Search

Introduction: According to the World Health Organization (WHO), by 2050 at least 700 million people will need access to hearing care and hearing rehabilitation services. The search for cell or gene therapies has been intensifying, and stem cell therapy looks a promising candidate to support hearing regeneration and reduce these numbers. The aim of this study is to provide an overview of current advances in stem cell-based therapies for cochlear hair cell regeneration and the processes being developed for future applicability. Material and methods: Identification and review of all articles in the databases PubMed, Web of Science, and PLoS One using the terms stem cell, auditory hair cell regeneration, and mammalian during February 2023 and following the PRISMA guidelines. Results: 50 articles were obtained, published between 2003 and 2022 and were systematically analyzed. The current research quantity is limited and further studies are needed, particularly in human tissue. Conclusion: The simultaneous use of cell therapy and gene therapy may lead to more promising results. Moreover, advances in cochlear hair cell regeneration with stem cells suggest there is a realistic potential to make the technique a useful future therapy. [ABSTRACT FROM AUTHOR]

Background and Objectives: Cleft lip alone or a combination of cleft lip and palate (CLP) is a common developmental abnormality in the craniofacial region. This umbrella review aims to identify promising avenues for treatment using stem cell therapy. Materials and Methods: Systematic reviews from 2014 to 2024 were searched among databases like PubMed, Medline, and Google Scholar. PRISMA guidelines were employed to ensure the thoroughness of the search. A quality assessment (ROBIS) of the included reviews was conducted to ensure the reliability and validity of the synthesized evidence. Results: Five systematic reviews were selected for this umbrella review. Results show that stem cell therapy, specifically using mesenchymal stem cells (MSCs) and adipocyte stem cells (ADSCs), promotes bone regeneration in CLP deformities. Although multiple studies have established the effectiveness of diverse types of stem cells in treating CLP, important considerations including safety concerns, methodological variability, and the need for standardization have been identified. The fact that the number of relevant systematic reviews that matched our inclusion criteria was limited could affect this research's robustness and may limit the breadth and depth of evidence synthesis. Definitive conclusions could not be reached due to variation among treatments and outcomes. Conclusions: The examined studies highlight the potential of stem cell therapy as a complementary approach to existing treatments for CLP. However, there are challenges that need to be addressed, including concerns regarding safety, variations in methodologies, and the need for standardization. Exploring the potential of other stem cell types may further enhance treatment outcomes for CLP patients. [ABSTRACT FROM AUTHOR]

A targeted micellar formation of doxorubicin (Dox) and curcumin (Cur) was evaluated to enhance the efficacy and reduce the toxicity of these drugs in KG1a leukemic stem cells (LSCs) compared to EoL-1 leukemic cells. Dox-Cur-micelle (DCM) was developed to improve the cell uptake of both compounds in LSCs. Cur-micelle (CM) was produced to compare with DCM. DCM and CM were conjugated with two FLT3 (FMS-like tyrosine kinase)-specific peptides (CKR; C and EVQ; E) to increase drug delivery to KG1a via the FLT3 receptor (AML marker). They were formulated using a film-hydration technique together with a pH-induced self-assembly method. The optimal drug-to-polymer weight ratios for the DCM and CM formulations were 1:40. The weight ratio of Dox and Cur in DCM was 1:9. DCM and CM exhibited a particle size of 20–25 nm with neutral charge and a high %EE. Each micelle exhibited colloidal stability and prolonged drug release. Poloxamer 407 (P407) was modified with terminal azides and conjugated to FLT3-targeting peptides with terminal alkynes. DCM and CM coupled with peptides C, E, and C + E exhibited a higher particle size. Moreover, DCM-C + E and CM-C + E showed the highest toxicity in KG-1a and EoL-1 cells. Using two peptides likely improves the probability of micelles binding to the FLT3 receptor and induces cytotoxicity in leukemic stem cells. [ABSTRACT FROM AUTHOR]

BACKGROUND Chemotherapy-associated ovarian damage (CAOD) is one of the most feared short- and long-term side effects of anticancer treatment in premenopausal women. Accumulating detailed data show that different chemotherapy regimens can lead to disturbance of ovarian hormone levels, reduced or lost fertility, and an increased risk of early menopause. Previous studies have often focused on the direct effects of chemotherapeutic drugs on ovarian follicles, such as direct DNA damage-mediated apoptotic death and primordial follicle burnout. Emerging evidence has revealed an imbalance in the ovarian microenvironment during chemotherapy. The ovarian microenvironment provides nutritional support and transportation of signals that stimulate the growth and development of follicles, ovulation, and corpus luteum formation. The close interaction between the ovarian microenvironment and follicles can determine ovarian function. Therefore, designing novel and precise strategies to manipulate the ovarian microenvironment may be a new strategy to protect ovarian function during chemotherapy. OBJECTIVE AND RATIONALE This review details the changes that occur in the ovarian microenvironment during chemotherapy and emphasizes the importance of developing new therapeutics that protect ovarian function by targeting the ovarian microenvironment during chemotherapy. SEARCH METHODS A comprehensive review of the literature was performed by searching PubMed up to April 2024. Search terms included 'ovarian microenvironment' (ovarian extracellular matrix, ovarian stromal cells, ovarian interstitial, ovarian blood vessels, ovarian lymphatic vessels, ovarian macrophages, ovarian lymphocytes, ovarian immune cytokines, ovarian oxidative stress, ovarian reactive oxygen species, ovarian senescence cells, ovarian senescence-associated secretory phenotypes, ovarian oogonial stem cells, ovarian stem cells), terms related to ovarian function (reproductive health, fertility, infertility, fecundity, ovarian reserve, ovarian function, menopause, decreased ovarian reserve, premature ovarian insufficiency/failure), and terms related to chemotherapy (cyclophosphamide, lfosfamide, chlormethine, chlorambucil, busulfan, melphalan, procarbazine, cisplatin, doxorubicin, carboplatin, taxane, paclitaxel, docetaxel, 5-fluorouraci, vincristine, methotrexate, dactinomycin, bleomycin, mercaptopurine). OUTCOMES The ovarian microenvironment shows great changes during chemotherapy, inducing extracellular matrix deposition and stromal fibrosis, angiogenesis disorders, immune microenvironment disturbance, oxidative stress imbalances, ovarian stem cell exhaustion, and cell senescence, thereby lowering the quantity and quality of ovarian follicles. Several methods targeting the ovarian microenvironment have been adopted to prevent and treat CAOD, such as stem cell therapy and the use of free radical scavengers, senolytherapies, immunomodulators, and proangiogenic factors. WIDER IMPLICATIONS Ovarian function is determined by its 'seeds' (follicles) and 'soil' (ovarian microenvironment). The ovarian microenvironment has been reported to play a vital role in CAOD and targeting the ovarian microenvironment may present potential therapeutic approaches for CAOD. However, the relation between the ovarian microenvironment, its regulatory networks, and CAOD needs to be further studied. A better understanding of these issues could be helpful in explaining the pathogenesis of CAOD and creating innovative strategies for counteracting the effects exerted on ovarian function. Our aim is that this narrative review of CAOD will stimulate more research in this important field. REGISTRATION NUMBER Not applicable. [ABSTRACT FROM AUTHOR]

Clinical relevance: Findings from this study examining Australian optometrists' insights into ocular stem cell (SC) therapies have capacity to inform continuing professional development (CPD) about these interventions. Background: This study investigated Australian optometrists' knowledge, views, experiences, and preferred education sources regarding ocular SC therapies. Methods: An online survey was distributed to optometrists via Optometry Australia, Mivision magazine, professional groups, and social media from August 2020 to March 2021. Data were collected on demographics, and SC knowledge, awareness and experience. Results: Of 81 optometrists who completed the survey, many were metropolitan-based (85%), worked in independent practice (47%), female (56%) and >46 years of age (45%). Approximately one-fifth indicated awareness of ocular SC therapies used in standard practice; one-third had knowledge of SC clinical trials. The most noted SC therapies were for corneal disease in the United States [US] (72%) and Australia (44%). Respondents identified the availability of SC therapies for dry eye disease in Australia and the US (39% and 44% respectively), despite no regulatory-approved treatments for this indication. Clinical trials investigating inherited retinal and corneal diseases in Australia were the most commonly identified (44% and 36%, respectively). Half the respondents felt 'unsure' about the quality of evidence for treating eye conditions using SCs. One-fifth indicated concerns with these therapies; of these, most mentioned efficacy (82%), safety (76%) and/or cost (71%). About one-fifth reported being asked for advice about SCs by patients. Two-thirds felt neutral, uncomfortable, or very uncomfortable providing this advice, due to lack of knowledge or the topic being beyond their expertise. Over half (57%) were unsure if clinical management should change if patients received SC therapies. Respondents were receptive to face-to-face education. Conclusion: Some optometrists responding to this survey were aware of ocular SC therapies and/or clinical trials. CPD programs may assist with maintaining currency in this evolving field. [ABSTRACT FROM AUTHOR]

