Stem Cell Reviews and Reports ( IF 4.5 ) Pub Date : 2021-02-14 , DOI: 10.1007/s12015-021-10131-z Hélia Fernandes 1 , João Moura 1 , Eugénia Carvalho 1, 2, 3
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Blood is generated throughout life by continued proliferation and differentiation of hematopoietic progenitors, while at the top of the hierarchy, hematopoietic stem cells (HSCs) remain largely quiescent. This way HSCs avoid senescence and preserve their capacity to repopulate the hematopoietic system. But HSCs are not always quiescent, proliferating extensively in conditions such as those found in the fetal liver. Understanding the elusive mechanisms that regulate HSC fate would enable us to comprehend a crucial piece of HSC biology and pave the way for ex-vivo HSC expansion with clear clinical benefit. Here we review how metabolism, endoplasmic reticulum stress and oxidative stress condition impact HSCs decision to self-renew or differentiate and how these signals integrate into the mammalian target of rapamycin (mTOR) pathway. We argue that the bone marrow microenvironment continuously favors differentiation through the activation of the mTOR complex (mTORC)1 signaling, while the fetal liver microenvironment favors self-renewal through the inverse mechanism. In addition, we also postulate that strategies that have successfully achieved HSC expansion, directly or indirectly, lead to the inactivation of mTORC1. Finally, we propose a mechanism by which mTOR signaling, during cell division, conditions HSC fate. This mechanism has already been demonstrated in mature hematopoietic cells (T-cells), that face a similar decision after activation, either undergoing clonal expansion or differentiation.
Graphical Abstract
中文翻译：
mTOR 信号作为造血干细胞命运的调节剂
血液是通过造血祖细胞的持续增殖和分化在整个生命中产生的，而在层次结构的顶部，造血干细胞 (HSC) 基本上保持静止。通过这种方式，HSC 可以避免衰老并保持其重新填充造血系统的能力。但 HSC 并不总是静止的，它们会在胎儿肝脏等条件下广泛增殖。了解调节 HSC 命运的难以捉摸的机制将使我们能够理解 HSC 生物学的关键部分并为离体铺平道路HSC 扩增具有明显的临床益处。在这里，我们回顾了代谢、内质网应激和氧化应激状况如何影响 HSC 自我更新或分化的决定，以及这些信号如何整合到哺乳动物雷帕霉素靶蛋白 (mTOR) 通路中。我们认为骨髓微环境通过激活 mTOR 复合物 (mTORC)1 信号持续有利于分化，而胎肝微环境通过反向机制有利于自我更新。此外，我们还假设成功实现 HSC 扩增的策略直接或间接导致 mTORC1 失活。最后，我们提出了一种机制，在细胞分裂过程中，mTOR 信号传导调节 HSC 的命运。这种机制已经在成熟的造血细胞（T细胞）中得到证实，
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