Stem Cells Translational Medicine最新文献

Human-induced pluripotent stem cell (hiPSC) technologies have provided access to in vitro models of inaccessible human cardiomyocytes (CMs), providing new insights into human disease mechanisms, therapy strategies, and cardiac toxicology. However, the robustness of reproducible outcomes and integration of data among research groups are hampered due to the variation between cell lines, clones, and batches-to-batch differences. These variable outcomes in hiPSC models are caused by differences in human donors, genetic stability, and experimental variability, which affect morphology, cellular heterogeneity, transcript and protein abundance, and differentiation potency. This review summarizes the usage of hiPSC-CMs obtained from multiple lines and evaluates the corresponding experimental variation between studies to perform in-depth in vitro power calculations. Our meta-analyses show that although 4 or more hiPSC lines are used in 21 published case-control studies, these reports still contain high heterogeneity between functional parameters. In specific CM readouts, the SD is >40%, meaning that the variation between different cell lines is larger than the effect of the studied mutation, drug response, or toxicity. Results indicate a need for careful selection of hiPSC lines, controls, and readout stability and these insights will further guide the power of hiPSC lines in biomedical applications.

Objective: This meta-analysis comprehensively evaluates the therapeutic efficacy and mechanisms of mesenchymal stem cells (MSCs) and their exosomes in rodent models of hepatic ischemia-reperfusion injury (HIRI), providing preclinical support for future clinical translation.

Methods: In accordance with the PRISMA guidelines, we systematically searched PubMed, Web of Science, Embase, Cochrane Library, and ClinicalTrials.gov for studies published from inception to January 13, 2025, and identified 64 eligible studies. Risk of bias was evaluated using the SYRCLE tool, and Review Manager 5.4.1 was employed for meta-analysis, calculating SMD and 95%CI. Primary outcomes included liver function (ALT/AST), histopathological scores (Suzuki's score, necrotic area ratio), inflammatory cytokines (TNF-α), and apoptosis markers (c-caspase 3).

Results: MSCs and their exosomes significantly ameliorated HIRI. In the 60-minute ischemia group, ALT (SMD = 3.49, P < .00001) and AST (SMD = 3.86, P < .00001) decreased, along with lower Suzuki scores (SMD = 3.12), necrotic area ratios (SMD = 3.56), and TNF-α levels (SMD = 2.83). In the 90-minute group, ALT (SMD = 4.09, P < .00001) and AST (SMD = 3.78, P < .00001) were also reduced. Mechanistically, MSCs exert therapeutic effects through antioxidative, anti-inflammatory, anti-apoptotic, and pro-regenerative pathways. Considerable heterogeneity (I2 = 52-86%) was observed, likely due to variations in dosage (1 × 105-1 × 109 cells), administration routes (intravenous/portal vein), and reperfusion durations (3-24 hours). Genetic modifications (e.g., HO-1 overexpression) further enhanced therapeutic outcomes.

Conclusion: MSCs and their exosomes mitigate HIRI through multi-target mechanisms but requires standardized protocols. Future studies should prioritize large-animal validation and translational research to facilitate precision clinical application.

Cardiovascular diseases, particularly myocardial infarction, remain a leading cause of mortality globally, primarily due to the adult heart's limited regenerative capacity. Recent discoveries have highlighted the epicardium, a mesothelial layer surrounding the heart, as a critical player in cardiac repair and regeneration. During development, the epicardium plays a central role in heart formation by providing progenitor cells, structural components, and paracrine signals. Emerging evidence indicates that this developmental potential can be reactivated in the adult heart following injury. Upon activation, epicardial cells undergo epithelial-to-mesenchymal transition, proliferate, and secrete a range of paracrine factors that influence angiogenesis, inflammation resolution, and extracellular matrix remodeling. This review explores the mechanisms underlying epicardial activation, its contributions to heart development and myocardial repair, and its therapeutic potential. We discuss small molecule modulators, gene therapy, cellular therapies, and biomaterial-based approaches that aim to harness the regenerative capacity of the epicardium. These approaches, which move beyond scar tissue formation to possible regeneration, have the potential to transform the landscape of cardiac regenerative medicine. Despite promising preclinical results, however, challenges such as interindividual variability, incomplete differentiation of epicardial-derived cells, and delivery constraints must be addressed. Advances in single-cell technologies, biomaterial engineering, and translational research are paving the way for personalized and effective epicardium-based therapies. By redefining the role of the epicardium in cardiac biology, epicardial activation offers a novel paradigm for treating ischemic heart disease and heart failure.

Background: Clinical application of mesenchymal stromal cells (MSCs) for cartilage regeneration has been hampered by their poor retention of chondrogenic potential during in vitro culture, which has led to highly variable cartilage repair outcomes. Consequently, there is an urgent need for a reliable assay to predict MSC chondrogenic potential during cell manufacturing.

