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

TY - JOUR

T1 - Hematopoietic stem cells are regulated by Cripto, as an intermediary of HIF-1α in the hypoxic bone marrow niche

AU - Miharada, Kenichi

AU - Karlsson, Göran

AU - Rehn, Matilda

AU - Rörby, Emma

AU - Siva, Kavitha

AU - Cammenga, Jörg

AU - Karlsson, Stefan

N1 - © 2012 New York Academy of Sciences.

PY - 2012/8

Y1 - 2012/8

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Hypoxia

KW - Epidermal Growth Factor/chemistry

KW - GPI-Linked Proteins/chemistry

KW - Gene Expression

KW - Glycolysis

KW - Heat-Shock Proteins/metabolism

KW - Hematopoietic Stem Cells/classification

KW - Humans

KW - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism

KW - Intercellular Signaling Peptides and Proteins/chemistry

KW - Membrane Glycoproteins/chemistry

KW - Mice

KW - Mice, Knockout

KW - Models, Biological

KW - Neoplasm Proteins/chemistry

KW - Proto-Oncogene Proteins c-akt/metabolism

KW - Signal Transduction

KW - Stem Cell Niche

U2 - 10.1111/j.1749-6632.2012.06564.x

DO - 10.1111/j.1749-6632.2012.06564.x

M3 - Review

C2 - 22901256

SN - 0077-8923

VL - 1266

SP - 55

EP - 62

JO - Annals of the New York Academy of Sciences

JF - Annals of the New York Academy of Sciences

ER -