The formation of stomata presents a compelling model system for comprehending the initiation, proliferation, commitment and differentiation of de novo lineage‐specific stem cells. Precise, timely and robust cell fate and identity decisions are crucial for the proper progression and differentiation of functional stomata. Deviations from this precise specification result in developmental abnormalities and nonfunctional stomata. However, the molecular underpinnings of timely cell fate commitment have just begun to be unravelled. In this review, we explore the key regulatory strategies governing cell fate commitment, emphasizing the distinctions between embryonic and postembryonic stomatal development. Furthermore, the interplay of transcription factors and cell cycle machineries is pivotal in specifying the transition into differentiation. We aim to synthesize recent studies utilizing single‐cell as well as cell‐type‐specific transcriptomics, epigenomics and chromatin accessibility profiling to shed light on how master‐regulatory transcription factors and epigenetic machineries mutually influence each other to drive fate commitment and maintenance. Summary statement: In this review, we delve into the molecular mechanisms underlying timely and precise cell fate commitment during stomatal development. Emphasis is made on the differences between embryonic and postembryonic stomatal differentiation. We highlight recent discoveries on the transcriptional circuits that initiate and fortify stomatal fate transitions, as well as the epigenetic processes that facilitate fate commitment and maintenance. [ABSTRACT FROM AUTHOR]

This study aimed to compare the clinically established autologous extrasynovial tendon graft to a newly developed tissue‐engineered allograft (Eng‐allograft) in terms of functional outcomes following flexor tendon reconstruction in a canine model. The second and fifth flexor digitorum profundus (FDP) tendons from 16 dogs were transected and repaired in Zone II. After 6 weeks of cage activity, the repaired tendons were intentionally ruptured, creating a clinically relevant model for reconstruction. The re‐ruptured FDP tendons were then reconstructed using either the clinically standard autologous extrasynovial tendon graft or the Eng‐allograft, which had been revitalized with autologous bone marrow‐derived mesenchymal stem cells (BMSCs) and synovialized using carbodiimide derivatized synovial fluid (cd‐SYN). Following 12 weeks of postoperative rehabilitation, the functional outcomes of the surgical digits were evaluated. The Eng‐allograft group exhibited improved digital function, including lower digit work of flexion and reduced adhesion status, while maintaining similar tendon gliding resistance compared to the autograft group. However, the failure load of both the distal and proximal host/graft conjunctions in the Eng‐allograft group was significantly lower than that of the autograft group with higher graft rupture at the host−graft junction. In conclusion, the decellularized allogenic intrasynovial tendon, when revitalized BMSCs and synovialized with cd‐SYN, demonstrates positive effects on digital function improvement and adhesion reduction. However, the healing at both proximal and distal graft/host junctions is far lower than the autograft. Further research is needed to enhance the healing capacity of allograft conjunctions, aiming to achieve a comparable level of healing seen with autografts. [ABSTRACT FROM AUTHOR]

This study aimed to explore the therapeutic potential of human induced pluripotent stem cell (hiPSC)-derived cardiac tissues (HiCTs) in the emerging approach of bridge to recovery for severe heart failure with ventricular assist devices. We used a rat model of heterotopic heart transplantation (HTx) to mimic ventricular assist device support and heart unloading. HiCTs were created by inserting gelatin hydrogel microspheres between cell sheets made from hiPSC-derived cardiovascular cells. Male athymic nude rats underwent myocardial infarction (MI) and were divided into the following groups: MI (loaded, untreated control), MI + HTx (unloaded, untreated control), MI + HTx + HiCT (unloaded, treated), and MI + HiCT (loaded, treated). HiCTs were placed on the epicardium of the heart in treated groups. We evaluated HiCT engraftment, fibrosis, and neovascularization using histologic analysis. After 4 weeks, HiCTs successfully engrafted in 5 of 6 rats in the MI + HTx + HiCT group (83.3%). The engrafted HiCT area was greater under unloaded conditions (MI + HTx + HiCT) than loaded conditions (MI + HiCT) (P <.05). MI + HTx + HiCT had a significantly smaller infarct area compared with MI and MI + HTx. The MI + HTx + MiCT group exhibited greater vascular density in the border zone than MI and MI + HTx. HiCT treatment suppressed cardiomyocyte atrophy due to left ventricular unloading (P =.001). The protein level of muscle-specific RING finger 1, an atrophy-related ubiquitin ligase, was lower in the MI + HTx + HiCT group than in MI + HTx (P =.036). Transplanting HiCTs into ischemic hearts under unloaded conditions promoted engraftment, neovascularization, attenuated infarct remodeling, and suppressed myocyte atrophy. These results suggest that HiCT treatment could contribute to future advancements in bridge to recovery. [ABSTRACT FROM AUTHOR]

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As 3D culture technology advances, new avenues have opened for the development of physiological human cancer models. These preclinical models provide efficient ways to translate basic cancer research into clinical tumor therapies. Recently, cancer organoids have emerged as a model to dissect the more complex tumor microenvironment. Incorporating cancer organoids into preclinical programs have the potential to increase the success rate of oncology drug development and recapitulate the most efficacious treatment regimens for cancer patients. In this review, four main types of cancer organoids are introduced, their applications, advantages, limitations, and prospects are discussed, as well as the recent application of single‐cell RNA‐sequencing (scRNA‐seq) in exploring cancer organoids to advance this field. [ABSTRACT FROM AUTHOR]

Stem cells are widely used in scientific research because of their ability to self-renew and differentiate into a variety of specialized cell types needed for body functions. However, the self-renewal and differentiation of stem cells are regulated by various stimuli, with mechanical stimulation being particularly notable due to its ability to mimic the physical environment in the body. This study systematically collected 2638 research papers published between 1994 and 2024, employing tools such as VOSviewer, CiteSpace, and GraphPad Prism to uncover research hotspots, publication trends, and collaboration networks. The results indicate a yearly increase in global research on the shear stress stimulation of stem cells, with significant contributions from the United States and China in terms of research investment and output. Future research directions include a deeper understanding of the mechanisms underlying mechanical stimulation's effects on stem cell differentiation, the development of new materials and scaffold designs to better replicate the natural cellular environment, and advancements in regenerative medicine. Despite considerable progress, challenges remain in translating basic research findings into clinical applications. [ABSTRACT FROM AUTHOR]

Decellularized tissues are an attractive scaffolds for 3D tissue engineering. Decellularized animal tissues have certain limitations such as the availability of tissue, high costs and ethical concerns related to the use of animal sources. Plant-based tissue decellularized scaffolds could be a better option to overcome the problem. The leaves of different plants offer a unique opportunity for the development of tissue-specific scaffolds, depending on the reticulate or parallel veination. Herein, we decellularized spinach leaves and employed these for the propagation and osteogenic differentiation of dental pulp stem cells (DPSCs). DPSCs were characterized by using mesenchymal stem cell surface markers CD90, CD105 and CD73 and CD34, CD45 and HLA-DR using flow cytometry. Spinach leaves were decellularized using ethanol, NaOH and HCL. Cytotoxicity of spinach leaf scaffolds were analysed by MTT assay. Decellularized spinach leaves supported dental pulp stem cell adhesion, proliferation and osteogenic differentiation. Our data demonstrate that the decellularized spinach cellulose scaffolds can stimulate the growth, proliferation and osteogenic differentiation of DPSCs. In this study, we showed the versatile nature of decellularized plant leaves as a biological scaffold and their potential for bone regeneration in vitro. [ABSTRACT FROM AUTHOR]

