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.

The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

“…Ceradini et al have demonstrated that SDF-1 expression in ischemic sites is directly correlated with the amplitude of hypoxia [12]. Signaling activated by hypoxia leading to SDF-1 upregulation involves the recruitment of integrin-linked kinase and hypoxia-inducible factor-1 (HIF-1) [12,13]. Increased expression of SDF-1 in human and rodent models of infarcted myocardium has been confirmed by several studies [14][15][16][17].…”

“…Indeed, hypoxic and/ or apoptotic conditions are the trigger to induce expression of cytokines and chemokines. Ceradini et al have demonstrated that SDF-1 expression in ischemic sites is directly correlated with the amplitude of hypoxia [12]. Signaling activated by hypoxia leading to SDF-1 upregulation involves the recruitment of integrin-linked kinase and hypoxia-inducible factor-1 (HIF-1) [12,13].…”

Inhibitory efficacy of hypoxia-inducible factor 1α short hairpin RNA plasmid DNA-loaded poly (D, L-lactide-co-glycolide) nanoparticles on choroidal neovascularization in a laser-induced rat model

“…13 Over the past few years, in vivo gene transfer efficiency has increased significantly. However, as the gene-silencing effect of siRNA and shRNA-expressing pDNA is transient, attention should be paid to the duration of the RNAi effect.…”

“…10 However, a potential drawback of these therapies is that there has been some evidence showing that suppressed expression of VEGF alone is not sufficient to inhibit CNV. [11][12][13] The initiation of a submacular wound-healing response may require a hypoxic stimulus, which in turn leads to the production of hypoxia-inducible factor-1(HIF-1), a transcription factor that functions as a master regulator of oxygen homeostasis. 14 Clinical studies have shown that the age-related changes in Bruch's membrane and the dropout of choriocapillaris cause impaired diffusion of oxygen.…”

Biliary Epithelial Cells Are Not the Predominant Source of Hepatic CXCL12

“…32 The relationship between CXCL12 and low oxygen tension is also seen within the bone marrow stem cell niche, where regions of hypoxia demonstrate increased CXCL12 expression. 33,34 Similar to the bone marrow compartment, the liver is considered a low oxygen tension organ. The hepatic lobule can be divided into three functional zones, each with different oxygen tensions that decrease from zone 1 (60 to 65 mmHg), directly adjacent to the portal tract, to zone 3 (30 to 35 mmHg), at the level of the central vein.…”