International journal of stem cells最新文献

Preterm premature rupture of membranes (PPROM) is a major cause of preterm birth and neonatal morbidity, with no established treatment to restore membrane integrity. Mesenchymal stem cells (MSCs), known for their regenerative and immunomodulatory properties, harbor promising therapeutic potential for fetal membranes repair. This study aimed to evaluate the rapid barrier reinforcement effect of Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) using in vitro and ex vivo models of PPROM. A wound healing assay was conducted to assess the effect of WJ-MSCs on human amniotic epithelial cells proliferation and migration. An ex vivo PPROM model was established using incised human fetal membranes to simulate membrane rupture. WJ-MSCs were directly applied to the lesion site at varying doses. Therapeutic efficacy was evaluated by a leak test and histological analysis. WJ-MSCs and their conditioned medium significantly enhanced epithelial wound closure in vitro, demonstrating that soluble paracrine factors secreted by WJ-MSCs have the potential to aid membrane injury restoration. In the ex vivo PPROM model, WJ-MSCs treatment reduced both leakage area and frequency of fetal membranes, with the most significant effect observed at a medium dose (5.0×10⁵ cells). Histological evaluations revealed partial recovery of the fetal membranes, particularly the chorion layer. These findings suggest that WJ-MSCs contribute to rapid barrier reinforcement of injured fetal membranes. Taken together, WJ-MSCs enhance epithelial healing and support restoration of membrane integrity, highlighting their potential as a therapeutic approach for PPROM. Further, in vivo studies are required to confirm therapeutic efficacy and evaluate safety.

Arts syndrome is a rare X-linked recessive neurodevelopmental disorder arising from pathogenic variants in PRPS1, which encodes phosphoribosyl pyrophosphate synthetase 1-an enzyme essential for de novo nucleotide biosynthesis. Affected individuals typically exhibit sensorineural hearing loss, intellectual disability, cerebellar ataxia, and recurrent infections. However, despite the severity of these clinical manifestations, therapeutic interventions remain limited, largely due to an incomplete understanding of the cellular pathophysiology underlying the disorder. In this study, we generated patient-specific induced pluripotent stem cells harboring the PRPS1 p.V42L variant and differentiated them into neural stem cells (NSCs) and neurons to elucidate disease mechanisms and explore potential therapeutic strategies. Patient-derived NSCs demonstrated significantly reduced proliferative capacity, aberrant nuclear morphology, and increased neuronal senescence, while mitochondrial integrity and function were largely preserved. Neurons differentiated from these NSCs exhibited impaired neurite outgrowth and reduced branching complexity, indicative of disrupted neurodevelopmental processes. Notably, supplementation with nicotinamide mononucleotide, a precursor of nicotinamide adenine dinucleotide (NAD^＋), partially ameliorated defects in NSC proliferation, nuclear architecture, and neuronal morphology. Collectively, these findings delineate key cellular mechanisms underlying PRPS1-associated neurodevelopmental pathology and identify NAD^＋ metabolic augmentation as a promising therapeutic avenue for Arts syndrome and related PRPS1-mediated disorders.

As global societies age, the prevalence of neurodegenerative disorders, such as Alzheimer's disease, is rapidly increasing, intensifying the need to understand the mechanisms of aging and their contribution to these conditions. Consequently, the focus of aging research has shifted from the traditional concept of chronological age to a more nuanced understanding of biological age. This has spurred active investigation into robust biomarkers, including cellular senescence. However, the application of classical senescence markers to the brain presents a substantial challenge, as their validity in post-mitotic cells, such as neurons, remains unclear. In this review, we highlight the limitations of the current metrics for cellular senescence as indicators of biological aging, and propose a path forward focused on identifying and modeling cell-type-specific aging markers within the brain.

Induced pluripotent stem cells (iPSCs) are a promising cell source for regenerative medicine. Clinical applications require a large number of functional red blood cells (RBCs), making it essential to ensure the proliferation of actively dividing, nucleated erythroblasts derived from iPSCs. Small molecules can enhance the efficiency and frequency of iPSC-derived cell differentiation. Sirtuin 1, a key enzyme in multiple biological processes, has been implicated in enhancing iPSC-derived cell differentiation. However, the specific effects of Sirtuin 1 on erythroblast proliferation from iPSCs remain unclear. Here, we developed a protocol to examine the effects of Sirtuin 1 on erythroblasts after endothelial-to-hematopoietic transition (EHT). We found that Sirtuin 1 activation increased the frequency of CD71^＋CD235a^＋ erythroblasts at the early stage after EHT, suggesting a role for Sirtuin 1 in the proliferation of these specified erythroblasts. These findings reveal that Sirtuin 1 activation benefits erythroblast proliferation and could be considered for translational application in large-scale RBC culture.

