Pivotal role of the CCL5/CCR5 interaction for recruitment of endothelial progenitor cells in mouse wound healing
Yuko Ishida, … , Naofumi Mukaida, Toshikazu Kondo
Yuko Ishida, … , Naofumi Mukaida, Toshikazu Kondo
Published January 3, 2012
Citation Information: J Clin Invest. 2012;122(2):711-721. https://doi.org/10.1172/JCI43027.
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Pivotal role of the CCL5/CCR5 interaction for recruitment of endothelial progenitor cells in mouse wound healing

Abstract

BM-derived endothelial progenitor cells (EPCs) are critical and essential for neovascularization in tissue repair and tumorigenesis. EPCs migrate from BM to tissues via the bloodstream, but specific chemotactic cues have not been identified. Here we show in mice that the absence of CCR5 reduced vascular EPC accumulation and neovascularization, but not macrophage recruitment, and eventually delayed healing in wounded skin. When transferred into Ccr5–/– mice, Ccr5+/+ BM cells, but not Ccr5–/– cells, accumulated in the wound site, were incorporated into the vasculature, and restored normal neovascularization. Consistent with these observations, CCL5 induced in vitro EPC migration in a CCR5-dependent manner. Moreover, expression of VEGF and TGF-β was substantially diminished at wound sites in Ccr5–/– mice, which suggests that EPCs are important not only as the progenitors of endothelial cells, but also as the source of growth factors during tissue repair. Taken together, these data identify the CCL5/CCR5 interaction as what we believe to be a novel molecular target for modulation of neovascularization and eventual tissue repair.

Authors

Yuko Ishida, Akihiko Kimura, Yumi Kuninaka, Masanori Inui, Kouji Matsushima, Naofumi Mukaida, Toshikazu Kondo

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Figure 4

Effects of BM transplantation on skin wound healing of recipient mice transplanted with BM cells from WT or Ccr5–/– donors.

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Effects of BM transplantation on skin wound healing of recipient mice tr...
(A) Kinetic analysis of skin excisional wound healing. Representative results from 2 independent experiments with at least 5 animals per group are shown. (B) Percent wound area at each time point relative to original area (n = 5). (C) Quantitative RT-PCR analysis for Col1a1 mRNA at wound sites (n = 5). (D) Immunohistochemical analysis with anti-CD31 mAb at 6 days after injury. Representative results from 6 individual animals are shown. (E) Vascular area, identified as percent CD31+ area with Adobe Photoshop (n = 6). (F) Migration of PKH26-labeled BM cells at wound sites in BM chimeric mice at day 6 after injury. Representative results from 6 individual animals are shown. (G) PKH26-labeled BM cells recruited at the wound sites colocalized with CD31+ endothelial cells. Nuclear staining is blue. Original magnification, ×200 (D and F); ×400 (G). All values represent mean ± SEM. *P < 0.05, **P < 0.01 versus respective recipients of Ccr5–/– BM cells.