Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1

Daniel J. Ceradini; Anita R. Kulkarni; Matthew J. Callaghan; Oren M. Tepper; Nicholas Bastidas; Mark E. Kleinman; Jennifer M. Capla; Robert D. Galiano; Jamie P. Levine; Geoffrey C. Gurtner

doi:10.1038/nm1075

Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1

Daniel J. Ceradini, Anita R. Kulkarni, Matthew J. Callaghan, Oren M. Tepper, Nicholas Bastidas, Mark E. Kleinman, Jennifer M. Capla, Robert D. Galiano, Jamie P. Levine, Geoffrey C. Gurtner^*

^*Corresponding author for this work

Surgery, Plastic Surgery Division

Research output: Contribution to journal › Article › peer-review

2321 Scopus citations

Abstract

The trafficking of circulating stem and progenitor cells to areas of tissue damage is poorly understood. The chemokine stromal cell-derived factor-1 (SDF-1 or CXCL12) mediates homing of stem cells to bone marrow by binding to CXCR4 on circulating cells. SDF-1 and CXCR4 are expressed in complementary patterns during embryonic organogenesis and guide primordial stem cells to sites of rapid vascular expansion. However, the regulation of SDF-1 and its physiological role in peripheral tissue repair remain incompletely understood. Here we show that SDF-1 gene expression is regulated by the transcription factor hypoxia-inducible factor-1 (HIF-1) in endothelial cells, resulting in selective in vivo expression of SDF-1 in ischemic tissue in direct proportion to reduced oxygen tension. HIF-1-induced SDF-1 expression increases the adhesion, migration and homing of circulating CXCR4-positive progenitor cells to ischemic tissue. Blockade of SDF-1 in ischemic tissue or CXCR4 on circulating cells prevents progenitor cell recruitment to sites of injury. Discrete regions of hypoxia in the bone marrow compartment also show increased SDF-1 expression and progenitor cell tropism. These data show that the recruitment of CXCR4-positive progenitor cells to regenerating tissues is mediated by hypoxic gradients via HIF-1-induced expression of SDF-1.

Original language	English (US)
Pages (from-to)	858-864
Number of pages	7
Journal	Nature Medicine
Volume	10
Issue number	8
DOIs	https://doi.org/10.1038/nm1075
State	Published - Aug 2004

Funding

We thank L.E. Huang and G.L. Semenza for HIF plasmids, and R. Schneider and E. Fisher for critically reviewing the manuscript. This study was supported by the National Institutes of Health/National Institute for Biomedical Imaging and Bioengineering (grant EB002265 to G.C.G.), the Sarnoff Endowment for Cardiovascular Research (G.C.G) and the Juvenile Diabetes Research Foundation (O.M.T).

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1038/nm1075

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@article{5d2195becc43484381df7ddfa0672022,

title = "Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1",

abstract = "The trafficking of circulating stem and progenitor cells to areas of tissue damage is poorly understood. The chemokine stromal cell-derived factor-1 (SDF-1 or CXCL12) mediates homing of stem cells to bone marrow by binding to CXCR4 on circulating cells. SDF-1 and CXCR4 are expressed in complementary patterns during embryonic organogenesis and guide primordial stem cells to sites of rapid vascular expansion. However, the regulation of SDF-1 and its physiological role in peripheral tissue repair remain incompletely understood. Here we show that SDF-1 gene expression is regulated by the transcription factor hypoxia-inducible factor-1 (HIF-1) in endothelial cells, resulting in selective in vivo expression of SDF-1 in ischemic tissue in direct proportion to reduced oxygen tension. HIF-1-induced SDF-1 expression increases the adhesion, migration and homing of circulating CXCR4-positive progenitor cells to ischemic tissue. Blockade of SDF-1 in ischemic tissue or CXCR4 on circulating cells prevents progenitor cell recruitment to sites of injury. Discrete regions of hypoxia in the bone marrow compartment also show increased SDF-1 expression and progenitor cell tropism. These data show that the recruitment of CXCR4-positive progenitor cells to regenerating tissues is mediated by hypoxic gradients via HIF-1-induced expression of SDF-1.",

