Role of the mitochondrial protein cyclophilin D in skin wound healing and collagen secretion
Ritu Bansal, … , Etty Bachar-Wikstrom, Jakob D. Wikstrom
Ritu Bansal, … , Etty Bachar-Wikstrom, Jakob D. Wikstrom
Published April 2, 2024
Citation Information: JCI Insight. 2024;9(9):e169213. https://doi.org/10.1172/jci.insight.169213.
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Research Article Dermatology

Role of the mitochondrial protein cyclophilin D in skin wound healing and collagen secretion

Abstract

Central for wound healing is the formation of granulation tissue, which largely consists of collagen and whose importance stretches past wound healing, including being implicated in both fibrosis and skin aging. Cyclophilin D (CyD) is a mitochondrial protein that regulates the permeability transition pore, known for its role in apoptosis and ischemia-reperfusion. To date, the role of CyD in human wound healing and collagen generation has been largely unexplored. Here, we show that CyD was upregulated in normal wounds and venous ulcers, likely adaptive as CyD inhibition impaired reepithelialization, granulation tissue formation, and wound closure in both human and pig models. Overexpression of CyD increased keratinocyte migration and fibroblast proliferation, while its inhibition reduced migration. Independent of wound healing, CyD inhibition in fibroblasts reduced collagen secretion and caused endoplasmic reticulum collagen accumulation, while its overexpression increased collagen secretion. This was confirmed in a Ppif-KO mouse model, which showed a reduction in skin collagen. Overall, this study revealed previously unreported roles of CyD in skin, with implications for wound healing and beyond.

Authors

Ritu Bansal, Monica Torres, Matthew Hunt, Nuoqi Wang, Margarita Chatzopoulou, Mansi Manchanda, Evan P. Taddeo, Cynthia Shu, Orian S. Shirihai, Etty Bachar-Wikstrom, Jakob D. Wikstrom

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Figure 3

Cyclophilin D inhibition impairs porcine wound closure, granulation, and collagen formation.

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Cyclophilin D inhibition impairs porcine wound closure, granulation, and...
(A) Illustration of treatments and experiments conducted. (B and C) Representative H&E-stained sections (B) used for quantification (mean ± SEM) of reepithelialization on day 7 post wounding (C). The superimposed line highlights the neoepidermis. n = 4 pigs and 2 wounds per group (8 wounds per pig). (D–G) Representative H&E-stained sections for wound granulation assessments at day 7 and day 14 after the wound infliction and treatment vehicle (D and F) or NIM811 (E and G). The interface of the granulation tissue and the dermal edge is marked with a black line. Scars (granulation tissue) are covered by a thick fibrinopurulent crust (spanned by double-headed arrows). Fibroblasts are oriented perpendicular to blood vessels (arrows). The scar is located between 2 black lines on the right and left. DE, dermal edge; GT, granulation tissue; mod, moderate; RE, reepithelialization; S, scar; SC, s.c.; v, vehicle; Ti-2, NIM811 treatment. (H and I) Quantification (mean ± SEM) of mean granulation tissue width in vehicle- and NIM811-treated wounds at 1 week and 4 weeks. (J) Representative Masson’s trichrome– and Herovici combination–stained sections of porcine wounds to assess collagen density and mature versus newly formed collagen, respectively. Note that Masson’s trichrome stains collagen with blue color (unprocessed images/without AI) or green color (processed images/with AI). Herovici combination stains mature dense collagen red while and newly formed collagen as blue. Scale bar: 50 μm. (K) Histopathological scoring of collagen density. Two-tailed, unpaired t test. n = 3. *P < 0.05.