STEM CELLS最新文献

The adult heart consists of a fixed number of cardiomyocytes (CMs) determined at birth. CMs once lost due to injury in the adult heart are never replaced, initiating a viscous cycle of adverse events leading to heart failure. Therapeutic interventions that drive cardiac repair by proliferation of the endogenous CMs or adoptive transfer of stem cells such as cardiac tissue derived stem/progenitor cells (CPCs) are promising albeit limited in their ability to repair the heart. Numerous studies have identified an inherent regenerative power of the heart during embryonic and postnatal development. The developmental cardiac tissue can initiate a robust regenerative response leading to complete resolution of injury. Unique cellular and molecular mechanisms in the developmental heart are at the core of this regenerative ability. Upon cardiac maturation, cellular differentiation and changes in molecular signaling hubs active developmentally are 'switched off' in the adult heart. Recent work has shown convincing results for promoting cardiac repair in the adult heart by reactivation of developmental signaling. CPCs engineering with developmental factors or their CMs specific delivery of can reactivate regenerative signaling to augment cardiac structure and function in the adult heart. This review aims to summarize efforts regarding reactivation of developmental signaling factors in the heart using CPCs and CMs. A special emphasis is on embryonic/developmental microRNAs governed signaling pathways for cardiac repair. We provide an in-depth analysis of the current state of the field including discussion of some of the limitations that will be beneficial for future studies. Significance statement: Reactivation of developmental signaling in the heart is promising approach to increase cardiac regeneration after myocardial injury. This article summarizes current state of the field regarding signaling factors that regulated developmental signaling in the context of cardiac progenitor cells and cardiomyocytes to promote cell proliferation and increase their overall repair ability.

Hematopoietic stem cell (HSC) transplantation is a lifesaving therapy for hematologic diseases, but its broader application remains constrained by challenges in sourcing, manipulating, and reliably expanding functional HSCs. In this review, we discuss strategies to expand and engineer HSCs by recreating essential aspects of the bone marrow niche. These include defined cytokine cocktails, small molecule modulators, stromal co-culture systems, and biomaterials that promote self-renewal while limiting differentiation. We highlight advances in three-dimensional organoid models and microfluidic platforms that better support long-term repopulating cells and reflect native microenvironments. In parallel, progress in gene delivery platforms, including both viral and nonviral approaches, is enabling more efficient and targeted modification of HSCs for therapeutic use in genetic disorders such as sickle cell disease and β-thalassemia. While these tools have advanced significantly, significant hurdles remain in scaling, preserving stem cell identity, and reducing culture-induced stress. Continued refinement of biomimetic systems and genome engineering technologies will be central to expanding the clinical utility of HSC-based therapies.

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: Adipose-derived stem cells exosome (ADSC-exo) has been reported to be effective in alleviating organ dysfunction in sepsis, including acute liver injury (ALI). Whether ADSC-exo protects the liver via suppression of vascular endothelial cell (VEC) ferroptosis is unclear.

Methods: We evaluated the viability and migration of VECs and their ferroptosis-related indices. To further elucidate this mechanism, we examined the Nrf2/GPX4 pathway. Cecal ligation and puncture (CLP) was performed to establish a sepsis model to observe the protective effect of ADSC-exo. The death rate and liver tissue injury were observed. We also evaluated inflammation- and ferroptosis-related indices. Next, we examined the expression of nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) pathway-related molecules to elucidate the underlying mechanism.

Results: ADSC-exo reduced cell injury and ferroptosis in VECs. ADSC-exo increased the expression and nuclear translocation of Nrf2. In the CLP-induced sepsis model, ADSC-exo relieved liver injury and reduced the death rate. Further observations showed that ADSC-exo significantly alleviated oxidative stress injury and ferroptosis in liver tissue, while remarkably increasing the expression of Nrf2 and GPX4.

Conclusion: These findings demonstrate the remarkable ability of ADSC-exo to alleviate sepsis-induced ALI by mitigating endothelial cell ferroptosis, providing evidence for the potential clinical application of ADSC-exo in ALI therapy.

