Despite good acute burn management, hypertrophic scars (HTSs) can develop, and has been reported in 70% of healed burns. An understudied symptom of HTS is the dyschromia of the epidermal cells, and no current treatments seek to treat dyschromia based on mechanistic interventions, which was the goal of this work. The epidermis is composed of keratinocytes and melanocytes: the epidermal-melanin unit. This unit responds to damage from UV light to make melanin by the up-regulation and secretion of a-MSH from keratinocytes. Melanocytes receive this signal through the melanocortin 1 receptor (MC1R), and initiate signal transduction in melanocytes to undergo melanogenesis. Melanocytes then transfer melanin to keratinocytes through dendritic processes, resulting in skin pigmentation.
In a red Duroc pig model, full thickness excisional wounds formed HTSs, and samples of distinct regions of hyper-, hypo-, and normal pigmentation were taken and used to study pigmentation signaling and melanocyte presence. Samples from similar lesions in burn patients were likewise studied. Hypo-pigmented melanocytes isolated from burn patient scars were treated with a pigmentation stimulator, and their response was evaluated in vitro. Hypo- pigmented epidermal cells in a nude mouse model of porcine xenografts were treated with the same pigmentation stimulator, and their response was evaluated in vivo.
Melanocytes are present in regions of hypo- and hyper-pigmentation by multiple validation metrics in porcine and patient HTS. The most up-stream molecule in the pigmentation signaling cascade that is up-regulated in hyper- vs. hypo pigmented scar is POMC. The POMC promoter was hypothesized to be hyper-methylated in hypo-pigmented scar; however, the data suggests that this is not the mechanism for POMC down-regulation. Although the mechanism for POMC down-regulation was not discovered, POMC’s down-stream protein cleavage product, a- MSH, was confirmed to be dysregulated. A synthetic form of a-MSH, NDP a-MSH, has been shown to induce pigmentation. Using this compound, melanocytes derived from burn patient hypo-pigmented scar can be stimulated to make melanin in vitro. In addition, melanocytes derived from porcine hypo-pigmented scar can be stimulated in vivo in a nude mouse model of porcine xenografting. This treatment for hypo-pigmentation may contribute towards improved quality of life for burn survivors.
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|Advisor:||Rosenthal, Dean S., Shupp, Jeffrey W.|
|Commitee:||Banerjee, Partha P., Lumpkin, Michael J., Simbulan-Rosenthal, Cynthia M.|
|Department:||Biochemistry & Molecular|
|School Location:||United States -- District of Columbia|
|Source:||DAI-B 81/12(E), Dissertation Abstracts International|
|Subjects:||Biochemistry, Molecular biology|
|Keywords:||Alpha melanocyte stimulating hormone, Duroc pig, Dyschromia, Hypertrophic scar, Melanocytes, Xenograft model|
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