Cripto Regulates Hematopoietic Stem Cells as a Hypoxic-Niche-Related Factor through Cell Surface Receptor GRP78.

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Cripto Regulates Hematopoietic Stem Cells as a Hypoxic-Niche-Related Factor through Cell Surface Receptor GRP78. / Miharada, Kenichi; Karlsson, Göran; Rehn, Matilda; Rörby, Emma; Siva, Kavitha; Cammenga, Jörg; Karlsson, Stefan.

I: Cell Stem Cell, Vol. 9, Nr. 4, 2011, s. 330-344.

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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

PY - 2011

Y1 - 2011

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.

U2 - 10.1016/j.stem.2011.07.016

DO - 10.1016/j.stem.2011.07.016

M3 - Article

VL - 9

SP - 330

EP - 344

JO - Cell Stem Cell

JF - Cell Stem Cell

SN - 1934-5909

IS - 4

ER -