Dental Pulp Stem Cells (DPSCs) represent a new therapeutic alternative for treating superficial burn wounds. This study aimed to evaluate the effectiveness of DPSC-derived secretome on superficial burn wounds in an animal model. The study employed a post-test-only controlled group design using 15 rats with superficial burns. Rats were divided into a negative control group of 0.9% NaCl (K1), a positive control group of moist-exposed burn ointment or MEBO (K2), and a treatment group of DPSC-secretome (K3). The effectiveness of the DPSC-secretome was assessed by wound area percentage and histopathological observations on days 5, 14, and 21. DPSCsecretome significantly reduced the burn wound area (p<0.05). Histology data showed that the DPSC-secretome promoted re-epithelialization, fibroblasts, and collagen formation. Polymorphonuclear cells were also reduced after 21 days, indicating that the DPSCs-secretome has an anti-inflammatory effect. In addition, the DPSC-secretome and MEBO showed equal effects on angiogenesis after 14 days. The DPSC-secretome was more effective than MEBO on superficial dermal burns. This study showed that the DPSC secretome has therapeutic potential for burn wounds. [ABSTRACT FROM AUTHOR]

Objectives : This study aimed to analyze the efficacy of stem cell-based tissue engineering for the treatment of alveolar cleft (AC) and cleft palate (CP) defects in animal models. Design : Systematic review and meta-analysis. Setting : Preclinical studies on alveolar cleft repair in maxillofacial practice. Patients, Participants : Electronic search was performed using PubMed, Embase, and Cochrane databases. Pre-clinical studies, where stem cell-based tissue engineering was used in the reconstruction of AC and CP in animal models were included. Quality of the selected articles was evaluated using SYRCLE (SYstematic Review Centre for Laboratory animal Experimentation). Interventions : Review of alveolar cleft bone augmentation interventions in preclinical models. Main Outcome Measures : Outcome parameters registered were new bone formation (NBF) and/or bone mineral density (BMD). Results : Thirteen large and twelve small animal studies on AC (21) and CP (4) reconstructions were included. Studies had an unclear-to-high risk of bias. Bone marrow mesenchymal stem cells were the most widely used cell source. Meta-analyses for AC indicated non-significant benefits in favor of: (1) scaffold + cells over scaffold-only (NBF P =.13); and (2) scaffold + cells over empty control (NBF P =.66; BMD P =.31). Interestingly, dog studies using regenerative grafts showed similar to superior bone formation compared to autografts. Meta analysis for the CP group was not possible. Conclusions : AC and CP reconstructions are enhanced by addition of osteogenic cells to biomaterials. Directions and estimates of treatment effect are useful to predict therapeutic efficacy and guide future clinical trials of bone tissue engineering. [ABSTRACT FROM AUTHOR]

ImportanceThe hepatitis C virus (HCV) causes liver disease, affecting millions. Even though we have effective antivirals that cure HCV, they cannot stop terminal liver disease. We used an adult stem cell-derived liver organoid system to understand how HCV infection leads to the progression of terminal liver disease. Here, we show that HCV maintains low-grade infections in liver organoids for the first time. HCV infection in liver organoids leads to transcriptional reprogramming causing cancer cell development and altered immune response. Our finding shows how HCV infection in liver organoids mimics HCV infection and patient pathogenesis. These results reveal that HCV infection in liver organoids contributes to liver disease progression.

Endogenous retroviruses (ERVs) are remnants of ancient parasitic infections and comprise sizable portions of most genomes. Although epigenetic mechanisms silence most ERVs by generating a repressive environment that prevents their expression (heterochromatin), little is known about mechanisms silencing ERVs residing in open regions of the genome (euchromatin). This is particularly important during embryonic development, where induction and repression of distinct classes of ERVs occur in short temporal windows. Here, we demonstrate that transcription-associated RNA degradation by the nuclear RNA exosome and Integrator is a regulatory mechanism that controls the productive transcription of most genes and many ERVs involved in preimplantation development. Disrupting nuclear RNA catabolism promotes dedifferentiation to a totipotent-like state characterized by defects in RNAPII elongation and decreased expression of long genes (gene-length asymmetry). Our results indicate that RNA catabolism is a core regulatory module of gene networks that safeguards RNAPII activity, ERV expression, cell identity, and developmental potency.

IntroductionThe regeneration of pulp tissue is crucial for true regenerative endodontic treatment, which requires a reduction in osteogenic differentiation. Garcinol, a histone acetyltransferase inhibitor, is a natural regulator that is known to suppress the osteogenic differentiation of dental pulp stem cells. In this study, the inhibitory effect of garcinol on the osteogenic differentiation of human dental pulp stem cells (hDPSCs) was evaluated using three-dimensional culture under in vitro and in vivo conditions.MethodshDPSCs were obtained from caries-free third molars and cultured with 10 μM garcinol for 7 days in an ultra-low attachment plate. The cell stemness and expression of osteogenic differentiation-related genes were analyzed using reverse transcription-polymerase chain reaction and single-cell analysis. A transplantation experiment was performed in mice to investigate whether garcinol-treated hDPSCs showed restrained osteogenic differentiation.ResultshDPSCs cultured in the U-shaped ultra-low attachment plate showed the highest expression of stemness-related genes. Garcinol-treated hDPSCs demonstrated downregulation of osteogenic differentiation, with lower expression of bone sialoprotein, which is related to bone formation, and higher expression of dentin sialophosphoprotein, which is related to dentin formation. However, the garcinol-treated hDPSCs did not show any alterations in their stemness. Consistent results were observed in the transplantation experiment in mice.ConclusionsGarcinol reduced the osteogenic differentiation of hDPSCs, which can contribute to true regenerative endodontic treatment.

Abstract Myocardial infarction (MI) is a leading cause of heart failure, disability and mortality worldwide. In this study, the effects of intramyocardial injection of human platelet lysate (HPL), bone marrow mesenchymal stem cells pretreated with HPL (PMSCs), and PMSC lysate (lys), alone and in combination were investigated on MI-induced by LAD ligation in male Wistar rats. The experiment was carried out on sham, vehicle (Veh), HPL, PMSCs, PMSC lysate (PMSC lys), HPL + PMSCs, and HPL + PMSC lys groups. SBP, DBP, and ± dp/dt max were monitored by the PowerLab physiograph. The MSC characteristics and CD31, NKX2.5, and cardiac troponin I (cTnI) contents were determined by flow cytometry, immunohistochemistry, and immunofluorescence, respectively. SBP, DBP, and ± dp/dt max that decreased in the MI group were recovered by HPL, PMSC, PMSC lys, HPL + PMSC, and HPL + PMSC lys treatments. CD31 density was higher in all treated groups compared to the Veh group. CD31 density in the HPL + PMSCs and HPL + PMSC lys groups was higher than in the PMSCs group. The number of Dil+/NKX2.5 + and Dil+/cTnI + cells was higher in the HPL + PMSCs group compared to the PMSCs group. The HPL and PMSCs mitigates heart injuries and cardiac dysfunction after MI. HPL provides an appropriate environment for cardiomyocyte differentiation from PMSCs.

Abstract The intestine, is responsible for food digestion, nutrient absorption, endocrine secretion, food residue excretion, and immune defense. These function performances are based on the intricate composition of intestinal epithelial cells, encompassing differentiated mature cells, rapidly proliferative cells, and intestinal stem cells. Although the characteristics of these cell types are well-documented, in-depth exploration of their representative markers and transcription factors is critical for comprehensive cell fate trajectory analysis. Here, we unveiled the feature genes in different cell types of the human and mouse gut through single-cell RNA sequencing analysis. Further, the locations of some specific transcription factors and membrane proteins were determined by immunofluorescence staining, and their role in regulating the proliferation and differentiation of intestinal epithelial cells were explored by CRISPR/Cas9 knockout. Therefore, this study not only reports new markers for various intestinal epithelial cell types but also elucidates the involvement of relevant genes in the determination of epithelial cell fate and maintenance of stem cell homeostasis, which facilitates the tracing and functional elucidation of intestinal epithelial cells.

