The maintenance of blood homeostasis relies heavily on hematopoietic stem cells (HSC), whose function is highly sensitive to oxidative stress caused by disrupted equilibrium between reactive oxygen species (ROS) and antioxidant systems. This review provides a comprehensive examination of the current strategies aimed at therapeutically targeting oxidative stress in HSC, outlining both the challenges and the advancements in this domain. We discuss the intricate mechanisms by which oxidative stress disrupts HSC self‐renewal, quiescence, and differentiation, as well as the implications for aging and hematological malignancies. The function of the hypoxic bone marrow microenvironment in reducing oxidative damage is highlighted alongside the metabolic adaptations that support HSC viability. Furthermore, we explore emerging therapeutic approaches, including antioxidants, gene editing technologies, and niche modulation, that aim to enhance HSC function and resilience in the face of oxidative stress. Drawing on recent preclinical and clinical findings, this review highlights the need for novel strategies that integrate a deeper understanding of redox biology with therapeutic interventions to enhance outcomes in HSC transplantation and regeneration. This integration of current findings and emerging strategies provides valuable insights for developing targeted therapies aimed at preserving HSC integrity in the treatment of hematologic diseases.
Background Poor retention of transplanted stem cells in the liver cirrhosis milieu (LCM) which critically blunts long‐term efficacy, remains unexplained. This study investigated the effects of a small peptide chemical compound (icMet) delivered intravenously for cMet receptor inhibition at the diethylnitrosamine (DEN)‐induced middle‐to‐late cirrhotic liver stage (CLS 8/9 ), focusing on apoptosis prevention, endogenous hepatic regeneration and the long‐term efficacy of transplanted hepatic stem/progenitor cells (MLpvNG2 cells). Methods C57BL/6 mice with CLS 8/9 liver injury were used as recipients. icMet was used before or during MLpvNG2 cell therapy. Tissues from CLS 8/9 livers were also used to generate conditioned medium (CM, CLS 8/9 CM) to observe MLpvNG2 cell activity in response to the injured liver‐related cues. Results: Compared with CLS 8/9 mice without icMet, mice subjected to icMet administration showed increased survival rates of transplanted MLpvNG2 cells in the CLS 8/9 livers, as well as enhanced downstream hepatic repair and long‐term healing. In CLS 8/9 CM cultures, the survival of MLpvNG2 cells within icMet was similar to that observed in CLS 8/9 livers. In terms of the underlying mechanisms, it is possible that icMet pretreatment promotes proliferation and prevents apoptosis of grafted MLpvNG2 cells, activating host hepatic functional differentiation, particularly sinusoidal reconstruction, which can initiate hepatocyte regeneration. In addition, the relieved fibrotic load could also favor repopulation by donor cells, leading to long‐term treatment efficacy. Conclusions A strategy involving a pre‐ or during cell treatment that blocks the cMet receptor achieves apoptosis resistance of transplanted MLpvNG2 cells in the LCM and promotes endogenous hepatic regeneration, leading to long‐term treatment efficacy.
Astaxanthin exerts potent protective effects against stem cell apoptosis. This study investigated the protective efficacy of astaxanthin against oxidized low-density lipoprotein (ox-LDL)-induced oxidative stress and apoptosis in endothelial progenitor cells (EPCs). Human early EPCs cultured in vitro were challenged with ox-LDL in the presence or absence of astaxanthin. Results showed that ox-LDL exposure significantly reduced nuclear factor-E2-related factor 2 (Nrf2) nuclear translocation in EPCs, while increasing oxidative stress and apoptosis rates. Astaxanthin pretreatment attenuated ox-LDL-induced reactive oxygen species (ROS) generation and EPC apoptosis, preserved mitochondrial membrane potential (MMP), and concomitantly enhanced nuclear Nrf2 accumulation while upregulating NQO1, HO-1, and glutathione (GSH) levels. Nrf2 small interfering RNA (siRNA)-mediated knockdown completely abolished astaxanthin-induced NQO1 and HO-1 upregulation. Mechanistically, astaxanthin promoted Akt phosphorylation (activation) and inhibited glycogen synthase kinase 3 beta (GSK-3 beta) phosphorylation. Pretreatment with LY294002 (a phosphoinositide 3-kinase/PI3K inhibitor) suppressed astaxanthin-induced Nrf2 nuclear translocation, exacerbated ROS production, and reduced NQO1 and GSH levels. Additionally, astaxanthin blocked ox-LDL-induced caspase-3 upregulation and preserved EPC migration and tube formation. Nrf2 siRNA eliminated the protective effects of astaxanthin on EPC ROS production, MMP preservation, apoptosis, and migration; tube formation was not assessed. Overall, these in vitro findings using cells from healthy donors provide mechanistic support for the potential role of astaxanthin in the PI3K/Akt/GSK-3/Nrf2 pathway. However, the application of astaxanthin in the prevention and treatment of atherosclerotic disease requires further validation in disease-relevant models and clinical studies, as the present study was limited to in vitro results.
