Stem Cell Research & Therapy最新文献

Background: Chronic lower extremity ulcers (CLEUs) remain a major clinical challenge due to their prolonged healing process and risk of amputation. Stem cell therapy (SCT) has emerged as a promising regenerative strategy, with various cell types being explored for their efficacy in treating CLEUs. This umbrella review aims to consolidate the existing evidence on stem cell interventions for CLEUs, providing a comprehensive overview of the current research landscape.

Methods: This umbrella review was conducted following the PRIOR and PRISMA guidelines. We searched across PubMed, Embase, Web of Science, and Cochrane Library databases for systematic reviews (SRs) and meta-analyses (MAs) that included randomized controlled trials (RCTs) on SCT for CLEUs. The methodological quality and evidence quality of the SRs/MAs were assessed by AMSTAR 2 and GRADE. A quantitative synthesis of all RCTs included in the SRs/MAs to obtain objective and updated conclusions.

Results: A total of 28 SRs/MAs involving 72 RCTs were included. Our updated meta-analysis reinforces that SCT offers potential therapeutic benefits for CLEUs, including improved healing rates, amelioration of tissue perfusion and pain-related indicators, and more favorable prognostic outcomes. No significant difference in all-cause mortality was observed between the SCT and control groups.

Conclusion: SCT represents a promising adjunctive therapy for CLEUs, with many studies demonstrating its safety and potential benefits. Since current evidence is limited by methodological flaws and study heterogeneity, high-quality RCTs in the future are crucial to prove the benefits of SCT for CLEUs truly.

Background: Kidney fibrosis is one of the pathological hallmarks of chronic kidney disease, likely contributing to the loss of kidney function. The mechanisms leading to kidney fibrosis and its reversibility is only partially understood, which hampers the development of therapeutic targets. Therefore, it is crucial to establish a robust human in vitro model that can be used to study kidney fibrosis and potential regeneration.

Methods: Human induced pluripotent stem cells (iPSC) were differentiated into kidney organoids. Fibrotic injury was induced by mimicking hypoxia (1% O₂ 48 h), inflammation (interleukin-1 beta (IL-1β) 96 h) or a combination (hypoxia and IL-1β). Organoids were harvested at injury onset and up to 2 weeks post-injury. Fibrosis was assessed by mRNA and protein expression of fibronectin (FN1) and collagen type I, regeneration was evaluated through the presence of CD133+ and CD24+ progenitor cells and markers for differentiated kidney cell types.

Results: The combination of hypoxia and IL-1β induced the strongest fibrotic response with significant upregulation of FN1 and collagen type I, and loss of tubular and glomerular markers. Over time, FN1 levels realigned with the control group, whereas collagen type I remained elevated. Tubular markers (Villin and ECAD) recovered to near-control levels, coinciding with increased CD133+ and CD24+ cell population and Ki67 expression. In contrast, PODXL+ glomerular structures showed limited recovery.

Conclusions: We present a reproducible human kidney organoid model that captures both fibrotic remodeling and tubular regeneration following clinically relevant injury. This platform offers a valuable tool for studying kidney-specific fibrosis dynamics and testing anti-fibrotic or pro-regenerative strategies.

Stepwise pancreatic β-cell differentiation protocols, designed to recapitulate key developmental milestones of pancreatic organogenesis-from definitive endoderm to mature, glucose-responsive β-cells-draw on insights from both rodent and human developmental biology. These protocols consist of three critical stages: the formation of definitive endoderm, the induction of pancreatic progenitors, and the maturation of functional β-cells. Here, we discuss human and rodent embryonic development together with stem-cell differentiation protocols in concert to identify gaps and bottlenecks that limit the practicality and scalability of current protocols. Ultimately, the aim of refining these processes is to produce functional β-cells from pluripotent stem cells to treat, and potentially cure, diabetes.