Abstract Osteoarthritis (OA) is a chronic degenerative joint condition characterised by cartilage deterioration and changes in bone morphology, resulting in pain and impaired joint mobility. Investigation into the pathophysiological mechanisms underlying OA has highlighted the significance of mitochondrial dysfunction in its progression. Mitochondria, which are cellular organelles, play a crucial role in regulating energy metabolism, generating reactive oxygen species, and facilitating essential biological processes including apoptosis. In recent years, the utilisation of exogenous drugs and MT to improve mitochondrial function in chondrocytes has shown great promise in OA treatment. Numerous studies have investigated the potential of stem cells and extracellular vesicles in mitochondrial transfer. This review aims to explore the underlying mechanisms of mitochondrial dysfunction in OA and assess the progress in utilising mitochondrial transfer as a therapeutic approach for this disease.

Abstract Objective Long non-coding RNAs (lncRNAs) LINC02466 is an lncRNA newly linked to the adverse outcomes in primary liver cancer patients, and its crucial involvement in the disease's escalation. Decoding the specific role of LINC02466 in HCC progression is of great significance to provide a potential therapeutic target for HCC. Methods RT-qPCR and Western Blot techniques was used to analyze the expression levels of LINC02466 in both malignant and surrounding healthy liver tissues. CCK8 assays and colony formation experiments indicates the LINC02466's effect on the proliferation rates of liver cancer cells. Flow cytometry was pivotal in revealing its significant influence on the cell cycle of these cells. Kaplan–Meier survival analysis with log-rank tests were employed. Results The suppression of LINC02466 markedly reduces the stemness attributes of liver cancer cells, indicating a potential therapeutic target. LINC02466 overexpression significantly increased tumor growth rates and final volumes. Further research indicated that LINC02466 significantly influences liver cancer progression through regulating the mTOR signaling pathway. Conclusion LINC02466 regulating cell proliferation, the cell cycle, and stemness characteristics via the mTOR pathway, suggesting LINC02466 as a potential therapeutic target for primary liver cancer.

Abstract Extracellular vesicles (EVs) carry a variety of bioactive molecules and are becoming a promising alternative to cell therapy. Scale-up EV isolation is necessary for their functional studies and biological applications, while the traditional methods are challenged by low throughput, low yield, and potential damage. Herein, we developed an ion osmolarity-driven sequential concentration-enrichment strategy (IOSCE) for the EV isolation. IOSCE is composed of a novel superabsorbent polymers (SAPs) for EV concentration and a charged polymer for EV enrichment. Based on the driving force of ionic osmotic pressure, IOSCE can isolate EVs on a large scale from cell culture medium. The saturated water absorption capacity of IOSCE is 13.62 times higher than that of commercial SAPs. Compared with the ultracentrifugation method, IOSCE exhibited a 2.64 times higher yield (6.33 × 108 particles/mL). Moreover, the mesenchymal stem cell-derived EVs isolated using IOSCE demonstrate strong biological activity and can reduce neuroinflammation by affecting RNA metabolism and translation processes. IOSCE provides a cost-effective, high-throughput, and low-damage method for the scale up EV isolation, which is promising for disease diagnosis and treatment. Graphical Abstract

Abstract Perianal fistulizing Crohn’s disease (CD) is a severe gastrointestinal disorder causing extensive mucosal damage with limited treatment options. Severe manifestations of the disease appear at higher rates in non-Europeans but the genetic and cellular mechanisms driving the disease phenotypes remain poorly understood. Herein, we tested whether pathologic determinants in the epithelial stem cell compartment could be detected at the transcript level in rectal organoids derived from a diverse patient population. Rectal organoid and mucosal cells from endoscopic biopsies of each patient having perianal fistulizing CD or no disease controls were prepared for and sequenced at the single cell level. After cell type annotations based on expressed marker genes, samples were analyzed by principal components, for differential transcript expression, cell type proportions, and pathway enrichment. After QC, we produced 77,044 rectal organoid cells (n = 13 patients; 8 CD, 5 controls) with high quality sequences that identified 10 distinct epithelial subtypes, that we compared to 141,367 mucosal epithelial cells (n = 29 patients; 18 CD, 11 controls). Consistent with mucosal epithelial cells, rectal organoids prominently displayed disease signatures represented by the stem and transit amplifying regions of the rectal crypt, including alterations in transcriptional signatures of metabolic, epigenetic, and proliferating pathways. Organoids also retained their gender- and ancestral-specific gene expression signatures. However, they lacked many of the inflammatory signatures observed in epithelial cells from diseased mucosa. Perianal CD patient derived rectal organoids reflect gene expression signatures related to disease, gender, and ancestry, suggesting they harbor inherent properties amenable to further patient-specific, disease-related experimentation.

Abstract Background Regulatory applications for cell therapy face more objections compared to conventional small molecule or biological drugs, leading to delays in market approval and clinical adoption. Increased regulatory objections frequently relate to issues regarding preclinical evidence, such as experimental design of animal studies, selection of animal models, endpoints, and determination of mechanism of action. Synthesis and clarification of the preclinical evidence necessary to demonstrate treatment efficacy and advance into early-phase clinical trials is needed to help researchers avoid regulatory objections. Methods We conducted a scoping review in which we searched repositories of the International Council for Harmonisation and all national member organizations (N = 38) for documents related to preclinical studies of cell therapies. Active guidance documents related to cell therapy were included, with no restrictions based on the year or language of publication. Data extraction was conducted in duplicate with conflicts resolved through consensus discussion. Results From 1215 identified documents, a total of 182 were included and analyzed, with 71% originating from ten major regulatory agencies. The most prevalent preclinical item addressed was the mechanism of action (n = 161, 88% of documents), underscoring its importance in bridging preclinical findings to clinical application. Most documents (n = 140, 77%) emphasized the importance of using clinically relevant preclinical models, though specific recommendations on models of disease were less common (n = 81, 45%). Selection of clinically relevant intervention parameters (n = 136, 75%) and outcome measures (n = 121, 66%) were also frequently recommended, but selection of relevant comparator groups appeared less frequently (n = 35, 19%). Furthermore, robust study design elements such as randomization and blinding were less frequently recommended, appearing in 31% of documents (n = 57). Comparison with clinical trial guidance revealed a significant gap in the rigor of study design recommendations for preclinical research. Conclusions Regulatory guidance for preclinical efficacy studies often recommends a strong emphasis on the clinical relevance of animal models, intervention parameters, outcomes, and mechanism of action. Incorporating these recommendations into early preclinical studies should improve the acceptability of preclinical evidence for approval by the relevant national regulators and can be used as a guide to ensure that all evidence that regulators say they expect is efficiently assembled into new clinical trial applications.

Yameng Song,1,2 Caiyun Yin,2 Ning Kong1 1Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, People’s Republic of China; 2National Health Commission (NHC) Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, People’s Republic of ChinaCorrespondence: Ning Kong, Email kongning@jlu.edu.cnAbstract: Diabetic retinopathy is one of the complications of diabetes mellitus that occurs in the early stages. It is a disease that has a serious impact, and may lead to blindness when the disease progresses to advanced stages. Currently, treatments for diabetic retinopathy are mainly limited to its advanced stages of the disease, being restricted to a single therapeutic mechanism. Stem cells hold the promise of regenerative therapy and have the potential to comprehensively improve diabetic retinopathy. However, direct stem cell therapy carries some risk of carcinogenesis. Exosomes secreted by stem cells have shown a similar overall improvement in disease as stem cells. Exosomes can carry a number of biologically active materials from donor cells to recipient cells or distant organs, regulating intercellular signaling. Exosomes have shown remarkable efficacy in alleviating oxidative stress, inhibiting inflammatory responses, suppressing angiogenesis, reducing apoptosis and protecting neural tissues. Currently, the experimental literature using stem cell exosomes in the treatment of diabetic retinopathy tends to converge on the above experimental results. With this in mind, we have chosen to explore exosomes in depth from a subtle molecular perspective. We will elaborate on this perspective in this paper and propose to advocate exosome therapy as one promising approach for the treatment of diabetic retinopathy to ameliorate the lesions through multiple mechanisms.Keywords: stem cell, exosomes, diabetic retinopathy, versatile mechanisms, treatment