Background Abnormal polarization of macrophages toward the M1 phenotype is a key pathogenic mechanism in acute lung injury (ALI). Bone marrow mesenchymal stem cell (MSC)-derived exosomes (BMSC-Exos) represent a promising therapeutic approach to inhibit macrophage M1 polarization and alleviate ALI, but the molecular mediators involved are incompletely defined. This study aimed to identify the responsible exosomal mediator and to define its downstream signaling.Methods An ALI mouse model was established via intratracheal LPS instillation, and a cell injury model was constructed using LPS-stimulated RAW264.7 cells. Exos were isolated from human BMSCs. Lung injury was assessed through HE staining, lung wet/dry weight ratio, bronchoalveolar lavage fluid (BALF) protein concentration, and total BALF cell count. The expression levels of related genes and proteins were assessed using RT-qPCR, western blotting, ELISA, and immunofluorescence.Results Treatment with BMSC-Exos significantly ameliorated lung damage in ALI mice and reduced the lung wet/dry weight ratio, BALF protein concentration, and total inflammatory cell count. Additionally, BMSC-Exos reduced the expression of M1 macrophage markers (iNOS, CD80, and CD86) and proinflammatory cytokines (IL-1 beta, IL-6, and TNF-alpha), thereby inhibiting macrophage M1 polarization. Mechanistically, BMSC-Exos suppressed the LPS-induced activation of the PI3K/AKT signaling pathway, whereas the PI3K/AKT activator 740 Y-P weakened the inhibitory effect of BMSC-Exos on M1 polarization. The expression of miR-451a was significantly downregulated in ALI and enriched in BMSC-Exos. miR-451a inhibits the PI3K/AKT signaling pathway by targeting and suppressing TLR4 expression. miR-451a knockdown or TLR4 overexpression attenuated the therapeutic effects of BMSC-Exos on ALI.Conclusion BMSC-Exos-derived miR-451a inhibited the PI3K/AKT signaling pathway by downregulating TLR4 expression, thereby suppressing macrophage M1 polarization and alleviating ALI.
Ischemic stroke is a refractory cerebrovascular disorder characterized by high incidence, disability, and mortality rates. Its core pathological features include extensive neuronal death within the ischemic zone and irreversible damage to neural circuits. Given the limited regenerative capacity of the central nervous system, regulating endogenous neurogenesis and reconstructing functional circuits are important strategies for treating neurological deficits. This narrative review summarizes the dynamic processes of activation, proliferation, migration, and differentiation of endogenous neural stem cells (NSCs) following ischemic stroke, and explores the therapeutic potential of exogenous NSC transplantation and its current applications. Distinct from existing reviews, this work systematically integrates neuroimmune crosstalk, metabolic reprogramming, and meningeal‑choroid‑plexus‑mediated niche regulation, further proposing a staged multimodal precision intervention framework. We also highlight critical confounding factors, including aging‑driven regenerative decline, and explicitly separate preclinical animal findings from limited human clinical evidence. Meanwhile, this review elucidates the core mechanisms through which neurogenesis mediates tissue repair and functional recovery in ischemic brain tissue. Furthermore, this review refines future research directions, such as spatiotemporally specific precision interventions and multimodal combination therapies, providing a systematic theoretical basis and research framework for developing novel NSC‐based therapeutic strategies for ischemic stroke.
