Department for Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund University, Lund, Sweden.
Ann N Y Acad Sci. 2012 Aug;1266:55-62. doi: 10.1111/j.1749-6632.2012.06564.x.
Cripto has been known as an embryonic stem (ES)- or tumor-related soluble/cell membrane protein. In this study, we demonstrated that Cripto has a role as an important regulatory factor for hematopoietic stem cells (HSCs). Recombinant Cripto sustained the reconstitution ability of HSCs in vitro. Flow cytometry analysis uncovered that GRP78, one of the candidate receptors for Cripto, was expressed on a subset of HSCs and could distinguish dormant/myeloid-biased HSCs and active/lymphoid-biased HSCs. Cripto is expressed in hypoxic endosteal niche cells where GRP78(+) HSCs mainly reside. Proteomics analysis revealed that Cripto-GRP78 binding stimulates glycolytic metabolism-related proteins and results in lower mitochondrial potential in HSCs. Furthermore, conditional knockout mice for HIF-1α, a master regulator of hypoxic responses, showed reduced Cripto expression and decreased GRP78(+) HSCs in the endosteal niche area. Thus, Cripto-GRP78 is a novel HSC regulatory signal mainly working in the hypoxic niche.
Cripto 已被确认为一种与胚胎干细胞 (ES) 或肿瘤相关的可溶性/细胞膜蛋白。在这项研究中，我们证明了 Cripto 作为造血干细胞 (HSCs) 的重要调节因子发挥作用。重组 Cripto 维持了 HSCs 的体外重建能力。流式细胞术分析揭示，Cripto 的候选受体之一 GRP78 表达在 HSCs 的一个亚群上，可区分休眠/髓系偏向的 HSCs 和活跃/淋巴系偏向的 HSCs。Cripto 表达在低氧骨内膜龛细胞中，GRP78(+) HSCs 主要存在于这些细胞中。蛋白质组学分析表明，Cripto-GRP78 结合刺激糖酵解代谢相关蛋白，导致 HSCs 中的线粒体潜能降低。此外，缺氧反应的主要调节因子 HIF-1α 的条件敲除小鼠显示出 Cripto 表达减少和骨内膜龛区的 GRP78(+) HSCs 减少。因此，Cripto-GRP78 是一种新型的 HSC 调节信号，主要在低氧龛中发挥作用。
