literature since 2010 was searched, and 74 articles were finally included after excluding the literature that had little to do with the topic of the article, poor quality and outdated content. RESULTS AND CONCLUSION: (1) Mesenchymal stem cells play significant roles in antioxidation, inhibition of inflammation and induction of angiogenesis and have great potential in the treatment of flap ischemia-reperfusion injury. (2) However, the defects of mesenchymal stem cells themselves and the decline of therapeutic effect in recent years have put the development and application of mesenchymal stem cells into a bottleneck period, and the research on the plasticity of mesenchymal stem cells conditioned medium and its exosomes and mesenchymal stem cells came into being, and the therapeutic effect was significantly better than the use of mesenchymal stem cells alone. (3) Therefore, a more comprehensive understanding of the mechanism of action and the latest treatment progress of mesenchymal stem cells in the treatment of flap ischemia-reperfusion injury is of great significance for the research of mesenchymal stem cells and the treatment of flap ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

Background: Human mesenchymal stem cells have attracted interest in regenerative medicine and are being tested in many clinical trials. In vitro expansion is necessary to provide clinical-grade quantities of mesenchymal stem cells; however, it has been reported to cause replicative senescence and undefined dysfunction in mesenchymal stem cells. Quality control assessments of in vitro expansion have rarely been addressed in ongoing trials. Young small extracellular vesicles from the remnant pulp of human exfoliated deciduous teeth stem cells have demonstrated therapeutic potential for diverse diseases. However, it is still unclear whether young small extracellular vesicles can reverse senescence-related declines. Results: We demonstrated that mitochondrial structural disruption precedes cellular dysfunction during bone marrow-derived mesenchymal stem cell replication, indicating mitochondrial parameters as quality assessment indicators of mesenchymal stem cells. Dynamin-related protein 1-mediated mitochondrial dynamism is an upstream regulator of replicative senescence-induced dysfunction in bone marrow-derived mesenchymal stem cells. We observed that the application of young small extracellular vesicles could rescue the pluripotency dissolution, immunoregulatory capacities, and therapeutic effects of replicative senescent bone marrow-derived mesenchymal stem cells. Mechanistically, young small extracellular vesicles could promote Dynamin-related protein 1 translocation from the cytoplasm to the mitochondria and remodel mitochondrial disruption during replication history. Conclusions: Our findings show that Dynamin-related protein 1-mediated mitochondrial disruption is associated with the replication history of bone marrow-derived mesenchymal stem cells. Young small extracellular vesicles from human exfoliated deciduous teeth stem cells alleviate replicative senescence by promoting Dynamin-related protein 1 translocation onto the mitochondria, providing evidence for a potential rejuvenation strategy. [ABSTRACT FROM AUTHOR]

Stem cells transplantation (SCT) is known as a newfound strategy for multiple sclerosis (MS) treatment. Human umbilical cord mesenchymal stem cells (hUCMSCs) contain various regenerative features. Experimental autoimmune encephalomyelitis (EAE) is a laboratory model of MS. This meta-analysis study was conducted to assess the overall therapeutic effects of hUCMSCs on reduction of clinical score (CS) and restoration of active movement in EAE-induced animals. For comprehensive searching (in various English and Persian databases until May 1, 2024), the main keywords of "Experimental Autoimmune Encephalomyelitis", "Multiple Sclerosis", "Human", "Umbilical Cord", "Mesenchymal", and "Stem Cell" were hired. Collected data were transferred to the citation manager software (EndNote x8) and duplicate papers were merged. Primary and secondary screenings were applied (according to the inclusion and exclusion criteria) and eligible studies were prepared for data collection. CS of two phases of peak and recovery of EAE were extracted as the difference in means and various analyses including heterogeneity, publication bias, funnel plot, and sensitivity index were reported. Metaanalysis was applied by CMA software (v.2), P<0.05 was considered a significant level, and the confidence interval (CI) was determined 95% (95% CI). Six eligible high-quality (approved by ARRIVE checklist) papers were gathered. The difference in means of peak and recovery phases were -0.775 (-1.325 to -0.225; P=0.006; I²=90.417%) and -1.230 (-1.759 to -0.700; P<0.001; I²=93.402%), respectively. The overall therapeutic effects of SCT of hUCMSCs on the EAE cases was -1.011 (95% CI=-1.392 to -0.629; P=0.001). hUCMSCs transplantation through the intravenous route to the animal MS model (EAE) seems a considerably effective procedure for the alleviation of motor defects in both phases of peak and recovery. [ABSTRACT FROM AUTHOR]

Stimulating erythropoiesis is essential in the treatment of various types of anemia. Sheng Xue Ning (SXN) is commonly used in China as an iron supplement to treat iron deficiency anemia, renal anemia, and anemia in pregnancy. This research reports a novel effect of SXN in enhancing the proliferation of hematopoietic stem/progenitor cell (HSPC) to promote erythropoiesis in the bone marrow, which is distinct from conventional iron supplements that primarily aid in the maturation of red blood cells. Employing a model of hematopoietic dysfunction induced by X-ray exposure, we evaluated the efficacy of SXN in restoring hematopoietic function. SXN significantly promoted the recovery of peripheral erythroid cells and enhanced the proliferation and differentiation of Lin−/c-KIT+/Sca-1+ HSPC in mice exposed to X-ray irradiation. Our results showed that SXN elevated the expression of stem cell factor (SCF) and activated the SCF/c-KIT/PI3K/AKT signaling pathway, facilitating the proliferation and differentiation of HSPC. In vitro, SXN markedly enhanced the proliferation of bone marrow nucleated cell (BMNC) and the colony-forming capacity of BFU-E, CFU-E, and CFU-GM, while also elevating the expression of proteins involved in the SCF/c-KIT/PI3K/AKT pathway in BMNC. Additionally, SXN enhanced the proliferation and differentiation of mesenchymal stem cell (MSC) and increased SCF secretion. In conclusion, SXN demonstrates the capacity to enhance erythropoiesis by upregulating SCF expression, thereby promoting HSPC proliferation and differentiation via the SCF/c-KIT/PI3K/AKT pathway. SXN may offer a new strategy for improving the activity of HSPC and promoting erythropoiesis in the treatment of hematopoiesis disorders. [ABSTRACT FROM AUTHOR]

Pericytes are versatile cells integral to the blood vessel walls of the microcirculation, where they exhibit specific stem cell traits. They are essential in modulating blood flow, ensuring vascular permeability, and maintaining homeostasis and are involved in the tissue repair process. The human endometrium is a unique and complex tissue that serves as a natural scar-free healing model with its cyclical repair and regeneration process every month. The regulation of pericytes has gained increasing attention due to their involvement in various physiological and pathological processes. However, endometrial pericytes are less well studied compared to the pericytes in other organs. This review aims to provide a comprehensive overview of endometrial pericytes, with a focus on elucidating their physiological function and potential implications in uterine disorders. [ABSTRACT FROM AUTHOR]