Using adipose-derived stem cells (ADSCs) has recently become a crucial approach for treating bone defects owing to their ease of accessibility and substantial differentiation potential. N6-methyladenosine (m6A) modification greatly influences biological processes and determines the differentiation fate of stem cells. However, the specific mechanisms by which m6A modification influences the osteogenic differentiation of ADSCs remain unclear. We identified FOXO1 as the key m6A-modified gene during the osteogenesis of ADSCs. Furthermore, demethylase FTO enhanced RUNX2 expression while inhibiting PPARG expression by modifying FOXO1, thereby facilitating ADSC osteogenesis. FTO knockdown inhibited ADSC migration and proliferation and impaired osteogenesis by suppressing FOXO1. At the mechanistic level, we first revealed that FTO was exported to the cytoplasm and then directly bound with FOXO1 mRNA at its 1760th bp site. Consistent use of non-steroidal anti-inflammatory drugs (NSAIDs) containing FTO inhibitors impeded ADSC-mediated bone formation both in vivo and in vitro. In summary, our study reveals the role of m6A modification based on the FTO-FOXO1-RUNX2/PPARG axis in regulating the osteogenic differentiation of ADSCs, thereby improving the clinical use of ADSCs and providing strategies for related drug applications in bone regeneration.

Background: Psoriasis is a chronic skin disease featured with aberrant keratinocyte proliferation, inflammatory cell infiltration, and immune dysregulated. Although the imbalance of M1/M2 macrophage polarization is implicated in its pathogenesis, the underlying mechanisms remain unclear. Mesenchymal stem cells exhibited potent immunomodulatory properties, representing a promising therapeutic approach for psoriasis. This study aimed to explore the role and the underlying mechanism of human urine-derived stem cells (hUSCs) in mouse psoriatic models.

Methods: hUSCs were isolated from urine of heath volunteer and cultured in serum-free medium, and characterized by multiple approaches such as morphological analysis, biological markers examination, differentiation potentials and tumorigenicity assay. Histological analysis, immunofluorescence staining, ELISA, flow cytometry, antibody array, western blot and qRT-PCR analysis were used to assess the therapeutic effects and the underlying mechanism of hUSCs in imiquimod (IMQ)-induced mouse psoriasis models and multiple cell models.

Results: hUSCs had the potential for self-renewal and multipotent differentiation with low immunogenicity and lacking tumorigenicity both in vitro and in vivo. Our results showed that hUSCs significantly alleviated IMQ-induced psoriasis via their paracrine, evidenced by improving morphologies, inhibiting the infiltration of macrophages, reducing the releases of the pro-inflammatory cytokines. Mechanistically, we revealed that the protective effects of hUSCs on psoriasis were involved in suppressing M1 and promoting M2 macrophage polarization, and inhibiting NETs formation through inhibiting JAK2/STAT3 pathway. Finally, we further demonstrated that hUSCs-derived TGF-β1 selectively inhibited the JAK2/STAT3 pathway-mediated the polarization of M1 and M2 macrophages to alleviate psoriasis in mouse and cellular models.

Conclusions: Our data demonstrated that hUSCs remarkably ameliorated psoriasis by suppressing M1 and promoting M2 macrophage polarization through they-derived TGF-β1 inhibiting the JAK2/STAT3 pathway. Our results have revealed the molecular mechanism of hUSCs in treating psoriasis, highlighting a safe and effective cellular treatment method for psoriasis.

Background: COL4A1 defects are known to cause a variety of multisystem disorders with significant vascular dysfunction leading to neuronal damage. Case reports suggest that patients with COL4A1 mutations or extracellular COL4A1 deficiency in the basement membrane may put individuals at increased risk for developing visual deficits with neurotrauma. However, no experimental evidence is available. This study investigated the impact of Col4a1 deficiency on visual dysfunction following mild traumatic brain injury (mTBI) and evaluated the therapeutic efficacy of COL4A1-enriched adipose-derived stem cell-conditioned medium (ASC-CCM) in mitigating associated neurovascular deficits.

Methods: Using a retina-targeted knockdown approach in C57Bl/6 mice via intravitreal delivery of AAV2-Col4a1 shRNA, followed by a controlled 50-psi air-blast to induce mTBI, we assessed visual performance, retinal histopathology, and gene expression profiles for 4 weeks post-injury. Treatment with ASC-CCM was administered intravitreally post-blast. In-vitro, Col4a1 knockdown in human retinal endothelial cells (HRECs) assessed the therapeutic benefit of COL4A1-enriched ASC-CCM.