Methods: In this study, we developed a nondestructive MSCs iron flux monitoring methodology using spent culture media, utilizing micromagnetic resonance relaxometry (µMRR). We demonstrated that the dynamics of iron uptake and release by MSCs in culture can be reliably inferred from iron concentration changes in culture medium, with an unprecedented temporal resolution (<1 hour).

Results: Analysis of 3 MSC donors across 6 independent culture batches revealed a significant correlation between iron homeostasis (iron flux during culture) and chondrogenic differentiation outcomes, while a departure from iron homeostasis (significant iron uptake and accumulation) was correlated with impaired chondrogenesis. By contrast, cell proliferation, although essential for manufacturing to achieve sufficient cell numbers, did not reliably correlate with chondrogenic capacity. Furthermore, ascorbic acid supplementation during culture, which is known to promote MSCs proliferation and chondrogenic quality, regulated iron homeostasis by limiting iron flux.

Conclusion: Our findings identify iron homeostasis as a potential chondrogenic-associated critical quality attribute of MSCs. This rapid, nondestructive monitoring strategy offers a promising approach to improve manufacturing efficiency and consistency by providing real-time insight into cellular iron flux. In addition, the methodology here impacts broader iron biology by providing a time-resolved iron flux measurement that is not currently available.

Pelvic radiotherapy can lead to loss of bladder compliance, detrusor overactivity, and superficial vascular proliferation. Animal studies have demonstrated a reduction in radiation-induced inflammation and fibrosis following administration of mesenchymal stem cell products. We performed a first-in-human pilot study to assess the safety and feasibility of intravesical adipose stromal vascular fraction injection in an 82-year-old man with a history of brachytherapy for prostate cancer. Following FDA and IRB approval, subcutaneous adipose tissue harvested under local anesthesia was immediately processed using the SVF-2 device (GID Bio). The cell product, consisting of 4.58 × 107 stromal vascular fraction cells resuspended in 20 cc/s of lactated ringers, was injected into the bladder wall using a flexible cystoscope. Urinary symptoms, urologic flow parameters, repeat cystoscopy with bladder biopsy, and MRI were employed during the 16-month follow-up period. There were no postprocedural complications. The patient reported expected symptoms of self-limited dysuria, hematuria, and flank bruising in the 2 weeks following the procedure. Urinary symptoms and flow parameters remained stable for 6 months but progressed slightly at 15 months. A repeat cystoscopy with biopsy showed stabilization of disease without concern for secondary malignancy. The patient's 12-month postprocedural MRI and 15-month urodynamics study were unchanged from prior. This study demonstrates the safety and feasibility of adipose harvest under local anesthesia, followed by point-of-care isolation and administration of an adipose-derived cell product via cystoscopic-guided intravesical injection. This pilot is foundational for further clinical studies to elucidate effective dosing and patient selection in the treatment of bladder fibrosis with cell therapy.

Specifically differentiated cells exhibit greater therapeutic efficacy than mesenchymal stem cells (MSCs), and extracellular vesicles (EVs) present therapeutic benefits similar to those of parental cells and fewer safety issues. Ovarian granulosa cells (OGCs) play a critical role in the pathogenesis of premature ovarian insufficiency (POI), a common gynecological disease that can cause infertility and has no effective treatment. Here, we investigated whether umbilical cord mesenchymal stem cells (UCMSCs) can differentiate into ovarian granulosa-like cells (GLCs) and whether GLC-EVs are more effective in restoring ovarian function than UCMSC-EVs are in POI model rats. Here, we differentiated rat UCMSCs (rUCMSCs) into GLCs in vitro using cytokines and hormones and isolated GLC-EVs. We then used chemotherapy-induced POI model rats to verify the ability of GLC-EVs to repair ovarian function. We found that GLCs/GLCs-EVs expressed granulosa cell markers (FOXL2 and FSHR). We demonstrated that GLC-EVs outperformed rUCMSC-EVs by restoring the estrous cycle and ovarian morphology, increasing the number of follicles, regulating serum hormone levels, and restoring fertility in POI model rats. Mechanistically, GLC-EVs showed enhanced ovarian tropism. Proteomic analysis identified PLAU as a key component of GLC-EVs, and subsequent antibody blockade experiments demonstrated that PLAU contributes to primordial follicle activation through promoting FOXO3A phosphorylation (pFOXO3A). This study provides the first proof that EVs derived from differentiated cells enhance therapeutic precision for POI, improve the tissue targeting of EV therapy, and provide a generalized strategy for clinical cell-free therapy.

