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Cd26 Knockout And Inhibition Promotes Dorsal Wound Healing Via Modulation Of Engrailed-1 Positive Fibroblasts
Malini Chinta1, Deshka Foster, MD2, Alan Nguyen2, Heather desJardins-Park2, Michael Hu, MD2, Shamik Mascharak2, Ashley Titan, MD2, Ankit Salhotra2, R. Ellen Jones, MD2, Oscar Leon Da Silva2, Alessandra Moore, MD2, Eliza Foley2, Emma Briger2, Jeffrey A. Norton, MD2, Derrick C. Wan, MD2, Michael T. Longaker, MD, MBA2, H. Peter Lorenz, MD2.
1Stanford University, Pleasanton, CA, USA, 2Stanford University, Palo Alto, CA, USA.

Purpose: Engrailed-1 (En1) positive fibroblasts are responsible for scar formation in the dorsal skin of adult mice during the postnatal period. The cell surface marker CD26, also known as dipeptidyl-peptidase-4 (DPP4), is expressed by the vast majority of En1 positive fibroblasts and can be used to isolate this lineage of scar-forming fibroblasts. We have previously shown that inhibition of CD26 with Diprotin results in decreased cutaneous scarring during wound healing. To further interrogate this biology, we hypothesized that inhibition of CD26 with a small molecule CD26/DPP4 inhibitor (MK0626) or CD26 knockout mice, might improve the rate of wound healing, decrease scar fibrosis, and achieve a more regenerative phenotype in the context of wound healing. Methods: The effects of MK0626 were initially evaluated on NIH 3T3 fibroblasts in vitro. Migration, measured by scratch assay, and proliferation were assessed on treatment and control specimens at 12 and 24 hours. Results were analyzed using ImageJ. To test the effects of MK0262 in vivo, bilateral full thickness wounds were created in the dorsal dermis of 10-week old C57Bl/6 (wild-type) mice. Equivalent wounds were also made in the dorsal dermis of En1mTmG CD26 knockout mice (CD26-/+;En1Cre;R26mTmG). A stented-wound healing model developed in our laboratory, which better mimics human wound healing kinetics, was used. The wild-type mice received oral MK0626 at a high dose (30 mg/kg), low dose (3 mg/kg), or saline control every other day over the course of wound healing. Wounds were harvested at post-operative day 14. Results: In vitro scratch assay showed significantly increased fibroblast migration and increased proliferation with treatment of MK0626 compared with vehicle control (Fig. 1A). In vivo, orally-administered MK0626 significantly improved the rate of wound closure in wild-type mice (Fig. 1B). Dermal scar thickness (as well as En-1 expression) was decreased in En1mTmG CD26 knockout mice when compared with En1mTmG control mice (Fig. 1C). Conclusions: Modulation of CD26 expression shows therapeutic potential to encourage regenerative wound healing. Specifically, our in vivo experiments show that with oral CD26 inhibition or CD26 knockout, the wound closure rate is increased and the dermal scar is thinner, the latter of which correlates with decreased presence of the En1-lineage-positive fibroblasts. Accelerated wound closure with decreased scarring is immensely beneficial from a clinical perspective.


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