Bone marrow-derived cells serve as proangiogenic macrophages but not endothelial cells in wound healing

Abstract

Bone marrow-derived cells (BMDCs) contribute to postnatal vascular growth by differentiating into endothelial cells or secreting angiogenic factors. However, the extent of their endothelial differentiation highly varies according to the angiogenic models used. Wound healing is an intricate process in which the skin repairs itself after injury. As a process also observed in cancer progression, neoangiogenesis into wound tissues is profoundly involved in this healing process, suggesting the contribution of BMDCs. However, the extent of the differentiation of BMDCs to endothelial cells in wound healing is unclear. In this study, using the green fluorescent protein-bone marrow chimeric experiment and high resolution confocal microscopy at a single cell level, we observed no endothelial differentiation of BMDCs in 2 acute wound healing models (dorsal excisional wound and ear punch) and a chronic wound healing model (decubitus ulcer). Instead, a major proportion of BMDCs were macrophages. Indeed, colony-stimulating factor 1 (CSF-1) inhibition depleted approximately 80% of the BMDCs at the wound healing site. CSF-1-mutant (CSF-1 op/op ) mice showed significantly reduced neoangiogenesis into the wound site, supporting the substantial role of BMDCs as macrophages. Our data show that the proangiogenic effects of macrophages, but not the endothelial differentiation, are the major contribution of

The interplay between macrophages and angiogenesis in development, tissue injury and regeneration

“…Okuno and co-workers showed that CSF-1 is early up-regulated at the wound healing site and plays an important role in recruiting macrophages (Okuno et al, 2011). This was confirmed by inhibition of CSF-1R or CSF-1, which resulted in 80% reduction of the macrophage infiltrate.…”

“…Okuno and co-workers recently showed that the majority of BM-derived cells infiltrating both acute (dorsal excisional ear punch) and chronic (decubitus ulcer) skin wounds are macrophages (Okuno et al, 2011). Most of these macrophages display an "alternatively" activated or M2-like phenotype (Gordon, 2003;Gordon and Martinez, 2010), e.g., express high levels of MRC1 and low levels of nitric oxide synthase-2 (NOS2) and IL-6.…”

“…Most of these macrophages display an "alternatively" activated or M2-like phenotype (Gordon, 2003;Gordon and Martinez, 2010), e.g., express high levels of MRC1 and low levels of nitric oxide synthase-2 (NOS2) and IL-6. Interestingly, the authors found that the majority of these macrophages were located in perivascular areas at the wound healing site (Okuno et al, 2011).…”

“…However, the overall amounts of classic proangiogenic factors produced at the wounded site did not differ between Csf-1 op/ op and wild-type mice, whereas MMPs were significantly reduced. Thus, wound healing macrophages may exert their proangiogenic programs by physically interacting with sprouting blood vessels, facilitating their growth by degrading the ECM, and/or promoting vascular remodeling via non-canonical (e.g., VEGF-independent) angiogenic pathways (Okuno et al, 2011).…”

Fetal microchimerism in skin wound healing

“…1 Conflicting data have been published regarding the participation of distant endothelial progenitor cells (EPCs) to the angiogenesis in the wound bed. [2][3][4] These studies used chimeric mice obtained by transplantation of a tagged bone marrow from a transgenic mouse into a wild type (WT) recipient after a myeloablative treatment usually chemotherapy or irradiation. This conditioning may modify the natural course of the healing process.…”