Abstract Introduction Concentrated Growth Factor (CGF), rich in CD34 + stem cells, is widely used in treatments for androgenetic alopecia and skin rejuvenation due to its immune-modulating properties. Psoriasis, a chronic inflammatory skin condition, presents significant treatment challenges, particularly for patients who cannot use biologics due to conditions such as cancer and lesions resistant to treatments. The potential of CGF in treating psoriasis is promising, given its broad immunoregulatory effects which confirmed in our previous androgenetic alopecia work. Methods We evaluated the impact of CGF on IL-17 levels in two contexts: patients treated for androgenetic alopecia and a psoriasis mouse model. Twelve patients received three monthly injections of CGF, with serum IL-17 levels measured before and after treatment. In the psoriasis mouse model, groups were treated with CGF, and outcomes were assessed using the Psoriasis Area and Severity Index (PASI), skin barrier scores, histological analysis, and RNA sequencing. Additionally, in vitro experiments applied CD34 + cells from CGF to keratinocytes to measure levels of TNF-α, IFN-γ, IL-23, and IL-17. Results In patients with androgenetic alopecia, three monthly CGF injections resulted in significantly reduced serum IL-17 levels. In the psoriatic mouse model, CGF-treated groups exhibited lower PASI scores and improved skin barrier scores compared to controls. Histological analysis revealed enhanced skin characteristics, while RNA sequencing demonstrated downregulated IL-17 and upregulated CD34 expression, as well as improved expression of barrier-related genes. In vitro, the application of CD34 + cells from CGF to keratinocytes led to a significant reduction in TNF-α, IFN-γ, IL-23, and IL-17 levels, indicating strong anti-inflammatory effects. A clinical case of a psoriasis patient unresponsive to IL-23 therapy (Guselkumab) showed significant improvement following CGF treatment. Conclusion These findings indicate that CGF could serve as an effective and versatile treatment for psoriasis, especially for patients who have already undergone biologic therapies but continue to experience resistant lesions.

Abstract Background An ideal aesthetic restorative material should be attached to the tooth tissues by adhesion, have a smooth surface as possible, should not cause toxic reactions in the pulp and discoloration and microleakage. This study aims at comparatively assess the cytotoxicity of current adhesive systems on human dental pulp cells. Materials and methods The adequate density of human pulp cells was observed from the ready cell line. The passaging was performed and the 3rd passage cells were selected. Adhesive systems and MTA were used on the cultures. Trypan blue staining was conducted on the cells at the 1st, 2nd, 3rd days and a count of live and dead cells using a light microscope. The dead cells whose membrane integrity was impaired by staining with trypan blue and the viability rate was determined using live and dead cell numbers. Data analysis was performed using IBM SPSS Statistics 22. Results A significant difference in vialibity rates between adhesive systems was observed on the first day. No significant statistical differences were observed on the 2nd and 3rd days (p

Abstract Background The mitochondria are essential organelles not only providing cellular energy in the form of ATP, but also regulating the inflammatory response and the cell death program. Mitochondrial dysfunction has been associated with various human diseases, including metabolic syndromes as well as inflammatory and neurodegenerative diseases. Acute respiratory distress syndrome (ARDS) is an acute pulmonary disorder characterized by uncontrolled alveolar inflammation, apoptotic lung epithelial/endothelial cells, and pulmonary edema. Despite the high mortality of ARDS, an effective pharmacotherapy to treat this disease has not been established yet. Therefore, identifying a novel targeted therapy for ARDS is important. Recently, exogenous mitochondrial transplantation was reported to be beneficial for treating mitochondrial dysfunction. The current study aimed to investigate the therapeutic effect of mitochondrial transplantation on ARDS in vitro and in vivo. Methods Mitochondria were isolated from human stem cells. For in vitro efficacy of mitochondrial transplantation on the inflammation and cell death, murine alveolar macrophages MH-S and human pulmonary microvascular endothelial cells HPMECs were exposed to LPS, respectively. The ARDS mice model established by a single intratracheal instillation of LPS was used for in vivo efficacy of intravenously treated mitochondria. Results Our results showed that the mitochondria isolated from human stem cells exhibited an anti-inflammatory effect against alveolar macrophages and an anti-apoptotic effect against the alveolar epithelial cells. Furthermore, intravenous mitochondrial treatment was associated with the attenuation of lung injury in the LPS-induced ARDS mice. Conclusion Dual effects of mitochondria on anti-inflammation and anti-apoptosis support the potential of mitochondrial transplantation as a novel therapeutic strategy for ARDS.

Abstract Background There has been a significant surge in animal studies of stem cell-derived extracellular vesicles (EVs) therapy for the treatment of premature ovarian failure (POF) but its efficacy remains unknown and a comprehensive and up-to-date meta-analysis is lacking. Before clinical translation, it is crucial to thoroughly understand the overall impact of stem cell-derived EVs on POF. Methods PubMed, EMBASE, Cochrane Library, Web of Science were searched up to February 18, 2024. The risk of bias was evaluated according to Cochrane Handbook criteria, while quality of evidence was assessed using the SYRCLE system. The PRISMA guidance was followed. Trial sequential analysis was conducted to assess outcomes, and sensitivity analysis and publication bias analysis were performed using Stata 14. Results Data from 25 studies involving 339 animals were extracted and analyzed. The analysis revealed significant findings: stem cell-derived EVs increase ovary weight (SMD = 3.88; 95% CI: 2.50 ~ 5.25; P

To mediate critical host-microbe interactions in the human small intestine, Paneth cells constitutively produce abundant levels of α-defensins and other antimicrobials. We report that the expression profile of these antimicrobials is dramatically askew in human small intestinal organoids (enteroids) as compared to that in paired tissue from which they are derived, with a reduction of α-defensins to nearly undetectable levels. Murine enteroids, however, recapitulate the expression profile of Paneth cell α-defensins seen in tissue. WNT/TCF signaling has been found to be instrumental in the regulation of α-defensins, yet in human enteroids exogenous stimulation of WNT signaling appears insufficient to rescue α-defensin expression. By stark contrast, forkhead box O (FOXO) inhibitor AS1842856 induced the expression of α-defensin mRNA in enteroids by >100,000-fold, restoring DEFA5 and DEFA6 to levels comparable to those found in primary human tissue. These results newly identify FOXO signaling as a pathway of biological and potentially therapeutic relevance for the regulation of human Paneth cell α-defensins in health and disease.

Ischemic stroke is a leading cause of death and disability worldwide, with an increasing trend and tendency for onset at a younger age. China, in particular, bears a high burden of stroke cases. In recent years, the inflammatory response after stroke has become a research hotspot: understanding the role of inflammatory response in tissue damage and repair following ischemic stroke is an important direction for its treatment. This review summarizes several major cells involved in the inflammatory response following ischemic stroke, including microglia, neutrophils, monocytes, lymphocytes, and astrocytes. Additionally, we have also highlighted the recent progress in various treatments for ischemic stroke, particularly in the field of stem cell therapy. Overall, understanding the complex interactions between inflammation and ischemic stroke can provide valuable insights for developing treatment strategies and improving patient outcomes. Stem cell therapy may potentially become an important component of ischemic stroke treatment.

