ORCID ID

0000-0003-1207-9652

Publication Date

2021-05-26

Document Type

Doctoral Dissertation

Academic Program

MD/PhD

Department

Program in Molecular Medicine; Molecular, Cell and Cancer Biology

First Thesis Advisor

Craig J. Ceol

Keywords

Melanocytes, Melanocyte Stem Cells, McSC, Zebrafish, Danio rerio, Melanoma, Vitiligo, Single cell transcriptomics, scRNAseq, KIT, c-KIT, kita

Abstract

Tissue-resident stem cells are present in many adult organs, where they are important for organ homeostasis and repair in response to injury. However, the signals that activate these cells and the mechanisms governing how these cells self-renew or differentiate are highly context dependent and incompletely understood, particularly in non-hematopoietic tissues. In the skin, melanocyte stem cells (McSCs) are responsible for replenishing mature pigmented melanocytes. In mammals, these cells reside in the hair follicle bulge and bulb niches where they are activated during homeostatic hair follicle turnover and following melanocyte destruction, as occurs in vitiligo and other skin hypopigmentation disorders. Recently, we identified adult McSCs in the zebrafish. To elucidate mechanisms governing McSC self-renewal and differentiation fates we analyzed individual transcriptomes from thousands of melanocyte lineage cells during the regeneration process. We identified transcriptional signatures for McSCs, deciphered transcriptional changes and intermediate cell states during regeneration, and analyzed cell-cell signaling changes to discover mechanisms governing melanocyte regeneration. We identified KIT signaling via the RAS/MAPK pathway as a regulator of McSC direct differentiation. Analysis of the scRNAseq dataset also revealed a population of mitfa/aox5 co-expressing cells that divides following melanocyte destruction, likely corresponding to cells that undergo self-renewal. Our findings show how different subpopulations of mitfa-positive cells underlie regeneration and differentiation of at least one subpopulation requires reactivation of developmental KIT signaling to properly reconstitute the melanocyte stripe.

DOI

10.13028/xe9t-9a56

Rights and Permissions

Licensed under a Creative Commons license

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

Available for download on Sunday, June 11, 2023

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