Endometrial stem cells (EnSCs) are mesenchymal stem cells (MSCs) derived from endometrial tissue and serve as a valuable MSC source, as they are naturally replenished during menstruation. Exosomes, vesicles secreted by cells, contain various biomolecules such as proteins and nucleic acids and play crucial roles in intracellular communication, protein and nucleic acid metabolism, immune response regulation, and antigen presentation. This study investigated the protein profiles of EnSC-derived exosomes isolated from the endometrium of menstruating women and compared them with those of adipose-derived stem cell (ASC)-derived exosomes. After isolating EnSCs and ASCs, MSC characteristics were confirmed, and the purified exosomes were analyzed to determine their individual protein compositions. EnSCs, which can be obtained through non-invasive methods, exhibit multipotency similar to other MSCs and demonstrate rapid proliferation in vitro. Proteomic analysis of exosomal proteins revealed that 236 proteins were significantly more abundant in EnSC-derived exosomes than in ASC-derived exosomes, whereas 84 proteins were significantly more abundant in ASC-derived exosomes than in EnSC-derived exosomes. These findings indicate that EnSC-derived exosomes contain unique proteins compared to ASC-derived exosomes, as demonstrated through proteomic profiling. While further clinical studies are required, EnSCs hold promise as a potential therapeutic option in regenerative medicine, similar to current cell therapy products under development.

Extracellular vesicles (EVs) are crucial mediators of intercellular communication, which facilitate the transfer of bioactive molecules such as proteins, lipids, and nucleic acids. Their high biocompatibility and intrinsic targeting abilities make them promising candidates for therapeutics, drug delivery, and disease biomarkers. In liver diseases, EVs are essential in liver regeneration, fibrosis modulation, and ischemia-reperfusion injury repair, and EV-derived biomarkers have shown potential for non-invasive disease monitoring, particularly in hepatitis B virus infection, non-alcoholic fatty liver disease, and hepatocellular carcinoma. This review provides a comprehensive overview of EV biology, cellular sources, isolation techniques, and strategies to enhance their therapeutic potential. Furthermore, we discuss the role of EVs in liver regeneration and their clinical application in biomarker discovery. Despite significant advancements in EV-based therapies, challenges such as scalability, standardization, immunogenicity, and regulatory approval remain key hurdles for clinical translation. Future research should focus on optimizing EV bioengineering, refining isolation methods, and addressing regulatory concerns to facilitate successful application of EVs in liver disease management and precision medicine.

Human chemically derived hepatic progenitors (hCdHs) reprogrammed using three chemicals-HGF, A83-01, and CHIR99021 (collectively denoted as "HAC")-have been suggested as a novel therapeutic for patients with severe liver diseases in our previous study. Despite its high proliferation and re-differentiation ability into functional hepatocytes, the reprogramming mechanism of hCdHs remained unknown. Recently, it has been reported that autophagy, a self-degradation process, is responsible for stem cell metabolism. In this study, we investigated whether autophagy regulates the generation mechanism of CdHs, mainly using hepatocytes from C57BL/6 mice, with additional analysis using human hepatocytes. As a result, we found that autophagy flux is inhibited during the generation of mouse CdHs (mCdHs) by A83-01, which is compensated by CHIR99021. Moreover, the suppression of autophagy by bafilomycin A1 enhanced the proliferation ability of mCdHs during the generation process. hCdHs also showed a similar autophagy inhibition pattern to mCdHs during the generation process. Taken together, our study indicates that autophagy is downregulated during the generation of CdHs, promoting their proliferation. This may contribute to the production of hCdHs with stable productivity, which may serve as a therapeutic for severe liver diseases.