BACKGROUND: Magnetic nanomaterials have biological activities such as promoting osteogenic differentiation of stem cells and inhibiting osteoclast formation, and can effectively promote the healing of injured bone tissue under the synergistic effect of magnetic fields. They have a very broad application prospect in bone injury repair. OBJECTIVE: To review the mechanism of magnetic nanomaterials and magnetic fields promoting bone repair, as well as their research progress in the field of bone injury repair. METHODS: Relevant literature search was conducted in PubMed and Web of Science databases with the search terms "magnetic nanomaterials, magnetic field, bone repair, bone tissue engineering, stem cell, osteoblast, osteoclast." The time limit of literature search was from 2003 to 2023, which was screened and analyzed. Some classic articles were manually retrieved, and 98 articles were finally included for RESULTS AND CONCLUSION: (1) Magnetic nanomaterials have biological effects such as promoting osteoblast differentiation, inhibiting osteoclast formation and regulating the immune microenvironment. In addition, magnetic nanomaterials can regulate the physicochemical properties of tissue engineering scaffolds, such as mechanical properties and surface morphology, and endowed with magnetic properties, which is conducive to the regulation of the adhesion, proliferation and osteogenic differentiation of stem cells. (2) The magnetic field has the ability to regulate multiple cell signaling pathways to promote osteoblast differentiation, inhibit osteoclast formation, stimulate angiogenesis and other biological effects, thus accelerating the healing of damaged bone tissue. (3) The joint application of magnetic nanomaterials and magnetic field accelerates the repair of bone damage by activating mechanotransduction, increasing the content of intracellular magnetic nanoparticles, and enhancing the effect of micro-magnetic field, which provides a new idea for the research of bone tissue engineering. (4) Magnetic field has demonstrated definite efficacy in the treatment of clinical fractures, osteoporosis, and osteoarthritis diseases, which is beneficial for bone tissue growth, reducing bone loss, alleviating pain, and improving the quality of life of patients. (5) Magnetic nanomaterials and magnetic fields have great potential for application in bone damage repair and regeneration, but the interaction mechanism between magnetic nanomaterials, magnetic fields, and cells has not been fully elucidated. Moreover, the key parameters of magnetic fields that regulate intracellular molecular events, including the type, intensity, frequency, duration, and mode of the magnetic field, as well as the precise biological effects of a specific magnetic field on osteoblasts and the underlying mechanisms, have yet to be defined. (6) Further attention needs to be paid to the effects on osteoclasts, nerves, blood vessels, and immune cells in the microenvironment of damaged tissues. Finally, the safety of magnetic materials for human use is yet to be systematically studied in terms of their distribution, metabolism, and acute and chronic toxicities. [ABSTRACT FROM AUTHOR]

BACKGROUND: 3D organoids have characteristics that resemble physiological tissues and to some extent mimic organ function, making them excellent models for applications ranging from basic development/stem cell research to personalized medicine. OBJECTIVE: To review and discuss the types of diseases and application areas such as tumor modeling that organoids can be applied to, as well as their regulatory status and challenges. METHODS: With “organoid, stem cell, disease model, 3D printing technology, medical field” as Chinese and English search terms, we searched PubMed, Elsevier, WanFang, and CNKI databases to summarize and analyze organoid products at home and abroad, summarize the application of organoid technology in the medical field, and prospect the future development of organoid products in the medical field. RESULTS AND CONCLUSION: Organoids can break the limitations of traditional cell and animal models, avoid the ethical problems existing in clinical research, and have a high similarity to the source organ, a more similar performance to the physiology and pathology of human systems, and genetic stability, which has great advantages in current research. Organoids have been applied in the following fields: efficacy evaluation studies (preclinical models), including intestinal organoids, kidney organoids, liver organoids, gallbladder organoids, lung organoids, brain organoids, heart organoids, skin organoids, and reproductive system organoids; research on infectious diseases; cancer research and precision therapy; regenerative medicine; immune organoids. Although the United States, the European Union and China do not have perfect regulatory provisions, they are trying to promote the formulation of organoid regulatory laws and regulations. In China, although no organoid medical device products have been listed for the time being, its related regenerative medicine products have made breakthroughs. [ABSTRACT FROM AUTHOR]

BACKGROUND: The small-diameter blood vessel prosthesis faces the problem of lumen stenosis or even occlusion due to thrombogenesis and intimal hyperplasia after transplantation. The application of stem cells as seed cells to achieve endothelialization of blood vessel prosthesis helps to improve the long-term patency rate after vascular graft transplantation. OBJECTIVE: To summarize the research progress of the application of stem cells in the endothelialization of small-diameter blood vessel prosthesis. METHODS: The relevant articles published on PubMed and WanFang databases from 2013 to 2023 were retrieved by the first author. Chinese and English search terms included “vascular graft, tissue-engineered blood vessel/vascular tissue engineering, endothelialization, stem cells, endothelial progenitor cells, mesenchymal stem cells, induced pluripotent stem cells, embryonic stem cells.” The relative articles in the domestic and overseas about the application of stem cells in the endothelialization of small-diameter blood vessel prosthesis in the past 10 years were retrieved. A total of 552 articles were initially found and we finally selected 81 articles to review according to inclusion and exclusion criteria. RESULTS AND CONCLUSION: (1) The low long-term patency rate restricts the application of small-diameter blood vessel prosthesis in clinic. The main causes of low long-term patency rate are thrombogenesis and intimal hyperplasia. The endothelium of native vessels has the function of anti-thrombogenesis and intimal hyperplasia. Endothelialization can simulate the function of native vessels, which is an effective way to improve long-term patency rate. (2) The small-diameter blood vessel prosthesis will undergo in vivo endothelialization after being implanted, but it is difficult to form complete endothelium. Stem cells have the potential to differentiate into endothelial cells. Recruiting stem cells in vivo or seeding them on the inner surface of blood vessel prosthesis in vitro is research strategy to achieve endothelialization. (3) The long-term patency rate of small-diameter blood vessel prosthesis has been improved to a certain extent through seeding endothelial progenitor cells, mesenchymal stem cells, induced pluripotent stem cells, and embryonic stem cells. Each has its own advantages. Endothelial progenitor cells are easy to obtain and can be directly used for seeding. Mesenchymal stem cells come from a wide range of sources and have the function of paracrine and immunological regulation. Induced pluripotent stem cells are rich in sources and the immunogenicity can be eliminated. Embryonic stem cells have a strong proliferative ability and can differentiate into many cells. (4) The application of stem cells in blood vessel prosthesis has not yet been transformed into clinic. Further researches are needed to promote clinical translation. [ABSTRACT FROM AUTHOR]

Skin flaps are tissue transferred from a donor to a recipient site to fill covering defects in the surface of the body. During transfer, skin flaps are severely predisposed to ischemia not only due to ischemia but also to ischemia--reperfusion (I/R) injury, a paradoxical exacerbation of cellular death following blood flow restoration in tissues exposed to ischemic insults. This systematic review aimed to report the in vivo outcomes of the application of stem cell-derived conditioned medium (secretome) or its derivatives toward skin flap following I/R injury in experimental studies. This study was a systematic review with literature searched using Science Direct, PubMed, Directory of Open Access Journal, Cochrane Central, Clinicaltrials.gov, and Europe PMC on January 24, 2024, for studies reporting the effects of stem cell-derived conditioned medium (secretome) or its derivatives in the skin flap I/R injury in animal models. We obtained a total of 318 studies during the search, which were then screened. Ten studies were included in the review. Our study found that stem cell-conditioned medium increases overall flap survivability; promotes vascularization, perfusion, and angiogenesis; reduces inflammation, reduces apoptosis and oxidants; and increases collagen secretion and maturation. The effect was found to be even more profound when the stem cells were set to proliferate under hypoxic conditions. Secretome did not only exhibit prosurvival and proproliferation properties suitable for responding to ischemic insults but also anti-inflammatory and antiapoptotic properties suitable for responding to I/R injury. Furthermore, secretome also assisted native structure recovery. The results from the experimental studies found that secretome is a promising therapy to increase flap survivability when also promoting histology recovery. [ABSTRACT FROM AUTHOR]

Background: Lower lip avulsion is separation between lip and the associated soft tissue from the mandible. The degree of these type of injuries are varies and heavily affect the outcome of the case. Case Description: This study reported an extensive lower lip avulsion managed by surgery and stem cell metabolites preparation. A 1 year 9 month-old domestic cat was referred for lower lip avulsion surgery to the Veterinary Teaching Hospital Airlangga University. Owing to the limited amount of tissue, immediate successful result cannot be achieved after the first surgery. Furthermore, tissue necrosis and lack of physical restrain to the cat at home contributed in the delayed union between the soft tissue and mandible, resulting in repeated surgery. Stem cell metabolites preparation was applied at the surgical site and was incorporated to the therapy to support tissue growth. Conclusion: The combination of surgical treatment and stem cell metabolites preparation resulted in good wound healing in the present case. [Open Vet J 2024; 14(8.000): 2092-2096]

