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Transitioning from Scarless Fetal Wound Healing: Uncovering the Responsible Fibroblast Lineage.
Graham G. Walmsley, B.A., Michael S. Hu, M.D., Zeshaan N. Maan, M.D., Dominik Duscher, M.D., Rahul Sinha, Ph.D., Irving L. Weissman, M.D., Geoffrey C. Gurtner, M.D., H. Peter Lorenz, M.D., Michael T. Longaker, M.D..
Stanford University, Palo Alto, CA, USA.

PURPOSE:
Early in utero cutaneous wounds heal without a scar. Many studies have offered possible explanations for this phenomenon but no definitive answer has emerged. We have previously characterized a scar-forming fibroblast lineage in the dorsal skin of adult mice defined by embryonic expression of Engrailed-1 (En1). Here we investigate the role of this lineage during fetal wound healing.
METHODS:
En1-derived fibroblasts were traced by crossing En1-Cre and ROSA26-mTmG mice. A murine model of fetal scarless wound healing allowed for investigation of En1-derived fibroblast behavior before and after the scarless transition. En1-derived fibroblasts were characterized using flow cytometry and RNA sequencing analysis at various stages of embryonic development.
RESULTS:
Dorsal wounds created at embryonic day 16.5 (e16.5) healed scarlessly with minimal connective tissue deposition. However, wounds created at e18.5 healed with substantial scar deposited primarily by En1-derived fibroblasts. The relative number of En1-derived fibroblasts and the expression of CD26, a previously identified marker of the En1 lineage, steadily increased from e12.5 through postnatal day 1. RNA sequencing analysis of En1-derived fibroblasts revealed that e18.5 fibroblasts express a highly fibrogenic program in comparison to e16.5 fibroblasts in unwounded skin (*p<0.01).
CONCLUSION:
The En1 lineage of fibroblasts plays a critical role in the transition from scarless wound healing during fetal development. These results hold promise for the development of therapeutic approaches to fibrotic disease and adult wound healing.



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