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Hematopoietic stem cells are regulated by Cripto, as an intermediary of HIF‐1α in the hypoxic bone marrow niche
Author(s) -
Miharada Kenichi,
Karlsson Göran,
Rehn Matilda,
Rörby Emma,
Siva Kavitha,
Cammenga Jörg,
Karlsson Stefan
Publication year - 2012
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2012.06564.x
Subject(s) - haematopoiesis , niche , bone marrow , stem cell , microbiology and biotechnology , hypoxia (environmental) , hematopoietic stem cell , stem cell niche , biology , chemistry , immunology , progenitor cell , ecology , organic chemistry , oxygen
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.