Background. The purpose of the present study was to investigate the effect of aerobic-resistance training on the population of cardiac multipotent cells, thickness, and diameter of the ventricular through the C-Kit pathway of male rats during the growth stages. Methods. Overall, 30 male Wistar rats in three age groups of 2 (n = 10), 8 (n = 10), and 96 (n = 10) weeks were accidentally divided into exercise and control groups. Resistance training programs (resistance ladder, 3 days a week) and aerobics (treadmill running, 3 days a week) were performed for 6 weeks. Hematoxylin-Eosin staining was done the heart tissue and histological images were prepared. Afterward, C-Kit gene expression was examined by the real-time polymerase chain reaction method. The statistical method of one-way analysis of variance (P ≥ 0.05) and Tukey’s test were used at a significant level (P ≥ 0.01). Results. The trained neonatal group had higher values in heart weight to body weight index, and the trained neonatal and trained young adult groups had higher values in left ventricular thickness (P ≥ 0.01). The decrease in left ventricular internal diameter in the trained young adult group was significant compared to the control group (P ≥ 0.01). There was a significant increase in C-Kit gene expression in trained young adult and trained old groups (P ≥ 0.01). Conclusion. Aerobic-resistance training can be an effective stimulus for increasing the number of cardiac stem cells and creating structural adaptations of the heart, including increasing thickness and ventricular diameter in neonatal and young adult groups. Practical Implications. Participation in aerobic-resistance training programs leads to the improvement of the cardiac structure and an increase in cardiac stem cells.

Anal fistula can be a challenging condition to manage, with complex fistulas presenting even greater difficulties. The primary concerns in treating this condition are a risk of damage to the anal sphincters, which can compromise fecal continence, and refractoriness to treatment, as evidenced by a high recurrence rate. Furthermore, the treatment of complex anal fistula involves several additional challenges. Satisfactory solutions to many of these obstacles remain elusive, and no consensus has been established regarding the available treatment options. In summary, complex anal fistula has no established gold-standard treatment, and the quest for effective therapies continues. This review discusses and highlights groundbreaking advances in the management of complex anal fistula over the past decade.

Abstract Stem cell-derived exosomes exert comparable therapeutic effects to those of their parental stem cells without causing immunogenic, tumorigenic, and ethical disadvantages. Their therapeutic advantages are manifested in the management of a broad spectrum of diseases, and their dosing versatility are exemplified by systemic administration and local delivery. Furthermore, the activation and regulation of various signaling cascades have provided foundation for the claimed curative effects of exosomal therapy. Unlike other relevant reviews focusing on the upstream aspects (e.g., yield, isolation, modification), and downstream aspects (e.g. phenotypic changes, tissue response, cellular behavior) of stem cell-derived exosome therapy, this unique review endeavors to focus on various affected signaling pathways. After meticulous dissection of relevant literature from the past five years, we present this comprehensive, up-to-date, disease-specific, and pathway-oriented review. Exosomes sourced from various types of stem cells can regulate major signaling pathways (e.g., the PTEN/PI3K/Akt/mTOR, NF-κB, TGF-β, HIF-1α, Wnt, MAPK, JAK-STAT, Hippo, and Notch signaling cascades) and minor pathways during the treatment of numerous diseases encountered in orthopedic surgery, neurosurgery, cardiothoracic surgery, plastic surgery, general surgery, and other specialties. We provide a novel perspective in future exosome research through bridging the gap between signaling pathways and surgical indications when designing further preclinical studies and clinical trials.

Abstract The liver is the most important metabolic organ in the body. While mouse models and cell lines have further deepened our understanding of liver biology and related diseases, they are flawed in replicating key aspects of human liver tissue, particularly its complex structure and metabolic functions. The organoid model represents a major breakthrough in cell biology that revolutionized biomedical research. Organoids are in vitro three-dimensional (3D) physiological structures that recapitulate the morphological and functional characteristics of tissues in vivo, and have significant advantages over traditional cell culture methods. In this review, we discuss the generation strategies and current advances in the field focusing on their application in regenerative medicine, drug discovery and modeling diseases.

Abstract Background Cancer stem cells (CSCs) are critical factors that limit the effectiveness of gastric cancer (GC) therapy. Circular RNAs (circRNAs) are confirmed as important regulators of many cancers. However, their role in regulating CSC-like properties of GC remains largely unknown. Our study aimed to investigate the role of circUBA2 in CSC maintenance and the underlying mechanisms. Methods We identified circUBA2 as an upregulated gene using circRNA microarray analysis. qRT-PCR was used to examine the circUBA2 levels in normal and GC tissues. In vitro and in vivo functional assays were performed to validate the role of circUBA2 in proliferation, migration, metastasis and CSC-like properties of GC cell. The relationship between circUBA2, miR-144-5p and STC1 was characterised using bioinformatics analysis, a dual fluorescence reporter system, FISH, and RIP assays. Results CircUBA2 expression was significantly increased in GC tissues, and patients with GC with high circUBA2 expression had a poor prognosis. CircUBA2 enhances CSC-like properties of GC, thereby promoting cell proliferation, migration, and metastasis. Mechanistically, circUBA2 promoted GC malignancy and CSC-like properties by acting as a sponge for miR-144-5p to upregulate STC1 expression and further activate the IL-6/JAK2/STAT3 signaling pathway. More importantly, the ability of circUBA2 to enhance CSC-like properties was inhibited by tocilizumab, a humanised Interleukin-6 receptor (IL-6R) antibody. Thus, circUBA2 knockdown and tocilizumab synergistically inhibited CSC-like properties. Conclusions Our study demonstrated the critical role of circUBA2 in regulating CSC-like properties in GC. CircUBA2 may be a promising prognostic biomarker for GC. Graphical Abstract

Abstract The hallmarks of stem cells, such as proliferation, self-renewal, development, differentiation, and regeneration, are critical to maintain stem cell identity which is sustained by genetic and epigenetic factors. Super-enhancers (SEs), which consist of clusters of active enhancers, play a central role in maintaining stemness hallmarks by specifically transcriptional model. The SE-navigated transcriptional complex, including SEs, non-coding RNAs, master transcriptional factors, Mediators and other co-activators, forms phase-separated condensates, which offers a toggle for directing diverse stem cell fate. With the burgeoning technologies of multiple-omics applied to examine different aspects of SE, we firstly raise the concept of “super-enhancer omics”, inextricably linking to Pan-omics. In the review, we discuss the spatiotemporal organization and concepts of SEs, and describe links between SE-navigated transcriptional complex and stem cell features, such as stem cell identity, self-renewal, pluripotency, differentiation and development. We also elucidate the mechanism of stemness and oncogenic SEs modulating cancer stem cells via genomic and epigenetic alterations hijack in cancer stem cell. Additionally, we discuss the potential of targeting components of the SE complex using small molecule compounds, genome editing, and antisense oligonucleotides to treat SE-associated organ dysfunction and diseases, including cancer. This review also provides insights into the future of stem cell research through the paradigm of SEs.

Intestinal stem cells are regulated by the intestinal nervous system, and both of them are closely related to intestinal inflammation. Relevant studies have shown the existence of intestinal nerve dysfunction in intestinal inflammation. By summarizing the relationship among intestinal stem cells, intestinal nervous system and intestinal inflammation, this paper discusses that intestinal nervous system injury related to intestinal inflammation may be the basis for persistent alteration of intestinal function, while enteric neurons provide feasible targets for improving intestinal nerve dysfunction in inflammatory bowel diseases, so as to apply various types of stem cells to the improvement of intestinal nerve dysfunction in intestinal inflammation.

Banking of umbilical cord blood (UCB) is performed to collect and store umbilical cord stem cells. Both public and private cord blood banks have been established around the world. The study aimed to determine the level of awareness of UCB banking among pregnant couples and to assess the attitude of the couples toward UCB banking. We also tried to explore the factors influencing the UCB banking donation and the couple’s expectations of UCB banking in the future. A prevalidated questionnaire on UCB banking was administered, and the interview was conducted among the same pregnant couples (both husband and wife) attending the obstetrics and gynecology (OBG) outpatient department (OPD). Only 28% (N = 121) of the participants had heard of UCB banking, and only 12% had correct knowledge of UCB banking. Only 4.9% of participants had heard of public or private UCB banks. Only one couple of 121 has stored UCB in their previous pregnancy, and about 36% of couples were willing to store their newborn’s UCB in the present pregnancy. Poor understanding continues to be a significant barrier to reaping the benefits of UCB and preservation. Obstetricians and pediatricians should take a more active role in educating patients about the benefits and drawbacks of UCB banking.

