Stem Cell Reviews and Reports最新文献

A comprehensive understanding of how diverse adult stem cell populations function in harmony is crucial for maintaining homeostasis and ensuring the normal functioning of body tissues. Two types of stem cells in adult tissues have attracted attention, including very small embryonic-like stem cells (VSELs) and multi-lineage differentiating stress-enduring cells (MUSE), reported for the first time in 2006 and 2010, respectively. VSELs are pluripotent stem cells developmentally linked to the primordial germ cells, while MUSE cells, initially described as multipotent, are now being defined as having pluripotent characteristics and further differentiate into MSCs. VSELs are the most primitive, virtually immortal and pluripotent stem cells that survive lifelong in all tissues in small numbers and undergo asymmetrical divisions to give rise to tissue-specific progenitors of different sizes and fates. VSELs are 5-7 μm in size, spherical in shape, with a cell surface profile of LIN-CD133 + CD45- while MUSE cells are 10-15 μm in size, with abundant cytoplasm, horseshoe/bean-shaped nuclei, cytoplasmic OCT-4 and are CD45+, like hematopoietic stem cells. In the mouse uterus, VSELs undergo cyclic changes in response to circulatory hormones, regenerate both the epithelial and stromal compartments in an atrophied uterus (upon bilateral ovariectomy, in the absence of macrophages) and also upon chronic injury. Exposure to endocrine-disrupting chemicals disrupts the functions of VSELs and results in various pathologies, including endometrial cancer. The crucial role of dysfunctional VSELs resulting in cancer initiation, progression, metastasis and recurrence was recently discussed. On the other hand, multiple clinical trials have reported the potential of MUSE cells for ensuring regeneration upon transplantation. VSELs regenerate damaged and diseased tissues when a healthy paracrine support is provided by the transplanted MUSE cells/MSCs; however, remain elusive due to their small size and scarce nature. In summary, the view that MUSE cells phagocytose damaged cells and subsequently differentiate into the same cell type is fundamentally challenged and requires careful re-evaluation.

Percutaneous autologous expanded CD34⁺ cell therapy (ProtheraCytes^®) has demonstrated feasibility, manageable safety concerns and a regenerative potential in the EXCELLENT phase I/IIb trial (NCT02669810). Objective of our study was to assess HRQoL over 6 months following ProtheraCytes^® therapy in patients with recent large AMI and left ventricular (LV) dysfunction. EXCELLENT was a multicenter, randomized, open-label, controlled phase I/IIb trial enrolling 77 AMI patients. Participants were randomized 3:1 to standard-of-care (SoC) plus transendocardial ProtheraCytes^® injections or SoC alone. The per-protocol population included 49 subjects. Of those, 31 treated and 12 control patients were analyzable with complete baseline and follow-up 36-Item Short Form Survey (SF-36) data. HRQoL domains and composite scores were analyzed using repeated-measures ANCOVA adjusted for baseline values. At baseline, HRQoL was markedly impaired, consistent with severe LV dysfunction (mean physical functioning score at 63.3, LVEF 35.2%, elevated NT-proBNP). At 6 months, the treated group showed significant and sustained meaningful improvements in physical functioning (+ 16.6 PF, p = 0.0002), vitality (+ 12.7 VT, p = 0.0072), social functioning (+ 17.9 SF, p = 0.0059), and bodily pain (+ 17.0 BP, p = 0.0031). Between months 3 and 6, most HRQoL domains declined in controls but remained stable or improved in treated patients. In conclusion, ProtheraCytes^® therapy was associated with significant HRQoL gains sustained over 6 months, alongside biological improvements. These findings support further evaluation of expanded CD34⁺ cell therapy to address the unmet need for durable functional recovery post-AMI.

Mitochondrial protein import and transporter systems play essential roles in maintaining metabolic competence and proteostasis in stem cells. However, the transcriptional architecture of mitochondrial translocase (TOM/TIM) complexes and transporter genes in human spermatogonial stem cells (SSCs) remains poorly defined. We performed an integrative analysis combining bulk microarray profiling of human SSC-enriched populations (n=3 biological replicates per group) with complementary single-cell RNA-sequencing (scRNA-seq) datasets. Differential expression (limma; |log₂FC| ≥ 2, adj. P < 0.05), co-expression network construction (WGCNA), protein-protein interaction mapping (STRING/cytoHubba), and miRNA-mRNA regulatory inference were used to identify key mitochondrial transporter nodes. Validation of hub-gene expression patterns was performed using an independent scRNA-seq dataset. Cell-type identity of SSC-enriched cultures was confirmed by immunocytochemistry for established SSC markers. Integrated multi-omics analyses revealed a coordinated enrichment of mitochondrial transporter genes in SSCs, including upregulation of TOMM and TIMM family members and selected ATPase and SLC transporters relative to fibroblasts. Hub genes (TOMM22, TIMM17A, ATP6V1A, SLC25A3) showed high network centrality and were consistently enriched in undifferentiated SSC clusters across multiple scRNA-seq datasets. miRNA-mRNA interaction modeling identified several SSC-expressed miRNAs (e.g., hsa-miR-4732-3p, hsa-miR-6503-3p) as potential post-transcriptional regulators of mitochondrial transporter networks. Human SSCs exhibit a distinctive mitochondrial transporter gene program characterized by enhanced expression of protein-import machinery and metabolic transport components. These findings provide a comprehensive molecular framework for understanding mitochondrial regulation in SSCs and establish new candidate targets for probing germline metabolism and stem-cell maintenance.

