The Sidney Kimmel Comprehensive Cancer Center, and Division of Hematology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287.
Proc Natl Acad Sci U S A. 2013 Oct 1;110(40):16121-6. doi: 10.1073/pnas.1305937110. Epub 2013 Sep 16.
The high expression of aldehyde dehydrogenase 1, also known as retinaldehyde dehydrogenase, by hematopoietic stem cells (HSCs) suggests an important role for retinoic acid (RA) signaling in determining the fate of these cells. We found that primitive human bone marrow-derived CD34(+)CD38(-) cells not only highly express aldehyde dehydrogenase 1, but also the RA receptor α. Despite the up-regulation of early components of RA signaling, the downstream pathway remained inactive in the primitive CD34(+)CD38(-) cells. Primitive hematopoietic cells rapidly undergo terminal differentiation when cultured away from their microenvironment; however, we found that inhibition of RA signaling maintained their primitive phenotype and function, and promoted their self-renewal. HSCs reside in a complex microenvironment that enforces the balance between self-renewal and differentiation. The exact physiologic mechanisms by which the niche controls HSC fate remain elusive. The embryonic gonadal microenvironment has recently been shown to determine germ-cell fate by degrading RA through expression of the P450 retinoid-inactivating enzyme CYP26B1. We found that the bone marrow microenvironment similarly can control primitive hematopoietic cell fate via modulation of retinoid bioavailability. Accordingly, we found that bone marrow stromal cell CYP26 was also able to inactivate retinoids in serum, preventing RA signaling. Thus, primitive hematopoietic cells appear to be intrinsically programmed to undergo RA-mediated differentiation unless prevented from doing so by bone marrow niche CYP26. Modulation of RA signaling also holds promise for clinical HSC expansion, a prerequisite for the wide-scale use of these cells in regenerative medicine and gene therapy.
造血干细胞（HSCs）中醛脱氢酶 1 的高表达，也称为视黄醛脱氢酶，表明视黄酸（RA）信号在决定这些细胞命运方面起着重要作用。我们发现，原始的人骨髓来源的 CD34+CD38-细胞不仅高度表达醛脱氢酶 1，还表达 RA 受体 α。尽管 RA 信号的早期成分上调，但下游途径在原始 CD34+CD38-细胞中仍然不活跃。原始造血细胞在远离其微环境的情况下迅速经历终末分化；然而，我们发现 RA 信号的抑制维持了它们的原始表型和功能，并促进了它们的自我更新。HSCs 存在于一个复杂的微环境中，该微环境在自我更新和分化之间维持平衡。龛位控制 HSC 命运的确切生理机制仍然难以捉摸。最近已经表明，胚胎性腺微环境通过表达 P450 视黄醇失活酶 CYP26B1 降解 RA 来决定生殖细胞命运。我们发现，骨髓微环境同样可以通过调节视黄醇的生物利用度来控制原始造血细胞的命运。因此，我们发现骨髓基质细胞 CYP26 也能够在血清中使视黄醇失活，从而阻止 RA 信号。因此，原始造血细胞似乎内在地编程为进行 RA 介导的分化，除非骨髓龛 CYP26 阻止其进行。RA 信号的调节也为临床 HSC 扩增提供了希望，这是这些细胞在再生医学和基因治疗中广泛应用的前提。
