NO-GC in Pericytes as Modulator of Skin Fibrosis
European Tissue Repair Society Annual Meeting - 2019 Isarforum Munich, Germany
Background: Disturbed wound healing affects millions of people worldwide. Skin fibrosis is a failure of tissue repair, characterized by initial inflammation and appearance of myofibroblasts producing excessive extracellular matrix. There is evidence that nitric oxide (NO) plays an important role in skin fibrosis. NOsensitive guanylyl cyclase (NO-GC) is the main target for NO. In skin, the exact cell type expressing NO-GC as well its role during wound healing and fibrosis has yet to be identified. Methods: To investigate the function of NO-GC in skin, we used the bleomycin model of skin fibrosis induced by repetitive (21 days) subcutaneous bleomycin injections (0.5 mg/ml) in the neck. Reporter mice were used to lineage trace NO-GC+ cells within the course of the fibrotic reaction. Results: We found NO-GC expression in skin pericytes indicated by colocalization with the pericyte marker PDGFRß; NOGC+ pericytes were found to be closely associated with CD31+ endothelial cells in the hypodermis of the skin. Tamoxifen-induced expression of the reporter dye tdTomato under the control of SMMHC (smooth muscle myosin heavy chain) promotor was found to colocalize with NO-GC+ pericytes. tdTomato-labeled pericytes are spindle shaped and mainly located within a collagen IV matrix which surrounds the adipocytes of the hypodermis. After bleomycin injection, the fibrotic reaction occurred exclusively in the hypodermis. We showed an increase of collagen type III and type IV and a higher density of fibroblasts. tdTomato labelled pericytes remain in the collagen IV matrix. Summary: We assume that NOGC+ pericytes constitute an interesting therapeutic target to treat skin fibrosis. In the next step, we want to identify the role of NO-GC using additional promotor-specific lineage tracing of NOGC+ cells and knockdown of NO-GC.
Universität Würzburg, Physiology Institute, Würzburg, Germany; Universität Würzburg, Tissue Engineering and Regenerative Medicine, Würzburg, Germany