1. Hematopoietic stem cells are regulated by Cripto, as an intermediary of HIF-1α in the hypoxic bone marrow niche.
- Author
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Miharada K, Karlsson G, Rehn M, Rörby E, Siva K, Cammenga J, and Karlsson S
- Subjects
- Animals, Cell Hypoxia, Endoplasmic Reticulum Chaperone BiP, Epidermal Growth Factor chemistry, Epidermal Growth Factor genetics, GPI-Linked Proteins chemistry, GPI-Linked Proteins genetics, Gene Expression, Glycolysis, Heat-Shock Proteins metabolism, Hematopoietic Stem Cells classification, Humans, Intercellular Signaling Peptides and Proteins chemistry, Intercellular Signaling Peptides and Proteins genetics, Membrane Glycoproteins chemistry, Membrane Glycoproteins genetics, Mice, Mice, Knockout, Models, Biological, Neoplasm Proteins chemistry, Neoplasm Proteins genetics, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction, Stem Cell Niche, Epidermal Growth Factor metabolism, GPI-Linked Proteins metabolism, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells metabolism, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Intercellular Signaling Peptides and Proteins metabolism, Membrane Glycoproteins metabolism, Neoplasm Proteins metabolism
- Abstract
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., (© 2012 New York Academy of Sciences.)
- Published
- 2012
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