Results: After blast injury, Col4a1-deficient mice displayed significantly greater reductions in visual acuity and contrast sensitivity thresholds compared to control mice, which were substantially restored following ASC-CCM treatment. Histological and molecular analyses revealed marked glial activation, vascular instability, and synaptic disorganization in Col4a1-deficient retinas post-injury, which were attenuated upon ASC-CCM administration. In-vitro assays further confirmed that COL4A1 plays a crucial role in endothelial integrity. After Col4a1 knockdown, HRECs showed impaired cell migration and increased leukocyte transmigration, effects that were reversed by treatment with COL4A1-enriched, but not COL4A1-depleted, ASC-CCM. Moreover, COL4A1-enriched ASC-CCM suppressed inflammatory responses in cytokine-stimulated microglia and stabilized TNF-α-induced endothelial permeability.

Conclusions: These findings collectively identify COL4A1 deficiency as a sensitizing factor for post-traumatic visual dysfunction and demonstrate that ASC-CCM exerts therapeutic effects by preserving retinal vascular structure and modulating inflammatory responses, positioning it as a promising candidate for treating TBI-related ocular neurovascular injury.

Background: The Monopterus albus serves as a unique model for studying sex reversal, transitioning naturally from female to male. However, the origins of male germline stem cells (GSCs) and the roles of somatic cells during sex reversal remain poorly understood.

Methods: We performed single-cell RNA sequencing (scRNA-seq) on ovarian, ovotestis, and testicular tissues to construct a gonadal cell atlas. RNA fluorescence in situ hybridization (RNA-FISH) validated cell subpopulations.

Results: Cell types of germ cells and somatic cells in gonads were identified, and their differentiation trajectories during sex reversal were depicted. Our results show that GSCs^wdr17+tep1- in the ovaries possess bipotential differentiation capacity and can transform into GSCs^{wdr17+ tep1+} with the capability to differentiating into sperm during sex reversal. Two theca cell subpopulations cooperate to synthesize steroid precursors in ovaries, with Leydig cells in testes likely originating from theca cell transitions. Proliferative gdf9⁺ follicle cells promoted folliculogenesis and persisted in male gonads with reduced hsd17b1 expression. Stromal heterogen-eity analysis revealed bmp4⁺ mesenchymal stem cells (MSCs^bmp4+) as potential precursors for Sertoli cells in testes.

Conclusions: This study provides a comprehensive cellular roadmap of gonadal cell dynamics during sex reversal in Monopterus albus. Our findings unveil the molecular mechanisms underlying germline and somatic cell fate determination, offering novel insights into vertebrate sex reversal and potential therapeutic strategies for disorders of sex development (DSD).

Background: Non-alcoholic fatty liver disease (NAFLD) is characterized by abnormal lipid accumulation in hepatocytes and defective autophagy has been implicated in its pathogenesis. Human umbilical cord-derived MSCs (hUC-MSCs) have shown therapeutic potential in treating NAFLD, while underlying molecular mechanisms remained largely unknown.

Methods: Male C57BL/6J mice fed a choline-deficient high fat diet (CD-HFD) and HepG2 cells exposed to palmitic acid/oleic acid were established as in vivo and in vitro models of NAFLD, respectively. Both models were subjected to treatment with human umbilical cord-derived MSCs (hUC-MSCs). Lipid content, proinflammatory cytokines, fibrosis markers and the hepatic transcriptome were assessed to determine the effect of hUC-MSCs.

Results: Here, hUC-MSCs decreased hepatic lipid content and alanine aminotransferase/aspartate aminotransferase levels, as well as attenuated inflammation and fibrosis in choline-deficient high-fat diet (CD-HFD)-induced NAFLD mice. Mechanistically, hUC-MSCs restored impaired autophagic flux and mitigated liver steatosis through the AMPK-mTOR-TFEB pathway in both NAFLD mice and oleic acid/palmitic acid-induced "fatty" HepG2 cells. Of note, hUC-MSCs have been found to promote nuclear translocation of TFEB in PA/OA-induced HepG2 cells. Additionally, TFEB knockdown partially attenuated the effect of hUC-MSCs on enhancing autophagy and lipid metabolism in vitro.

Conclusions: This study suggests that hUC-MSCs represent a potential therapeutic approach to treating NAFLD through activating TFEB-mediated autophagy.