Faculty of Life Sciences and Medicine, Centre for Education, King's College London, London, UK.
J Cell Physiol. 2021 Oct;236(10):7266-7289. doi: 10.1002/jcp.30383. Epub 2021 Apr 5.
Mesenchymal stem cells (MSCs) are located in various tissues where these cells show niche-dependent multilineage differentiation and secrete immunomodulatory molecules to support numerous physiological processes. Due to their regenerative and reparative properties, MSCs are extremely valuable for cell-based therapy in tackling several pathological conditions including COVID-19. Iron is essential for MSC processes but iron-loading, which is common in several chronic conditions, hinders normal MSC functionality. This not only aggravates disease pathology but can also affect allogeneic and autologous MSC therapy. Thus, understanding MSCs from an iron perspective is of clinical significance. Accordingly, this review highlights the roles of iron and iron-related proteins in MSC physiology. It describes the contribution of iron and endogenous iron-related effectors like hepcidin, ferroportin, transferrin receptor, lactoferrin, lipocalin-2, bone morphogenetic proteins and hypoxia inducible factors in MSC biology. It summarises the excess-iron-induced alterations in MSC components, processes and discusses signalling pathways involving ROS, PI3K/AKT, MAPK, p53, AMPK/MFF/DRP1 and Wnt. Additionally, it evaluates the endogenous and exogenous saviours of MSCs against iron-toxicity. Lastly, it elaborates on the involvement of MSCs in the pathology of clinical conditions of iron-excess, namely, hereditary hemochromatosis, diabetes, β-thalassaemia and myelodysplastic syndromes. This unique review integrates the distinct fields of iron regulation and MSC physiology. Through an iron-perspective, it describes both mechanistic and clinical aspects of MSCs and proposes an iron-linked MSC-contribution to physiology, pathology and therapeutics. It advances the understanding of MSC biology and may aid in identifying signalling pathways, molecular targets and compounds for formulating adjunctive iron-based therapies for excess-iron conditions, and thereby inform regenerative medicine.
间充质干细胞（MSCs）位于各种组织中，这些细胞在这些龛位中表现出依赖于龛位的多谱系分化，并分泌免疫调节分子，以支持众多生理过程。由于其再生和修复特性，MSCs 在基于细胞的治疗中极具价值，可用于治疗多种病理状况，包括 COVID-19。铁对于 MSC 过程至关重要，但几种慢性疾病中常见的铁过载会阻碍正常的 MSC 功能。这不仅会加重疾病的病理，还会影响同种异体和自体 MSC 治疗。因此，从铁的角度理解 MSCs 具有临床意义。因此，本综述强调了铁和铁相关蛋白在 MSC 生理学中的作用。它描述了铁和内源性铁相关效应物（如铁调素、亚铁转运蛋白、转铁蛋白受体、乳铁蛋白、脂联素-2、骨形态发生蛋白和缺氧诱导因子）在 MSC 生物学中的贡献。它总结了过量铁引起的 MSC 成分、过程的改变，并讨论了涉及 ROS、PI3K/AKT、MAPK、p53、AMPK/MFF/DRP1 和 Wnt 的信号通路。此外，它评估了 MSC 对抗铁毒性的内源性和外源性保护剂。最后，它阐述了 MSCs 在铁过多的临床疾病病理中的参与，即遗传性血色素沉着症、糖尿病、β-地中海贫血和骨髓增生异常综合征。本综述独特地整合了铁调节和 MSC 生理学的不同领域。通过铁的视角，它描述了 MSC 的机制和临床方面，并提出了 MSC 对生理、病理和治疗的铁相关贡献。它促进了对 MSC 生物学的理解，并有助于确定信号通路、分子靶点和化合物，以制定针对铁过多情况的辅助铁基治疗方法，从而为再生医学提供信息。