Arthritis, encompassing degenerative disorders such as osteoarthritis (OA) and autoimmune diseases like rheumatoid arthritis (RA), remains a leading cause of chronic pain, disability, and socioeconomic burden worldwide. Conventional pharmacological and surgical therapies primarily offer symptomatic relief without addressing the underlying degeneration of cartilage and bone. Recent advances in regenerative medicine have introduced promising biological strategies, particularly mesenchymal stem cells, exosomes, and bioengineered tissue scaffolds, for functional joint restoration. MSCs exhibit remarkable differentiation potential, along with immunomodulatory and paracrine effects that support cartilage repair and immune homeostasis. MSC-derived exosomes replicate many of these therapeutic functions through their bioactive cargo of proteins, lipids, and microRNAs, offering a safer and more controllable cell-free alternative. Meanwhile, bioengineered scaffolds composed of natural or synthetic polymers provide essential structural and biochemical cues for tissue regeneration, especially when integrated with stem cells or exosomes. Despite encouraging preclinical and early clinical outcomes, challenges remain concerning safety, standardization, scalability, and regulatory approval. The integration of emerging technologies such as nanotechnology, artificial intelligence, and gene editing may further enhance regenerative outcomes and enable personalized arthritis therapies. Collectively, these convergent innovations represent a paradigm shift from symptomatic management toward true biological repair, positioning regenerative and stem cell-based therapies at the forefront of next-generation arthritis treatment.

Ischemic stroke (IS), also referred to as cerebral ischemia, is a neurological condition accompanied by long term or permanent physical disability. Various molecular mechanisms such as inflammation, oxidative stress, blood brain barrier (BBB) disruption, energy depletion, mitochondrial dysfunction etc., contribute to its pathophysiology and trigger death of neural tissues. Currently, there are limited therapeutic options for its treatment. Although, thrombectomy or thrombolytic drugs are available, but only beneficial for the management of acute phase and do not address the neurodegenerative aspects. Mesenchymal stem cells (MSCs) are predominantly used for regenerative applications due to their self-renewal, immunomodulatory, and neuronal differentiation potential which make them a suitable candidate for neural tissue regeneration at both pre-clinical and clinical levels. MSC derived exosomes and extracellular vesicles (EVs) also provide cell-free therapeutic option that potentially reduce inflammation, restore BBB integrity, and facilitate neural regeneration. The current review summarizes the molecular mechanisms associated with IS pathophysiology and therapeutic mechanisms exhibited by MSCs and their derived products. Furthermore, the review also highlights the clinical trials registered so far to examine the efficacy of MSCs and their derived products to validate the findings and address challenges associated with preclinical studies. A number of clinical trials have reported improvements in motor functions and neurological scores, demonstrating MSC based therapy as safe and effective to treat IS complications. However, there is still a need to fully optimize protocols for MSC source, delivery route, dose, and timing of administration to maximize therapeutic efficacy and ensure safety in future clinical applications.

Cerebral palsy (CP), the most prevalent pediatric motor disorder with significant cognitive comorbidity (> 50%), lacks therapies addressing both impairments in moderate-to-severe cases. This study demonstrates that human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exos) exert profound therapeutic effects in a rat model of moderate-to-severe CP established via bilateral carotid artery occlusion with hypoxia. Intravenously administered hUCMSC-Exos displayed sustained brain retention and significantly restored motor coordination and cognitive function. The recovery was primarily mediated through enhanced remyelination driven by promoted oligodendrocyte maturation and differentiation (elevated oligodendrocyte lineage transcription factor 2 and myelin basic protein). Concurrently, the treatment attenuated key pathological processes involving sustained neuroinflammatory responses (reduced ionized calcium-binding adapter molecule 1, tumor necrosis factor-α, and interleukin-6) while elevating brain-derived neurotrophic factor. Our findings establish hUCMSC-Exos as a promising dual-modality therapy for moderate-to-severe CP, mechanistically linked to robust remyelination and coordinated modulation of core disease mechanisms.