The brain-derived neurotrophic factor (BDNF) plays a crucial role in neuroprotection, and we have previously demonstrated BDNF-mediated neuroprotective effects in mesenchymal stromal cells (MSCs). The present study aimed to investigate whether BDNF-overexpressing MSCs enhance the therapeutic efficacy of naïve MSCs in a preclinical model of severe neonatal intraventricular hemorrhage (IVH). We exposed primary rat neuronal cells to 40 U of thrombin overnight in vitro. Subsequently, the neuronal cells were co-cultured with either naïve MSCs or BDNF-overexpressing MSCs (1×10⁵ cells in 1 mL media) for 24 hours. Next, 300 μL of maternal blood was injected into bilateral ventricles on postnatal day (P)4 to induce severe IVH in newborn Sprague-Dawley male rats. At P6, either naïve MSCs or BDNF-overexpressing MSCs (1×10⁵ cells in 10 μL saline) were transplanted intraventricularly. Behavioral function tests, including passive avoidance, followed by endpoint analyses of brain tissue and cerebrospinal fluid were performed at P35. BDNF-overexpressing MSCs enhanced the effects of naïve MSCs against cell death, cytotoxicity, and oxidative stress in vitro. Notably, naïve and BDNF-overexpressing MSCs did not attenuate post-hemorrhagic ventricular dilatation, neuronal cell death, or gliosis. However, BDNF-overexpressing MSCs attenuated microglial activation. Furthermore, inflammatory cytokine (interleukin [IL]-1α, IL-1β, IL-6, and tumor necrosis factor-α) levels and memory function assessed using a passive avoidance test significantly improved in the BDNF-overexpressing MSC transplanted group compared with the naïve MSC transplanted group. Our data suggest that BDNF-overexpressing MSCs may offer superior protective effects to naïve MSCs in a neonatal IVH model.

The advent of medical advances has resulted in the development of an array of treatments aimed at restoring damaged organs in humans. However, when chemical treatments, such as drug therapies, are constrained, organ transplantation may ultimately emerge as the sole viable solution. Nevertheless, despite the continually increasing demand for organ donations, the actual number of donated organs remains insufficient to meet this demand. Recently, a variety of organoids have been generated using stem cells and have been demonstrated to exhibit functionality comparable to that of native organs. This indicates that organoids may be a viable option for use in organ transplantation. However, while numerous recent publications have documented the regenerative effects of diverse organoid types when implanted into damaged regions, significant technical and ethical considerations must be addressed before organoids can be utilized as a replacement for human organs. This review presents an overview of experimental endeavors in regenerative therapies through organoid transplantation, while also addressing the challenges that must be overcome to enhance the feasibility of organoid use as a surrogate organ. As organoid technology continues to advance, organoids may eventually become a widely utilized surrogate source for organ replacement in clinical settings.

Idiopathic pulmonary fibrosis (IPF) is characterized by maladaptive epithelial-mesenchymal crosstalk and progressive extracellular matrix accumulation, whereas currently available antifibrotic agents merely decelerate functional decline. This study investigated whether exosomes derived from human mesenchymal stem cells derived from embryonic stem cells (ESC-MSCs) restore epithelial stress responses and attenuate fibrotic remodeling. Human IPF lung transcriptomes were integrated with a bleomycin-induced murine model analyzed by RNA sequencing and protein signaling, together with cigarette smoke extract-induced injury in A549 epithelial cells. ESC-MSCs-derived exosomes exhibited typical morphology and size distribution, enrichment of tetraspanins, and absence of endoplasmic reticulum contamination, consistent with high-purity preparations. Across human IPF and bleomycin-injured lungs, transcriptomic profiling revealed prominent enrichment of extracellular matrix and cytoskeletal gene programs, whereas mitogen-activated protein kinase (MAPK) and Smad families displayed only modest alterations at the mRNA level. In vivo administration of exosomes during the fibrotic remodeling phase, via either intravenous or intratracheal delivery, resulted in improved body weight, reduced lung weight-to-body weight ratios, and decreased collagen deposition and Ashcroft scores. These structural and functional improvements were accompanied by suppression of profibrotic and mesenchymal markers and selective attenuation of activator protein-1 (AP-1) activity. In epithelial injury models, ESC-MSCs-derived exosomes enhanced cell viability, restored redox homeostasis, and constrained stress-induced mesenchymal gene expression and MAPK phosphorylation in both co-treatment and post-treatment settings. Collectively, these data support an epithelial-centered mechanism in which ESC-MSCs-derived exosomes re-establish oxidative balance and selectively restrict AP-1-driven stress signaling, thereby secondarily limiting extracellular matrix accumulation and fibrotic remodeling.