STEM CELLS最新文献

ETV2 is a pioneer factor that regulates cell fate decisions and direct reprogramming of the endothelial lineage. While ETV2 drives the cell fate conversion through epigenetic remodeling, its downstream targets also contribute to ETV2-mediated cell fate conversion. In this study, we defined Ecscr as a direct transcriptional target of ETV2 and a key regulator of ETV2-mediated cell reprogramming. Single-cell RNA sequencing analyses of ETV2-overexpressing embryoid body differentiation and embryonic fibroblast reprogramming revealed upregulation of Ecscr in ETV2-induced cell populations. ATAC-seq, ChIP-seq, gel shift, and transcriptional assays confirmed ETV2 binding to the Ecscr gene. In vivo analyses using 3.9 kb-Etv2-EYFP reporter transgenic mice and Etv2 null mice, in combination with single-cell RNA-seq of developing mouse embryos, further validated Ecscr as an ETV2 downstream target. Functionally, the knockdown of Ecscr significantly enhanced reprogramming rate, suggesting that Ecscr functions in a feedback mechanism to decrease the ETV2-mediated cell fate conversion. Mechanistically, Ecscr knockdown led to upregulation of Rptor, a core component of mTORC1 complex. The inhibition of mTORC1 signaling with rapamycin partially reversed the effect, supporting the notion that mTORC1 functions as a downstream mediator. Our findings uncover a novel ETV2 downstream target ECSCR that modulates ETV2-driven reprogramming through mTORC1 regulation, offering a target to improve endothelial reprogramming for regenerative applications.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and malignant cancer of the pancreas characterized by various genetic mutations and metabolic dysregulations. Stem cells play a critical role in the initiation, progression, and resistance of PDAC due to their plasticity, self-renewal capabilities, and ability to drive tumorigenesis. The gut microbiome, a diverse ecosystem of microorganisms, has a profound influence on systemic health, including the development of cancer. Recent studies have highlighted that the microbiome composition within the tumor can modulate stem cell behavior by shaping the tumor microenvironment (TME), enhancing cellular plasticity, and promoting the stemness properties of PDAC. In this review, we explore the potential crosstalk between the gut microbiome and PDAC stem cells, focusing on how microbiome-derived signals impact stem cell maintenance, inflammation, metastasis, TME modulation, and metabolic reprogramming.

Background: Umbilical cord blood (UCB) and umbilical cord tissue (UCT) are non-invasive, readily available sources of stem cells with significant potential for regenerative medicine and hematopoietic transplantation. While hematopoietic stem cells from UCB and mesenchymal stem cells from both UCB and UCT are clinically applied, other cord-derived populations remain under investigation, offering novel therapeutic opportunities alongside translational challenges.

Main body: This review synthesizes current knowledge on stem cell populations derived from UCB and UCT. Hematopoietic and mesenchymal stem cells have established clinical roles, whereas unrestricted somatic stem cells, embryonic-like stem cells, MUSE cells, and multipotent progenitor cells show preclinical promise. These populations differ in differentiation potential, therapeutic application, and biological characteristics. Translational barriers include limited cell numbers, variable engraftment, immune compatibility, and challenges in long-term preservation. Emerging strategies, such as ex vivo expansion, co-transplantation, and nanoparticle-assisted delivery, aim to enhance efficacy, precision, and safety.

Conclusion: This narrative review highlights both opportunities and challenges of umbilical cord stem cell therapies. Standardized protocols, interdisciplinary collaboration, and continued innovation are essential to optimize clinical outcomes and fully realize the translational potential of these diverse populations.

A reduction in circulating endothelial progenitor cells (EPCs) comprise an important part of vascular aging. However, the underlying mechanisms that mediate this EPC decline remain unclear. Here, we demonstrate a novel molecular mechanism where aging increases inhibitory T cell subsets and impairs SDF1-mediated increase of circulating EPCs. SomaScan proteomics and western blot analysis revealed FABP4 as the top upregulated protein in plasma and was also increased in the bone marrow in aging. Importantly, treatment with FABP4 in bone marrow cells increased inhibitory T cells while decreased SDF-1 receptor, CXCR4 in EPCs, whereas blocking FABP4 signaling by BMS309403 or depleting these T cells restored surface expression of CXCR4 in EPCs. Notably, FABP4-mediated decrease of circulating EPC in aging were restored by therapeutic administration of mitochondria, wherein plasma FABP4 was decreased along with reducing inhibitory T cell induction in bone marrow and increasing circulating EPCs in older mice. Collectively, these findings provide new insight into the involvement of age-associated T cell immunity in EPC dysregulation, and FABP4 may be a therapeutic target to detain vascular aging.

