Abstract
Fibroblasts play a pivotal role in wound healing. However, the molecular mechanisms determining the reparative response of fibroblasts remain unknown. Here, we identify Notch1 signaling as a molecular determinant controlling the plasticity and function of fibroblasts in modulating wound healing and angiogenesis. The Notch pathway is activated in fibroblasts of diabetic wounds but not in normal skin and non-diabetic wounds. Consistently, wound healing in the FSP-1 +/- ;ROSA LSL-N1IC+/+ mouse, in which Notch1 is activated in fibroblasts, is delayed. Increased Notch1 activity in fibroblasts suppressed their growth, migration, and differentiation into myofibroblasts. Accordingly, significantly fewer myofibroblasts and less collagen were present in granulation tissues of the FSP-1 +/- ;ROSA LSL-N1IC+/+ mice, demonstrating that high Notch1 activity inhibits fibroblast differentiation. High Notch1 activity in fibroblasts diminished their role in modulating the angiogenic response. We also identified that IL-6 is a functional Notch1 target and involved in regulating angiogenesis. These findings suggest that Notch1 signaling determines the plasticity and function of fibroblasts in wound healing and angiogenesis, unveiling intracellular Notch1 signaling in fibroblasts as potential target for therapeutic intervention in diabetic wound healing.
Highlights
Skin wounds heal due to a coordination of a myriad of cell types including: keratinocytes, inflammatory cells, endothelial cells (ECs), and fibroblasts (Eming et al, 2014; Ojeh et al, 2015)
Primary fibroblasts were generated from diabetic foot ulcers (DFUs) at the site of wound edge from three patients and normal foot skin specimens of three non-diabetic donors and characterized as described previously (Liang et al, 2016; Jozic et al, 2017)
These results suggest that intracellular Notch pathway activation observed in diabetic foot ulcer fibroblast (DFUF) is dependent upon Notch receptor–ligand interaction
Summary
Skin wounds heal due to a coordination of a myriad of cell types including: keratinocytes, inflammatory cells, endothelial cells (ECs), and fibroblasts (Eming et al, 2014; Ojeh et al, 2015). Fibroblasts are stimulated and switch from a quiescent to activated state and transdifferentiate into myofibroblasts These myofibroblasts which express de novo α-smooth muscle actin (α-SMA), produce abundant ECM, produce remodeling enzymes and a variety of regulatory soluble factors, provide a structural scaffold, and generate contractions to modulate and facilitate wound closure and tissue regeneration (Moulin et al, 1999; Li & Wang, 2011; Hinz, 2016; Smith, 2018). These cells are critical throughout the inflammation, proliferation, and remodeling phases of wound healing (Werner et al, 2007; Liu & Velazquez, 2008; Greaves et al, 2013; O’Brien et al, 2018; Ridiandries et al, 2018; Wallace & Bhimji, 2018). As such, (myo)fibroblasts are increasingly recognized as important therapeutic targets
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