Specific disruption of Lnk in murine endothelial progenitor cells promotes dermal wound healing via enhanced vasculogenesis, activation of myofibroblasts, and suppression of inflammatory cell recruitment

Abstract

BackgroundAlthough endothelial progenitor cells (EPCs) contribute to wound repair by promoting neovascularization, the mechanism of EPC-mediated wound healing remains poorly understood due to the lack of pivotal molecular targets of dermal wound repair.Methods and ResultsWe found that genetic targeting of the Lnk gene in EPCs dramatically enhances the vasculogenic potential including cell proliferation, migration, and tubule-like formation as well as accelerates in vivo wound healing, with a reduction in fibrotic tissue and improved neovascularization via significant suppression of inflammatory cell recruitment. When injected into wound sites, Lnk -/- EPCs gave rise to a significant number of new vessels, with remarkably increased survival of transplanted cells and decreased recruitment of cytotoxic T cells, macrophages, and neutrophils, but caused activation of fibroblasts in the wound-remodeling phase. Notably, in a mouse model of type I diabetes, transplanted Lnk -/- EPCs induced significantly better wound healing than Lnk +/+ EPCs did.ConclusionsThe specific targeting of Lnk may be a promising EPC-based therapeutic strategy for dermal wound healing via improvement of neovascularization but inhibition of excessive inflammation as well as activation of myofibroblasts during dermal tissue remodeling.

Improving Chronic Diabetic Wound Healing through an Injectable and Self-Healing Hydrogel with Platelet-Rich Plasma Release

“…After evaluating the ability of biodegradation of the hydrogels, we further assessed the biosafety of these hydrogels in vitro and in vivo . Dermal fibroblasts, endothelial cells, and stem cells take part in wound repair. , Therefore, we examined the cytocompatibility of the hydrogels using L929 cells, human dermal fibroblasts (HDFs), human umbilical vein endothelial cells (HUVECs), and HUMSCs (as shown in Figure ). HDFs cultured with hydrogel extracts were observed to show vimentin-positive expression (red).…”

Cardiac Function Improvement and Bone Marrow Response –

“…Potential mechanisms of impaired angiogenesis response may be either the anti-angiogenic interference of inflammatory cytokines, such as IP10, or NT-proBNP that may influence EPC proliferation or release mechanisms ( Strieter et al, 1995 , Stamm et al, 2003 , Cesari et al, 2008 ). In this context, the first description of upregulated SH2B3 gene expression enhancement in the peripheral blood of non-responders associated with reduced EPC and thrombocyte counts suggests a potential regulatory role of SH2B3 with respect to suppression of the bone marrow response ( Cesari et al, 2008 , Kwon et al, 2009 , Lee et al, 2016 ). Experimental models have depicted the potential importance and diagnostic or therapeutic relevance of SH2B3 gene expression and lnk adaptor protein SH2B3 for regulation of bone marrow responses and impairment of angiogenesic capacity ( Ishige-Wada et al, 2016 , Takizawa et al, 2008 ).…”

Role of NADPH Oxidase-4 in Human Endothelial Progenitor Cells

“…Endothelial progenitor cells (EPCs) are a type of cell able to differentiate into mature endothelial cells and are involved in postnatal neovascularization (Takahashi et al, 1999 ; Asahara et al, 1999a , b ; Aicher et al, 2005 ; Real et al, 2008 ). Evidence continues to accumulate regarding the importance of EPCs for restoring endothelial function in injured blood vessels and neovascularization in ischemic tissues (Asahara et al, 1999a ; Assmus et al, 2002 ; Iba et al, 2002 ; Griese et al, 2003 ; Krankel et al, 2012 ; Galasso et al, 2013 ; Lee et al, 2016 ).…”