Hepatic macrophages, encompassing embryonic Kupffer cells (emKCs) and monocyte-derived macrophages (MoMFs), are recognized as important regulators of hepatic homeostasis and key players in the pathogenesis of liver diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD). Emerging research focuses on the critical role of hepatic macrophages in mediating liver repair and regeneration following injury, where they closely interact with hepatocytes as well as hepatic stellate cells (HSCs) to regulate inflammation, fibrosis, tissue remodeling, and regeneration. The latest single-cell and spatial omics technologies have profoundly deepened our understanding of the hepatic immune response, revealing the remarkable phenotypic and spatial heterogeneity of macrophages, including distinct subsets such as lipid-associated macrophages (LAMs) within steatotic and fibrotic regions. Macrophage subsets sense systemic (e.g. gut-liver axis, adipose tissue) and local stress signals and orchestrate disease-defining cellular responses in hepatocytes, HSC, and other immune cells. Dynamic tools such as intravital microscopy have further unveiled functional properties in the spatial context hitherto unknown. Herein, we review the multifaceted roles of hepatic macrophages in liver injury and repair, with an emphasis on their role in steatosis, inflammation, fibrosis, and regeneration. We also discuss how these insights may inform the development of novel macrophage-targeted therapeutic interventions.

Sirt7 is a member of the sirtuin family of proteins, which are NAD+-dependent deacetylases and ADP-ribosyltransferases. It is involved in a wide range of cellular processes. To study the specific role of Sirt7 in haematopoiesis during aging, the gene was specifically inactivated in hematopoietic stem cells (HSC). Vav1 promoter mediated expression of CRE recombinase in floxed Sirt7 mice resulted in specific inactivation of Sirt7 in the haematopoietic stem and progenitor cells. Young mice exhibited a normal peripheral blood count and no detectable haematological aberrancies. Peripheral blood of 19-month-old Sirt7 knockout mice revealed a diminished abundance of lymphocytes, but elevated count of monocytes compared to control mice. The number of erythrocytes, platelets and haemoglobin concentration remained unchanged. In the bone marrow of aged mice, a reduced abundance of myeloid undifferentiated cells could be observed. The development of hepatomegaly due to Sirt7 gene inactivation could indicate a myeloproliferative influence. Taken together, our data demonstrate that Sirt7 functions as a critical suppressor on haematopoietic stem cells differentiation in aged mice.

Background: The precise timing of stem cell specification and niche formation during murine incisor development is poorly understood, and it is unclear whether these processes occur simultaneously or in a sequential manner. Functional dental epithelial stem cells are marked by the expression of Sox2, a transcription factor that is broadly expressed in the dental epithelium at the dentition onset and restricted to stem cells in fully developed incisor.

Methods: Using genetic lineage tracing in Sox2CreERT2/+; R26RmT/mG and Sox2CreERT2/+; R26RtdT/+ embryos along with a single-cell RNA sequencing at different stages of incisor development, we investigated the timing of the stem cell specification and its temporal relationship with niche formation.

Results: Our results reveal the presence of a Sox2-expressing stem cell-like population prior to formation of the functional niche. These cells localize to the leading edge of the advancing incisor epithelium where they are maintained in an undifferentiated state. Our data demonstrate presence of actomyosin network and a generation of a contractile tension, which helps confine Sox2+ stem cells to the leading edge.

Conclusion: This mechanical confinement likely plays an important role in maintaining their stemness until the niche is functionally and structurally established. Partial or complete disruption of the actomyosin network disables the clustering of Sox2-expressing cells, potentially triggering their premature differentiation, and ultimately leads to impaired formation of the functional stem cell niche and abnormal growth of the incisor.

Background: Catechin (CH) exhibits protective effects on bone metabolism, but its underlying mechanism remains incompletely understood.