author = "Ceradini, {Daniel J.} and Kulkarni, {Anita R.} and Callaghan, {Matthew J.} and Tepper, {Oren M.} and Nicholas Bastidas and Kleinman, {Mark E.} and Capla, {Jennifer M.} and Galiano, {Robert D.} and Levine, {Jamie P.} and Gurtner, {Geoffrey C.}",

note = "Funding Information: We thank L.E. Huang and G.L. Semenza for HIF plasmids, and R. Schneider and E. Fisher for critically reviewing the manuscript. This study was supported by the National Institutes of Health/National Institute for Biomedical Imaging and Bioengineering (grant EB002265 to G.C.G.), the Sarnoff Endowment for Cardiovascular Research (G.C.G) and the Juvenile Diabetes Research Foundation (O.M.T).",

year = "2004",

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doi = "10.1038/nm1075",

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AU - Kulkarni, Anita R.

AU - Callaghan, Matthew J.

AU - Tepper, Oren M.

AU - Bastidas, Nicholas

AU - Kleinman, Mark E.

AU - Capla, Jennifer M.

AU - Galiano, Robert D.

AU - Levine, Jamie P.

AU - Gurtner, Geoffrey C.

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N2 - The trafficking of circulating stem and progenitor cells to areas of tissue damage is poorly understood. The chemokine stromal cell-derived factor-1 (SDF-1 or CXCL12) mediates homing of stem cells to bone marrow by binding to CXCR4 on circulating cells. SDF-1 and CXCR4 are expressed in complementary patterns during embryonic organogenesis and guide primordial stem cells to sites of rapid vascular expansion. However, the regulation of SDF-1 and its physiological role in peripheral tissue repair remain incompletely understood. Here we show that SDF-1 gene expression is regulated by the transcription factor hypoxia-inducible factor-1 (HIF-1) in endothelial cells, resulting in selective in vivo expression of SDF-1 in ischemic tissue in direct proportion to reduced oxygen tension. HIF-1-induced SDF-1 expression increases the adhesion, migration and homing of circulating CXCR4-positive progenitor cells to ischemic tissue. Blockade of SDF-1 in ischemic tissue or CXCR4 on circulating cells prevents progenitor cell recruitment to sites of injury. Discrete regions of hypoxia in the bone marrow compartment also show increased SDF-1 expression and progenitor cell tropism. These data show that the recruitment of CXCR4-positive progenitor cells to regenerating tissues is mediated by hypoxic gradients via HIF-1-induced expression of SDF-1.

AB - The trafficking of circulating stem and progenitor cells to areas of tissue damage is poorly understood. The chemokine stromal cell-derived factor-1 (SDF-1 or CXCL12) mediates homing of stem cells to bone marrow by binding to CXCR4 on circulating cells. SDF-1 and CXCR4 are expressed in complementary patterns during embryonic organogenesis and guide primordial stem cells to sites of rapid vascular expansion. However, the regulation of SDF-1 and its physiological role in peripheral tissue repair remain incompletely understood. Here we show that SDF-1 gene expression is regulated by the transcription factor hypoxia-inducible factor-1 (HIF-1) in endothelial cells, resulting in selective in vivo expression of SDF-1 in ischemic tissue in direct proportion to reduced oxygen tension. HIF-1-induced SDF-1 expression increases the adhesion, migration and homing of circulating CXCR4-positive progenitor cells to ischemic tissue. Blockade of SDF-1 in ischemic tissue or CXCR4 on circulating cells prevents progenitor cell recruitment to sites of injury. Discrete regions of hypoxia in the bone marrow compartment also show increased SDF-1 expression and progenitor cell tropism. These data show that the recruitment of CXCR4-positive progenitor cells to regenerating tissues is mediated by hypoxic gradients via HIF-1-induced expression of SDF-1.

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Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1

Abstract

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