Hematopoietic stem cells are regulated by Cripto, as an intermediary of HIF-1 α in the hypoxic bone marrow niche

摘要

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). Recom-binant 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-1 α, 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.