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

Research output: Contribution to journalArticlepeer-review

2079 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 languageEnglish (US)
Pages (from-to)858-864
Number of pages7
JournalNature Medicine
Volume10
Issue number8
DOIs
StatePublished - Aug 2004

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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