Mature B cells accelerate wound healing after acute and chronic diabetic skin lesions

Abstract

Chronic wounds affect 12–15% of patients with diabetes and are associated with a drastic decrease in their quality of life. Here we demonstrate that purified mature naïve B220+/CD19+/IgM+/IgD+ B cells improve healing of acute and diabetic murine wounds after a single topical application. B cell treatment significantly accelerated acute wound closure by 2–3 days in wild-type mice and 5–6 days in obese diabetic mice. The treatment led to full closure in 43% of chronic diabetic wounds, as compared to only 5% in saline-treated controls. Applying equivalent numbers of T cells or disrupted B cells failed to reproduce these effects, indicating that live B cells mediated pro-healing responses. Topically-applied B cell treatment was associated with significantly reduced scar size, increased collagen deposition and maturation, enhanced angiogenesis and increased nerve growth into and under the healing wound. β-III tubulin+ nerve endings in scars of wounds treated acutely with B cells showed increased relative expression of growth-associated protein 43. The improved healing associated with B cell treatment was supported by significantly increased fibroblast proliferation and decreased apoptosis in the wound bed and edges, altered kinetics of neutrophil infiltration, as well as an increase in TGF-β and a significant reduction in MMP2 expression in wound granulation tissue. Our findings indicate that the timeline and efficacy of wound healing can be experimentally manipulated through the direct application of mature, naive B cells, which effectively modify the balance of mature immune cell populations within the wound microenvironment and accelerate the healing process.

Skin-Associated B Cells in Health and Inflammation

“…As B-1-like B cells, which are CD19 hi , localize to skin (14), it is tempting to speculate that these cells promote wound healing. In further support of a role of B cells in wound healing is an observation that exogenous application of splenic B cells to wounds accelerates the healing process in wild-type and diabetic mice (109). Future studies are needed to dissect the mechanism by which different subsets of skin-associated B cells may contribute to the wound healing process and how this may be targeted for therapeutic purposes.…”

Reduction of BMP6‐induced bone formation by calcium phosphate in wild‐type compared with nude mice

“…Despite the significant accumulation of CD3+ cells in CopiOs and CaCl 2 gels at 3 days after implantation, distinct ratios of type 1 (M1) and type 2 (M2) macrophages could also help explain the differences in bone formation between CopiOs and CaCl 2 gels, as suggested by the significantly different ratio of CD11c/CD206 between conditions with and without Ca 2+ . Furthermore, it is conceivable that different ratios of T‐cells and B‐cells could be involved in balancing the proregenerative and antiregenerative environment, as this effect has been described in wound healing models (Sirbulescu et al, ).…”

T Lymphocytes Attenuate Dermal Scarring by Regulating Inflammation, Neovascularization, and Extracellular Matrix Remodeling

“…For instance, transfer of mature B cells, but not T cells, accelerated diabetic wound healing and reduced scar formation. 7 In contrast, the absence of CD8 + T cells in athymic nude mice correlated with reduced scar formation, 8,9 whereas Wong et al demonstrated that athymic nude mice lacking mature T cells had hypertrophic scarring. 10,11 Together, these studies suggest that B and T cells may impact scarring phenotypes, 12,13 but the contribution of specific lymphocyte subsets remain largely unclear.…”