Cripto regulates hematopoietic stem cells as a hypoxic-niche-related factor through cell surface receptor GRP78

TY - JOUR

T1 - Cripto regulates hematopoietic stem cells as a hypoxic-niche-related factor through cell surface receptor GRP78

AU - Miharada, Kenichi

AU - Karlsson, Göran

AU - Rehn, Matilda

AU - Rörby, Emma

AU - Siva, Kavitha

AU - Cammenga, Jörg

AU - Karlsson, Stefan

N1 - Copyright © 2011 Elsevier Inc. All rights reserved.

PY - 2011/10/4

Y1 - 2011/10/4

N2 - Hematopoietic stem cells (HSCs) are maintained in hypoxic niches in endosteal regions of bones. Here we demonstrate that Cripto and its receptor GRP78 are important regulators of HSCs in the niche. Flow cytometry analyses revealed two distinct subpopulations of CD34(-)KSL cells based on the expression of GRP78, and these populations showed different reconstitution potential in transplantation assays. GRP78(+)HSCs mainly reside in the endosteal area, are more hypoxic, and exhibit a lower mitochondrial potential, and their HSC capacity was maintained in vitro by Cripto through induction of higher glycolytic activity. Additionally, HIF-1α KO mice have decreased numbers of GRP78(+)HSCs and reduced expression of Cripto in the endosteal niche. Furthermore, blocking GRP78 induced a movement of HSCs from the endosteal to the central marrow area. These data suggest that Cripto/GRP78 signaling is an important pathway that regulates HSC quiescence and maintains HSCs in hypoxia as an intermediary of HIF-1α.

AB - Hematopoietic stem cells (HSCs) are maintained in hypoxic niches in endosteal regions of bones. Here we demonstrate that Cripto and its receptor GRP78 are important regulators of HSCs in the niche. Flow cytometry analyses revealed two distinct subpopulations of CD34(-)KSL cells based on the expression of GRP78, and these populations showed different reconstitution potential in transplantation assays. GRP78(+)HSCs mainly reside in the endosteal area, are more hypoxic, and exhibit a lower mitochondrial potential, and their HSC capacity was maintained in vitro by Cripto through induction of higher glycolytic activity. Additionally, HIF-1α KO mice have decreased numbers of GRP78(+)HSCs and reduced expression of Cripto in the endosteal niche. Furthermore, blocking GRP78 induced a movement of HSCs from the endosteal to the central marrow area. These data suggest that Cripto/GRP78 signaling is an important pathway that regulates HSC quiescence and maintains HSCs in hypoxia as an intermediary of HIF-1α.

KW - Animals

KW - Biomarkers/metabolism

KW - Bone and Bones/cytology

KW - Cell Hypoxia/genetics

KW - Epidermal Growth Factor/genetics

KW - Glycolysis

KW - Heat-Shock Proteins/metabolism

KW - Hematopoietic Stem Cells/cytology

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

KW - Membrane Glycoproteins/genetics

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Neoplasm Proteins/genetics

KW - Proto-Oncogene Proteins c-akt/metabolism

KW - Receptors, Cell Surface/metabolism

KW - Signal Transduction/genetics

KW - Stem Cell Niche

KW - Time Factors

KW - Up-Regulation/genetics

U2 - 10.1016/j.stem.2011.07.016

DO - 10.1016/j.stem.2011.07.016

M3 - Journal article

C2 - 21982233

SN - 1934-5909

VL - 9

SP - 330

EP - 344

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 4

ER -