STEM CELLS最新文献

Recent studies evidence an altered bioenergetic profile and higher adipogenic commitment in the mesenchymal stem cells (MSC) from neonates of mothers with obesity. We hypothesize that these alterations may also affect the secretome of these cells. The aim of this study was to characterize the secretome of MSCs from the offspring of women with obesity compared to the ones from normal-weight women, both before and during adipogenesis. Wharton's jelly-derived MSCs were isolated from newborns of normal-weight women (NW-MSC; Body Mass Index 18.5-24.5 kg/m2) and women with obesity (OB-MSC; Body Mass Index > 30 kg/m2) and cultured for 0, 5 and 21 days of adipogenesis. The secretome from these cells was collected during the three timepoints and characterized by mass spectrometry. Our findings reveal fundamental differences in the secretome profiles, primarily associated with pathways involved in cellular and metabolic processes. Maternal obesity was found to decrease redox capacity at day 0 but subsequently triggered a compensatory increase in redox proteins during adipogenesis of OB-MSCs. Additionally, OB-MSCs secreted higher levels of lipid synthesis-related proteins and proinflammatory adipokines, which may contribute to the dysregulated adipogenesis observed in obesity. These preliminary data indicate that maternal obesity programs the secretome of neonatal MSCs, supporting the hypothesis that maternal obesity imprints early progenitor cells and potentially dictates the future metabolic status of the offspring's adipocytes.

Despite breakthroughs in molecularly targeted and immune therapies, the prognosis for patients with urinary bladder cancer (UBC) has remained unsatisfactory over the past few decades. Understanding the molecular underpinnings of UBC treatment refractoriness is crucial for identifying novel therapeutic targets and strategies. Cancer stemness plays a pivotal role in the oncogenesis and treatment resistance of UBC, while the underlying molecular regulatory mechanisms are poorly understood. We identified isoform 1 of ASPM (ASPM-i1) as the most upregulated stemness-associated factor in tumorigenic UBC cells, predominantly expressed by ALDH1+ stem-like cancer cells. Pairing genetic ASPM-i1 inhibition with standard chemotherapeutic agents used in the treatment of UBC, including cisplatin and gemcitabine, circumvents the treatment resistance of tumorigenic and stem-like UBC cells. Mechanistically, ASPM-i1 interacts with the Disheveled (DVL) and intracellular NOTCH proteins, thereby attenuating CUL3- or FBXW7-mediated ubiquitination and the subsequent proteasomal degradation. The regulatory module concomitantly enhances the activities and ligand responsiveness of the Wnt and Notch signaling pathways in UBC cells. As a result, ASPM-i1 inhibition sensitized tumorigenic UBC cells to chemotherapy in a NOTCH- and DVL-dependent manner. In human UBC tissues, ASPM-i1 shows substantial cell-to-cell heterogeneity and is upregulated in a subset (46.4%) of tumors, correlating with poor clinical prognosis. This study reveals a crucial co-regulatory module of Notch and Wnt signaling that mediates stemness and chemotherapy resistance in tumorigenic UBC cells; its inhibition provides a novel approach to enhance chemosensitivity and improve therapeutic outcome in human UBC.

Bovine embryonic stem cells (bESCs) can greatly enhance the understanding of bovine embryonic development and applications for disease-resistance, biomedical, and zoonotic pre-clinical models. However, formative bESCs with distinct morphology and complete differentiation capacity are still unreported. We document here the generation of formative bESCs (bFSCs) which are pluripotent both in vitro and in vivo, and efficiently converted into neural progenitor cells (NPCs) and primordial germ cell-like cells (PGCLCs) by direct differentiation. Transcriptomic analysis reveals these cells exhibited distinct metabolic features from human and mouse ESCs and early embryos. bFSCs contributed to a wide range of cell types within embryonic and extraembryonic tissues after aggregating with mouse and bovine embryos, as confirmed by chimeric experiment and single cell RNA-seq (scRNA-seq). The establishment of bFSCs with dual developmental plasticity represents a milestone for agricultural biotechnology and decoding the underlying mechanism of bona fide bovine pluripotency.

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.

Determining the potency of MSCs is a critical component of their application as cellular therapies. The function of MSCs does not rely on a single mechanism but rather on overlapping and cumulative effector pathways, which necessitates the assay matrix strategy in potency analysis. Artificial intelligence (AI) tools can significantly enhance the assay matrix strategy by generating novel potency scores that capture unified critical quality attributes that may not be readily discernible through human analysis. AI can provide precise potency metrics for investigational MSC products by comparing them to appropriate controls. The next generation of MSC potency analysis will increasingly rely on AI tools, as they can match patients with MSC products exhibiting the most appropriate potency profiles for personalized and targeted therapies. A significant challenge in deploying AI tools is the need for robust predictors of efficacy that relates to the potency of investigational MSC products. Nevertheless, AI has the potential to stratify patients who are most likely to respond to MSC therapy by leveraging clinical data in combination with detailed potency analyses. We discuss these opportunities and challenges in this perspective article.

Background: Adipose-derived stem cell 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.

Conclusions: 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.

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.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely regarded as the most potent curative cell therapy for a range of malignancies, particularly hematologic cancers. However, its clinical application remains significantly constrained by acute graft-versus-host disease (aGVHD), a severe and potentially fatal complication. As such, developing more effective strategies to prevent and manage aGVHD has become an urgent priority in the field. In a groundbreaking study, the team led by Zhan Cheng and Zhu Xiaoyu introduced a novel time-based approach, revealing that the biological rhythm regulating the immune microenvironment can be harnessed to optimize the timing of hematopoietic stem cell infusion. Their findings demonstrate that this chronotherapeutic strategy can significantly reduce the incidence of aGVHD, offering a simple, drug-free, and cost-free innovation to improve outcomes in allo-HSCT.

Epicardial-to-mesenchymal transition (EMT) is essential for generating progenitor cells that shape cardiac development, but the molecular control of EMT and its paracrine effects on cardiomyocytes remain poorly elucidated. Here, we defined a novel PKR1-miR-124-SNAI2 signaling axis that orchestrates EMT and coordinates myocardial maturation. Conditional deletion of the prokineticin receptor (PKR1) in mice Tcf21+ epicardial cells caused embryonic lethality and congenital heart disease-like anomalies, including ventricular rupture, arrhythmia, myocardial fibrosis, and impaired contractility. Transcriptomic profiling revealed marked upregulation of miR-124, concurrent with deregulation of EMT genes and signatures of immature cardiomyocytes. Mechanistically, miR-124 directly targets the 3' untranslated region of SNAI2, suppressing this key EMT regulator, resulting in failed EMT, apoptosis, and fibrosis in the epicardium. Functional rescue through miR-124 inhibition or PKR1 reintroduction restores SNAI2 expression, revives EMT, enhances cell survival, and promotes proper cardiomyocyte maturation. Paracrine effects were substantiated by conditioned media and ex vivo assays, demonstrating that epicardial-derived miR-124 suppressed cardiomyocyte contractility and cardiac maturity gene expression-thereby functionally linking epicardial disruption to myocardial immaturity. These findings establish miR-124 as a critical mediator of epicardial-myocardial communication with PKR1 as its upstream regulator. By integrating epicardial plasticity, myocardial maturation, and ECM homeostasis, our work reveals that targeting the PKR1-miR-124-SNAI2 pathway offers a novel mechanistic framework and potential therapeutic target for preventing or treating congenital heart disease.