Kaimakis P, Crisan M, Dzierzak E
Erasmus Medical Center, Erasmus MC Stem Cell Institute, Dept. of Cell Biology, PO Box 2040, 3000 CA Rotterdam, Netherlands.
Biochim Biophys Acta. 2013 Feb;1830(2):2395-403. doi: 10.1016/j.bbagen.2012.10.004. Epub 2012 Oct 12.
The cornerstone of the adult hematopoietic system and clinical treatments for blood-related disease is the cohort of hematopoietic stem cells (HSC) that is harbored in the adult bone marrow microenvironment. Interestingly, this cohort of HSCs is generated only during a short window of developmental time. In mammalian embryos, hematopoietic progenitor and HSC generation occurs within several extra- and intraembryonic microenvironments, most notably from 'hemogenic' endothelial cells lining the major vasculature. HSCs are made through a remarkable transdifferentiation of endothelial cells to a hematopoietic fate that is long-lived and self-renewable. Recent studies are beginning to provide an understanding of the biochemical signaling pathways and transcription factors/complexes that promote their generation.
The focus of this review is on the biochemistry behind the generation of these potent long-lived self-renewing stem cells of the blood system. Both the intrinsic (master transcription factors) and extrinsic regulators (morphogens and growth factors) that affect the generation, maintenance and expansion of HSCs in the embryo will be discussed.
The generation of HSCs is a stepwise process involving many developmental signaling pathways, morphogens and cytokines. Pivotal hematopoietic transcription factors are required for their generation. Interestingly, whereas these factors are necessary for HSC generation, their expression in adult bone marrow HSCs is oftentimes not required. Thus, the biochemistry and molecular regulation of HSC development in the embryo are overlapping, but differ significantly from the regulation of HSCs in the adult.
HSC numbers for clinical use are limiting, and despite much research into the molecular basis of HSC regulation in the adult bone marrow, no panel of growth factors, interleukins and/or morphogens has been found to sufficiently increase the number of these important stem cells. An understanding of the biochemistry of HSC generation in the developing embryo provides important new knowledge on how these complex stem cells are made, sustained and expanded in the embryo to give rise to the complete adult hematopoietic system, thus stimulating novel strategies for producing increased numbers of clinically useful HSCs. This article is part of a Special Issue entitled Biochemistry of Stem Cells.
成体造血系统及血液相关疾病临床治疗的基石是存在于成体骨髓微环境中的造血干细胞（HSC）群体。有趣的是，这群造血干细胞仅在发育的短暂窗口期产生。在哺乳动物胚胎中，造血祖细胞和造血干细胞的产生发生在多个胚胎外和胚胎内微环境中，最显著的是来自主要脉管系统内衬的“造血”内皮细胞。造血干细胞是通过内皮细胞向具有长期存活和自我更新能力的造血命运的显著转分化而形成的。最近的研究开始揭示促进其产生的生化信号通路以及转录因子/复合体。
本综述的重点是血液系统中这些强大的、长期存活且自我更新的干细胞产生背后的生物化学机制。将讨论影响胚胎中造血干细胞产生、维持和扩增的内在（主要转录因子）和外在调节因子（形态发生素和生长因子）。
造血干细胞的产生是一个涉及许多发育信号通路、形态发生素和细胞因子的逐步过程。关键的造血转录因子是其产生所必需的。有趣的是，虽然这些因子对造血干细胞的产生是必需的，但它们在成体骨髓造血干细胞中的表达通常并非必需。因此，胚胎中造血干细胞发育的生物化学和分子调控有重叠部分，但与成体中造血干细胞的调控有显著差异。
临床可用的造血干细胞数量有限，尽管对成体骨髓中造血干细胞调控的分子基础进行了大量研究，但尚未发现一组生长因子、白细胞介素和/或形态发生素能充分增加这些重要干细胞的数量。了解发育中胚胎造血干细胞产生的生物化学机制，为这些复杂干细胞如何在胚胎中形成、维持和扩增以产生完整的成体造血系统提供了重要的新知识，从而激发了产生更多临床可用造血干细胞的新策略。本文是名为“干细胞生物化学”的特刊的一部分。
