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American Association of Plastic Surgeons

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Mechanical Stretch Mobilizes Lgr6+ Epidermal Stem Cells To Drive Skin Growth
Yingchao Xue, PhD, Ainsley L. Taylor, BS, Chenyi Lyu, MS, Amy van Ee, BS/MSE candidate, Ashley Kiemen, MS, YoungGeun Choi, BS, Nima Khavanian, MD, Dominic Henn, MD, Chaewon Lee, BS candidate, Lisa Hwang, BS candidate, Eric Wier, PhD, Saifeng Wang, PhD, Sam Lee, PhD, Ang Li, MD, PhD, Charles Kirby, BS, Pei-Hsun Wu, PhD, Denis Wirtz, PhD, Luis Garza, MD, PhD, Sashank K. Reddy, MD, PhD.
Johns Hopkins University, Baltimore, MD, USA.

PURPOSE: To uncover cellular and molecular determinants of skin growth with the goal of designing future therapies for conditions of excess or inadequate skin. Current research in the field has identified distinct populations of stem cells within specific skin components that regularly replenish the epidermis and hair follicles.
METHODS: A controlled tissue expansion mouse model was applied to all variables of interest. We used Lgr5/6-EGFP-CreERT2;tdTomato mice to lineage trace Lgr5/6+ stem cell progeny. YAP gain- and loss-of-function mouse models quantified YAP expression. 3D skin model reconstructions characterized skin components. RNA microarray and single-cell RNA sequencing identified changes in metabolic pathways. Pseudotime analysis assessed lineage trajectory of Lgr6+ cells.
RESULTS: Skin growth from mechanical tension is driven by proliferation of the epidermis. Epidermal growth is achieved through preferential activation and differentiation of not Lgr5+, but instead Lgr6+ stem cells of the interfollicular epidermis, driven in part by activation of the Hippo pathway effector YAP. A number of growth regulatory (PI3K-AKT), inflammatory (Toll-like receptor), and oxygen sensing (Hif1) pathways were up-regulated.
CONCLUSION: By defining the differential responses of skin elements to tension-dependent growth, we begin to identify targets to improve skin generation. Methods that may lead to more effective expansion include promoting fibroblast expansion, increasing the number of Lgr6+ stem cells, and direct activation of tension-responsive elements such as YAP. Up-regulated pathways offer additional molecular targets for enhancing skin growth. Future research may investigate the role of mechanical signaling as a driver of growth in other organs such as gut and lung.


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