Brain injury describes a variety of injuries to the tissues and blood vessels in the head. It can be external such as in road accident or physical assaults or internal such as a stroke. Regardless, they are largely incurable with a long route to recovery with symptoms-relieving medications and rehabilitation. As such, many therapies were explored including cell therapy. However, not all were evidence based and in many instances banking of patients' desperation, many treatments were done without any evidence from clinical trials. Here, we reviewed clinical trials on clinicaltrials.gov for stroke and spinal cord injury where there are cellular therapies transplanting neural, mesenchymal, and haemopoietic cells. We present and discuss 40 trials involving cell therapies for stroke and 32 for spinal cord injuries that are either completed or active. Although some trials began as long as 20 years ago and have shown encouraging improvements in various scale scores for both stroke and spinal cord injury, cell transplantation for brain injuries remains an evolving field that requires further research before it can be established as a standard treatment.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is reversible at early stages, making early identification critical. We previously demonstrated that patient-derived induced pluripotent stem cells (iPSCs) carrying MASLD-associated genetic risk variants exhibit greater oleate-induced intracellular lipid accumulation than those without these variants. This study aimed to develop an iPSC-based MASLD risk predictor using functional lipid accumulation assessments. We quantified oleate-induced lipid accumulation in iPSCs from three cohorts: (1) CIRM (22 cases, 20 controls), (2) POST (18 cases, 16 controls), and (3) UCSF (4 cases, 8 controls). Data from the CIRM cohort was used to define an iPSC-based MASLD risk score, which was subsequently validated in the POST and UCSF cohorts. Lipid accumulation was consistently higher in MASLD iPSCs across cohorts. The risk score achieved 44% sensitivity/75% specificity in POST and 75%/100% in UCSF. These findings suggest that oleate-induced lipid accumulation in iPSCs may be a predictor of MASLD risk. Larger studies incorporating additional cellular phenotypes, clinical, and genetic data could enhance predictive accuracy for MASLD surveillance and prevention.

Spinal cord injury (SCI) causes irreversible neurological damage and remains a major clinical challenge due to the lack of effective regenerative therapies. Human-induced pluripotent stem cells (hiPSCs) and their derivatives, hiPSC-derived neural stem/progenitor cells (hiPSC-NS/PCs), have demonstrated potential to promote neural repair and functional recovery. The world's first clinical trial using hiPSC-NS/PCs in the subacute phase of SCI has already been initiated. In contrast, chronic SCI-despite accounting for the majority of clinical cases-remains difficult to treat due to pathological barriers such as widespread demyelination, cavitation, scar formation, and persistent inflammation. Recent efforts to overcome these obstacles include combinatorial strategies incorporating rehabilitation, biomaterial scaffolds, pharmacological adjuvants, and robotic-assisted therapy as well as gliogenic or regionally patterned hiPSC-NS/PCs. Preclinical models have demonstrated that such multifaceted approaches can enhance graft survival, axonal regeneration, and functional recovery. In this review, we provide an overview of the biological characteristics, mechanisms of action, and recent advances in preclinical and clinical research on hiPSC-NS/PCs transplantation for SCI. We also discuss future perspectives and challenges toward clinical application. Collectively, these efforts underscore the diverse, innovative, and translational potential of hiPSC-based regenerative medicine for SCI.

Background: Cerebral palsy (CP), primarily caused by perinatal cerebral hypoxia and ischemia, is a devastating neurological disease in children characterized by motor, behavioral, and cognitive disorders. This study aimed to evaluate the therapeutic effects of amniotic membrane mesenchymal stem cell-derived exosome-rich conditioned medium (ERCM) in a CP model.

Methods: ERCM components were analyzed using enzyme-linked immunosorbent assay. Biodistribution was examined via fluorescence-labeled ERCM in both normal and CP induced animals. In vitro, the neuroprotective effects of ERCM against lipopolysaccharide and potassium cyanide-induced cytotoxicity were assessed in human neural stem cells and oligodendrocyte progenitor cells, focusing on apoptosis, inflammation, and oligodendrocyte differentiation. In vivo, ERCM was injected into CP-induced animals, followed by evaluation of antiapoptotic and anti-inflammatory signaling, motor and cognitive function, and white matter integrity.

Results: ERCM contained a broad array of growth factors and demonstrated enhanced retention in CP-affected brain regions. In vitro, ERCM significantly reduced apoptos is and inflammation, and promoted oligodendrocyte maturation via upregulation of Nkx2.2, CN Pase, and MBP. In vivo, ERCM treatment improved motor and cognitive performance, in hibited cell death and inflammatory responses, and increased expression of oligodendrocyte markers, including Nkx2.2, Olig2, CNPase, and MBP via increasing growth factor expression. Furthermore, ERCM attenuated demyelination in the corpus callosum, a region particularly vulnerable in CP.

Conclusion: ERCM confers therapeutic benefits in CP by preserving neural stem and oligodendrocyte progenitor cells, modulating apoptosis and inflammation, and enhancing oligodendrocyte differentiation. Accordingly, ERCM may present a good candidate as a CP therapeutic agent.