Abstract Objectives This study aimed to characterize incidences of CMV reactivations within one year post-allo-SCT and identify risk factors for CMV second reactivation episode in population with high seropositivity where first CMV reactivation episode deemed to be high. Methods This retrospective cohort study analyzed data from 359 allo-SCT patients aged 14 and older admitted to a tertiary academic hospital. Data on demographic and clinical factors, CMV serostatus, conditioning regimens, graft-versus-host disease prophylaxis, engraftment time, and CMV reactivations were collected. Results First and second CMV reactivations occurred in 88.9% and 18.4% of post-allo-SCT patients respectively. Patients were stratified into two groups based on primary disease necessitating allo-SCT, patients with malignant (Group 1) and non-malignant (Group 2) hematological disease. Factors associated with the second reactivation included cord blood as a stem cell source, human leukocyte antigen mismatch, acute graft-versus-host disease, and hematological malignancies. Patients with non-malignant hematological disease displayed better outcomes, including a higher rate of spontaneous clearance of first CMV reactivation (70% versus 49.4%) and lower rates of second CMV reactivation (9.6% versus 31%) than those with malignant hematological disease. The one-year overall survival rate was 87.7% (95.5% in non-malignant hematological disease and 78.13% in malignant hematological disease). Conclusion Our findings are concordant with previous local study in regard to high rate of first CMV reactivation post-allo-SCT. It appears that patients with nonmalignant hematological disease had better outcomes, such as lower second CMV reactivation and higher survival rates compared to patients with malignant hematological disease. Further investigation is needed to identify other factors affecting recurrent CMV reactivations in allo-SCT in patients with malignant hematological disease.

Abstract In order to survive and replicate, Salmonella has evolved mechanisms to gain access to intestinal epithelial cells of the crypt. However, the impact of Salmonella Typhimurium on stem cells and progenitors, which are responsible for the ability of the intestinal epithelium to renew and protect itself, remains unclear. Given that intestinal organoids growth is sustained by stem cells and progenitors activity, we have used this model to document the effects of Salmonella Typhimurium infection on epithelial proliferation and differentiation, and compared it to an in vivo model of Salmonella infection in mice. Among gut segments, the caecum was preferentially targeted by Salmonella. Analysis of infected crypts and organoids demonstrated increased length and size, respectively. mRNA transcription profiles of infected crypts and organoids pointed to upregulated EGFR-dependent signals, associated with a decrease in secretory cell lineage differentiation. To conclude, we show that organoids are suited to mimic the impact of Salmonella on stem cells and progenitors cells, carrying a great potential to drastically reduce the use of animals for scientific studies on that topic. In both models, the EGFR pathway, crucial to stem cells and progenitors proliferation and differentiation, is dysregulated by Salmonella, suggesting that repeated infections might have consequences on crypt integrity and further oncogenesis.

The effective treatment of various diseases requires not only medications but also precise delivery methods to the body and specific organs. In this regard, radiology plays a crucial role, acting as the eyes of physicians. In contrast, interventional radiology serves as its hands, acting as one of the most effective drug delivery systems. Among interventional radiology disciplines, arterial drug delivery through arteries holds paramount importance as organs primarily receive nourishment directly from them. Furthermore, regenerative medicine is a burgeoning field dedicated to repairing diverse body tissues without relying on pharmaceutical drugs. Stem cells, inherent in various parts of our bodies, are vital for tissue regeneration and reconstruction. Depending on the treatment approach, stem cells can be sourced from the patient's body (autologous) or another individual (allogeneic). There exist various types of stem cells across species, with regenerative properties observed in animals and even plants. However, targeted cell therapy is preferred over systematic injections throughout the body for better efficacy. This article aims to familiarize interventionalists with stem cells and provide them with a clear and helpful explanation of their functions, mechanisms of action, different sources, and other relevant aspects. This will help them select the most appropriate cells for their therapeutic purposes. By comprehensively understanding the significance of stem cells in interventional radiology, we can implement optimal methodologies to address diverse medical conditions efficiently.

Owing to the rapid increase in the number of people with severe heart failure, regenerative medicine is anticipated to play a role in overcoming the limitations inherent in existing surgical interventions. There are essentially two types of cardiac regenerative therapies for a failing heart. Cellular regenerative therapies using various stem cells improve the functional recovery of the heart mainly by cytokine paracrine effects. The implantation of induced pluripotent stem cell–derived cardiomyocytes can contribute not only to the inhibition of adverse heart remodeling by paracrine effects but also to the supply of newly born functional myocytes with the recipient myocardium as “mechanically working cells.” Cell transplantation, including autologous myoblast transplantation, reduces heart failure exacerbations and benefits patients without the need for other treatment options. Although cellular therapy is currently the mainstream approach, it requires an in-house cell-processing center with an aseptic environment. In addition, these stem cells are usually introduced via several invasive delivery methods, including intracoronary administration, and cellular sheet implantation. Simplifying the culture methods for these cells is a crucial problem that needs to be resolved.Drug-induced regenerative therapy is another option that enhances self-endogenous regenerative systems in the human body and does not require invasive methods or cell cultures. Therefore, drug-induced regenerative therapies may overcome the disadvantages of these cellular therapies. The purpose of this report is to summarize cell transplantation therapy in the cardiovascular system and regenerative therapy for heart failure using an autologous endogenous regenerative system.

The 24th and 19th International Congresses on Reproduction and Stem Cell Biology in the Islamic Republic of Iran broughttogether experts and researchers worldwide to explore the latest advancements in these fields. Different topics werediscussed, including such as reproductive health, infertility treatments, stem cell research, and regenerative medicine.This report provides a summary of the congress’s key findings by emphasizing pioneer research and technologies thatcan influence the future of reproduction and stem cell biology programs. The presence of keynote speakers such asProfessor Nicolas Rivron, Mohammad Ebrahim Parsanezhad, Ashraf Moini, Abbas Aflatoonian, Hadi Shafiee, AnnaBrini, Omid Camron Farokhzad, and Jeffrey Schweitzer added value to the event, which had over 1100 participantsfrom around the world. While foreign speakers were from various countries Iranian speakers mainly came from Tabriz,Isfahan, Shiraz, Babol, and Tehran that all discussed cutting-edge science and successful disease treatments. Toensure a more comprehensive representation, it is suggested that a wider geographic distribution of national andforeign speakers should be considered in future plan.

Abstract Our research endeavors are directed towards unraveling the stem cell characteristics of lower-grade glioma patients, with the ultimate goal of formulating personalized treatment strategies. We computed enrichment stemness scores and performed consensus clustering to categorize phenotypes. Subsequently, we constructed a prognostic risk model using weighted gene correlation network analysis (WGCNA), random survival forest regression analysis as well as full subset regression analysis. To validate the expression differences of key genes, we employed experimental methods such as quantitative Polymerase Chain Reaction (qPCR) and assessed cell line proliferation, migration, and invasion. Three subtypes were assigned to patients diagnosed with LGG. Notably, Cluster 2 (C2), exhibiting the poorest survival outcomes, manifested characteristics indicative of the subtype characterized by immunosuppression. This was marked by elevated levels of M1 macrophages, activated mast cells, along with higher immune and stromal scores. Four hub genes—CDCA8, ORC1, DLGAP5, and SMC4—were identified and validated through cell experiments and qPCR. Subsequently, these validated genes were utilized to construct a stemness risk signature. Which revealed that Lower-Grade Glioma (LGG) patients with lower scores were more inclined to demonstrate favorable responses to immune therapy. Our study illuminates the stemness characteristics of gliomas, which lays the foundation for developing therapeutic approaches targeting CSCs and enhancing the efficacy of current immunotherapies. By identifying the stemness subtype and its correlation with prognosis and TME patterns in glioma patients, we aim to advance the development of personalized treatments, enhancing the ability to predict and improve overall patient prognosis.