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Transcriptome Analysis of Fetal Versus Adult Hair Follicle Dermal Papilla Cells Reveals Key Differences to Explain the Lack of Human Adult Hair Follicle Regenerative Capacity
Erin L. Weber, MD PhD, Yung-Chih Lai, PhD, Warren Garner, MD, Cheng Ming Chuong, MD PhD.
Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.

PURPOSE
The ability to tissue engineer new hair follicles will help several patient populations, from people with androgenic alopecia to those who have suffered severe burns. In addition to cosmetic appearance, the hair follicle moisturizes the skin, provides protective sensation, and regulates body temperature. While the body can regenerate skin through normal wound healing and scarring, hair follicles are not replaced and burn patients suffer from dry, brittle skin and disfigurement.
Interestingly, human fetal skin can regenerate new hair follicles, a capability which is lost after birth. Isolated human fetal hair follicle dermal stem cells (dermal papilla or DP cells) induce hair follicle regeneration in mouse models while adult DP cells do so with very low efficiency. Clearly, a change occurs in the DP cell population over time, corresponding to a loss of regenerative capacity. To identify the genes and pathways responsible for follicular regeneration, we compared the transcriptomes of fetal and adult DP cells.
METHODS
Dermal papilla cells from mature hair follicles in anagen phase were manually microdissected from frozen sections of 16-18 week human fetal scalp and 36-56 year old adult scalp. The dermal sheath (DS) and portions of interfollicular dermis (IFD) were used as controls. There is evidence to suggest that the dermal sheath also serves as a stem cell niche for the hair follicle. Total RNA extracted from the dissected cells was processed into RNA-seq libraries using Nugen’s Ovation RNA-Seq System V2 and Ovation Ultralow Library System V2. 100 million total reads with a read length of 1x75 bp were sequenced for each sample using the Molecular Genomics Core at USC. Libraries were mapped to the human genome (hg19) using STAR and differential expression analysis was performed with EdgeR.
RESULTS
A set of genes uniquely upregulated in the fetal DP as compared to adult DP, fetal IFD, and adult IFD populations was identified. The fetal DP and DS transcriptomes differed more significantly from the IFD population than did the adult DP and DS groups, suggesting that the DP and DS stem cell populations become more similar to interfollicular dermal fibroblasts with age. Shh, Wnt/b-catenin, and Notch signaling pathways were upregulated in fetal DP cells compared with adult DP cells. Notably, the Shh pathway was largely absent from the adult DP cell population. Many of the factors upregulated in fetal DP cells, such as Hey2, Sox2, Shh, and Msx1 are known to play a role in morphogenesis, stem cell pluripotency, and embryogenesis.
CONCLUSIONS
Our data reveals many transcriptional differences between fetal DP cells, which can induce hair follicle regeneration, and adult DP cells, which cannot. Differential expression analysis demonstrated that multiple signaling pathways associated with stem cells and morphogenesis are upregulated in the fetal DP cells, suggesting that these same pathways may also confer the regenerative capacity. We have identified a set of candidate transcription factors to evaluate for use in transcriptional reprogramming of adult dermal fibroblasts into fetal-like DP cells with hair follicle-inducing capacity as a first step towards tissue engineering new hair follicles.


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