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Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes.

ABSTRACT: The mechanisms through which hematopoietic cytokines accelerate revascularization are unknown. Here, we show that the magnitude of cytokine-mediated release of SDF-1 from platelets and the recruitment of nonendothelial CXCR4+ VEGFR1+ hematopoietic progenitors, 'hemangiocytes,' constitute the major determinant of revascularization. Soluble Kit-ligand (sKitL), thrombopoietin (TPO, encoded by Thpo) and, to a lesser extent, erythropoietin (EPO) and granulocyte-macrophage colony-stimulating factor (GM-CSF) induced the release of SDF-1 from platelets, enhancing neovascularization through mobilization of CXCR4+ VEGFR1+ hemangiocytes. Although revascularization of ischemic hindlimbs was partially diminished in mice deficient in both GM-CSF and G-CSF (Csf2-/- Csf3-/-), profound impairment in neovascularization was detected in sKitL-deficient Mmp9-/- as well as thrombocytopenic Thpo-/- and TPO receptor-deficient (Mpl-/-) mice. SDF-1-mediated mobilization and incorporation of hemangiocytes into ischemic limbs were impaired in Thpo-/-, Mpl-/- and Mmp9-/- mice. Transplantation of CXCR4+ VEGFR1+ hemangiocytes into Mmp9-/- mice restored revascularization, whereas inhibition of CXCR4 abrogated cytokine- and VEGF-A-mediated mobilization of CXCR4+ VEGFR1+ cells and suppressed angiogenesis. In conclusion, hematopoietic cytokines, through graded deployment of SDF-1 from platelets, support mobilization and recruitment of CXCR4+ VEGFR1+ hemangiocytes, whereas VEGFR1 is essential for their angiogenic competency for augmenting revascularization. Delivery of SDF-1 may be effective in restoring angiogenesis in individuals with vasculopathies.

SUBMITTER: Jin DK

PROVIDER: S-EPMC2754288 | biostudies-literature | 2006 May

REPOSITORIES: biostudies-literature

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Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes.

Jin David K DK Shido Koji K Kopp Hans-Georg HG Petit Isabelle I Shmelkov Sergey V SV Young Lauren M LM Hooper Andrea T AT Amano Hideki H Avecilla Scott T ST Heissig Beate B Hattori Koichi K Zhang Fan F Hicklin Daniel J DJ Wu Yan Y Zhu Zhenping Z Dunn Ashley A Salari Hassan H Werb Zena Z Hackett Neil R NR Crystal Ronald G RG Lyden David D Rafii Shahin S

Nature medicine 20060430 5

The mechanisms through which hematopoietic cytokines accelerate revascularization are unknown. Here, we show that the magnitude of cytokine-mediated release of SDF-1 from platelets and the recruitment of nonendothelial CXCR4+ VEGFR1+ hematopoietic progenitors, 'hemangiocytes,' constitute the major determinant of revascularization. Soluble Kit-ligand (sKitL), thrombopoietin (TPO, encoded by Thpo) and, to a lesser extent, erythropoietin (EPO) and granulocyte-macrophage colony-stimulating factor (G ...[more]

PMID: 16648859

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Project description:Epithelial‑mesenchymal transition (EMT) has been demonstrated to serve a crucial role in the progression of interstitial fibrosis, which is one of the principal pathological features of chronic allograft nephropathy (CAN). However, to the best of our knowledge, the mechanisms of EMT in CAN have not been investigated. In the present study, the effect of stromal cell‑derived factor 1 (SDF‑1) and the Wnt signaling pathway on the progression of EMT following kidney transplantation was investigated. The CAN model was established using Fisher 344 and Lewis rats, treated with low‑dose cyclosporine with or without AMD3100. CAN was confirmed by the pathological alterations and chronic allograft damage index scoring, and EMT was confirmed by western blotting and reverse transcription‑quantitative polymerase chain reaction. In the AMD3100 group, there were lower expression levels of α‑SMA and higher expression levels of E‑cadherin, which indicated that CAN and EMT were ameliorated by AMD3100. The kidney tissue was analyzed using an mRNA + long noncoding (lnc)RNA microarray. A total of 506 mRNAs and 404 lncRNAs were demonstrated to be significantly differentially expressed between the two groups, which revealed the involvement of SDF‑1/CXC chemokine receptor 4 (CXCR4) and the Wnt pathway. SDF‑1 was demonstrated to induce EMT in vitro through the upregulation of α‑SMA, downregulation of E‑cadherin and the wound healing assay, and in the rat renal tubular epithelial cells via the nuclear accumulation of β‑catenin, which were all inhibited by either AMD3100 or DKK‑1. CXXC finger protein 5 (CXXC5), a negative regulator of the Wnt pathway, was downregulated following treatment with SDF‑1, which was inhibited by AMD3100 but not by DKK‑1. Thus, CXXC5 may be a regulator downstream of SDF‑1/CXCR4 in EMT. In conclusion, SDF‑1/CXCR4 induces EMT of renal tubular epithelial cells with the involvement of the Wnt pathway, which may be a novel mechanism and therapeutic target in kidney allograft fibrosis of rats.

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Dataset Information

Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes.

Publications

Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes.

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