Methods: We investigated the osteogenic effects of CH and its molecular pathways using bone marrow mesenchymal stem cells and MC-3T3-E1 preosteoblasts. Cell viability was assessed after CH treatment (1-100 μg/mL). Osteogenic differentiation was evaluated by ALP activity, mineralization, and the expression of key markers (Runx2, Opn, Ocn, Sp7). Mechanistic studies involved examining autophagy markers (LC3-II, P62) and the AMPK pathway, using pharmacological inhibitors (compound C for AMPK; 3-methyladenine for autophagy). The protective role of CH under oxidative stress was tested in hydrogen peroxide-treated cells by measuring viability, ROS levels, NRF2 translocation, and osteogenic capacity.

Results: CH showed no significant cytotoxicity up to 100 μg/mL. At 10 μg/mL, it significantly enhanced osteogenic differentiation, increasing alkaline phosphatase activity (ALP), mineralization, and the gene/protein levels of osteogenic markers. CH activated autophagy (elevated LC3-II, decreased P62) and the AMPK pathway. Inhibition of AMPK or autophagy partially suppressed CH-induced osteogenesis, which was significantly rescued by CH co-treatment. Under oxidative stress, CH improved cell viability, reduced intracellular ROS, inhibited NRF2 nuclear translocation, and restored osteogenic differentiation.

Conclusion: CH promotes osteogenesis primarily via the AMPK-autophagy axis and reverses oxidative stress-induced suppression of osteogenic differentiation through ROS clearance. These findings highlight its therapeutic potential for bone regeneration and related disorders.

Acquired aplastic anemia (AA) is an immune-mediated bone marrow failure in which cytotoxic T lymphocytes (CTLs) target hematopoietic stem cells (HSCs). Approximately 30% of AA patients develop immune escape clones lacking specific HLA class I alleles (HLA[-]) through loss of heterozygosity in chromosome 6p (6pLOH) or somatic loss-of-function mutations. Eltrombopag (EPAG), a thrombopoietin receptor agonist (TPO-RA), demonstrates clinical efficacy in AA in combination with immunosuppressive therapy; however, its impact on HLA(-) HSCs and hematopoietic progenitor cells (HPCs) remains poorly understood. In this study, we evaluated the hematopoietic effects of EPAG using umbilical cord blood-derived HPCs and a humanized hematopoiesis model in immunodeficient (BRGS) mice. Furthermore, we established induced pluripotent stem cell (iPSC)-derived hematopoietic models encompassing five wild-type (WT) clones and seven HLA-lacking clones, differentiated them into HPCs, and assessed their responses to EPAG. EPAG selectively conferred a proliferative advantage to specific hematopoietic fractions in HLA(-) HPCs, distinct from that observed in WT HPCs. Molecular analyses revealed clone-dependent differences in CD110 expression and downstream effectors, including phosphorylated STAT5, FOXM1, and E2F1, indicating differential activation of TPO receptor-mediated signaling pathways among clones. These findings highlight the functional diversity of HLA(-) hematopoiesis and suggest that the hematopoietic response to EPAG is governed by clone-intrinsic signaling programs. Furthermore, our results provide new insights into how eltrombopag modulates clonal competition and hematopoietic recovery in immune-escape hematopoiesis, with potential implications for optimizing therapeutic strategies and predicting clinical response in patients with acquired AA.

End-stage renal disease (ESRD) is a major global health burden, and current treatments, such as dialysis and kidney transplantation, remain constrained by donor shortages, procedure-related complications, and reduced long-term quality of life. Regenerative medicine, particularly stem cell-based approaches, offers promising next-generation strategies for kidney repair and replacement. This review summarizes the current understanding of kidney development and intrinsic regenerative capacity and evaluates the therapeutic potential of hematopoietic stem cells, mesenchymal stem cells (MSCs), kidney-derived stem cells, and induced pluripotent stem cell (iPSC)-derived kidney organoids. Evidence from preclinical models demonstrates renoprotective and immunomodulatory effects across multiple stem cell types, whereas early-phase clinical trials have reported favorable safety profiles and preliminary signals of the efficacy of MSC-based therapies. iPSC- and organoid-based approaches present additional challenges, including incomplete vascularization, immature nephron structures, risks of tumorigenicity, immune compatibility issues, and the need for reproducible good manufacturing practice (GMP)-compliant manufacturing. Advances in biomaterials, organoid engineering, and vascularization strategies may help overcome these barriers. Overall, stem cell-based regenerative therapies show substantial potential to complement or ultimately reduce the reliance on dialysis and transplantation. Continued technological innovations and rigorously designed clinical trials are critical to translate these promising approaches into clinical practice.