One of the most important properties of human embryonic stem cells (hESCs) is their ability to exist in primed and naive pluripotent states. Our previous meta-analysis indicated the existence of heterogeneous pluripotent states derived from diverse naive protocols. In this study, we characterized a commercial, RSeT-based pluripotent state under various growth conditions. Notably, RSeT hESCs can circumvent the hypoxic growth conditions required by naive hESCs, although some RSeT cells (eg, H1 cells) exhibit much lower single-cell plating efficiency and display altered or significantly retarded cell growth under both normoxia and hypoxia. Importantly, RSeT hPSCs lack many transcriptomic hallmarks of naive and formative pluripotency (the phase between naive and primed states). Integrative transcriptome analysis suggests that our primed and RSeT hESCs are similar to the early stage of post-implantation embryos, in line with previously reported primary hESCs and early hESC cultures. Moreover, RSeT hESCs do not express naive surface markers such as SUSD2 and CD75 at significant levels. At the biochemical level, RSeT hESCs show differential dependence on FGF2 and co-independency on both Janus kinase (JAK) and TGFβ signaling in a cell line-specific manner. Thus, RSeT hESCs represent a previously unrecognized pluripotent state downstream of naive pluripotency. Our data suggest that human naive pluripotent potentials may be restricted in RSeT medium, which sustains FGF2 activity. Hence, this study provides new insights into pluripotent state transitions in vitro.

Hematopoietic aging is characterized by diminished stem cell regenerative capacity and an increased risk of hematologic dysfunction. We previously identified that the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) regulates hematopoietic stem cell (HSC) activity. Here, we expand on this work and demonstrate that in aged mice: (1) 15-PGDH expression and activity remain conserved in the bone marrow (BM) and spleen, suggesting that it remains a viable therapeutic target in aging; (2) prolonged PGDH inhibition (PGDHi) significantly increases the frequency and number of phenotypic hematopoietic stem and progenitor cells across multiple compartments, with transcriptional changes indicative of enhanced function; (3) PGDHi-treated BM enhances short-term hematopoietic recovery following transplantation, leading to improved peripheral blood output and accelerated multilineage reconstitution; and (4) PGDHi confers a competitive advantage in primary hematopoietic transplantation while mitigating age-associated myeloid bias in secondary transplants. Notably, these effects occur without perturbing steady-state blood production, suggesting that PGDHi enhances hematopoiesis under regenerative conditions while maintaining homeostasis. Our work identifies PGDHi as a translatable intervention to rejuvenate aged HSCs and mitigate hematopoietic decline.

Mesenchymal stromal cells (MSCs), owing to their regenerative and immunomodulatory properties, have emerged as a potential therapeutic option for disorders affecting the cornea and ocular surface. Early-phase clinical studies have begun to demonstrate the safety and, to some extent, efficacy of MSC-based therapies in conditions such as dry eye disease, persistent corneal epithelial defects, ocular chemical injuries, corneal scarring, keratoconus, and limbal stem cell deficiency. However, evidence from some studies suggests that MSC-related improvements may be short-lived. Currently, the appropriate clinical indications, delivery methods, and long-term outcomes remain unclear, necessitating further laboratory and clinical investigations. In this review, we summarize published and ongoing clinical studies on the therapeutic applications of MSCs for ocular surface diseases, including our own group's experience. We critically evaluate the strengths and limitations of existing studies and highlight gaps and opportunities in this evolving field.

The study by Ye et al., published in Stem Cells, represents a significant advancement in the field of cellular reprogramming and pluripotency. The authors meticulously investigate the essential roles of the miR-290 and miR-302 microRNA clusters in the reprogramming of fibroblasts to induced pluripotent stem cells (iPSCs). This work is distinguished by its comprehensive experimental design and rigorous methodology, providing novel insights into the molecular mechanisms underlying iPSC formation.

Existing protocols for in vitro hyaline cartilage production utilizing human induced pluripotent stem cells (hiPSCs) have several challenges including a complex culturing process that uses undefined culture media, phenotypic instability, and batch-to-batch variability of the cell product. Here, our primary objective is to describe a simple, xeno- and feeder-free protocol for the generation of hyaline cartilage utilizing multi-tissue organoids (MTOs). We investigated gene regulatory networks during hiPSC-MTO differentiation using RNA sequencing and bioinformatics analyses, as well as histological and immunohistochemical methods. Interplays between bone morphogenetic protein (BMP) and neural fibroblast growth factor (FGF) pathways associated with the phenotypic transition of MTOs are described. Comparisons across transcriptomes revealed that the expression of chondrocyte-specific genes in MTOs correlates strongly with fetal lower limb chondrocytes. Single-cell RNA sequencing findings confirmed that the majority of cells belonged to the chondrogenic lineage and that they were similar across MTO batches, suggesting uniformity of the culture process. Collectively, these findings demonstrate the consistent emergence of hyaline cartilage in MTOs and the molecular pathways that govern this process, thereby establishing an accessible source of functional chondrocytes for future therapeutic evaluations.