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The Role of Extracellular Matrix Components in Hair Follicle Neogenesis and Cellular Reprogramming
Erin L. Weber, MD, PhD, Cheng-Ming Chuong, MD, PhD.
Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
The main objective of reconstructive plastic surgery is the restoration of form and function after wounding or deformity. Closure of complex wounds is now possible through the use of advanced flaps and skin grafts. However, while most wounds can be repaired with current methods, the reconstructed region often cannot approximate the normal skin in both cosmetics and function. There exists a strong need for successful tissue engineering for optimal wound reconstruction.
Advances in stem cell biology suggest that tissue engineering is possible through cellular reprogramming. Dermal fibroblasts have been reprogrammed to become neurons, cardiomyocytes, and hepatocytes through genetic modification. Endogenous reprogramming has been also been observed in adult mice where new hair follicles develop at the center of large wounds. Successes in reprogramming have demonstrated that both the expression of lineage-specific genes and environmental cues play important roles. Hair follicle development requires the early formation of aggregates of dermal and epidermal cells, followed by reciprocal epithelial-mesenchymal signaling, which remains largely uncharacterized. As the epidermal and dermal aggregates are spatially separated within the skin, it stands to reason that the extracellular matrix (ECM) may play a role in the signaling between the two cell groups.
One way to investigate the role of the extracellular matrix in hair follicle development and to identify factors for reprogramming is to use decellularized ECM, which retains the extracellular protein components of the dermis, including growth factors, in their native structural configuration. Normally, adult mice are unable to generate new hair follicles to replace those that are lost or non-functional. Newborn mice, however, are able to regenerate hair follicles for a short time after birth. Therefore, a comparison between newborn and adult murine ECM should help to identify important differences responsible for the lack of adult hair follicle neogenesis.
Newborn murine dermis was decellularized using Triton X-100 detergent. The decellularization process was optimized to minimize the loss of soluble growth factors and maintain scaffold structure. Newborn or adult murine skin was dissociated into individual dermal and epidermal cell populations and seeded onto newborn acellular ECM. Aggregate formation was evaluated using whole mount immunofluoresence. Complete hair follicle formation was demonstrated by transplantation of the ECM, with aggregates, into the full-thickness wound of a nude mouse.
Newborn acellular dermal matrix is able to support the formation of new hair follicles from dissociated newborn epidermal and dermal cells. In addition, we demonstrated rescue of hair follicle formation from adult murine epidermal and dermal populations. Current efforts are directed towards the identification of the extracellular matrix proteins, configuration, and associated molecules which may support hair follicle neogenesis. Comparative studies between newborn and adult murine matrices are ongoing.
The dermal extracellular matrix is believed to play an important role in hair follicle neogenesis and the use of crucial ECM components may facilitate tissue engineering. Reprogramming dermal fibroblasts into hair follicle precursor cells has the potential to create a renewable source of hair follicles for the treatment of alopecia and the reconstruction of wounds in hair-bearing areas.
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