Characteristics and Function of CD34+ Melanocyte Stem Cells

About This Grant

Background and Innovation: The proposed work is focused upon enhancing our understanding of CD34+ melanocyte stem cells (McSCs). These are cells previously described by us which localize to the bulge area of the hair follicle (HF) during its resting stage. Unlike their counterparts, CD34- McSCs which reside at the base of the resting HF and principally undergo melanocytic differentiation, CD34+ McSCs resemble a neural crest stem cell; and differentiate principally as neural crest derivatives other than melanocytes- including glia. The prospect of isolating and expanding a skin-derived stem cell type to treat demyelinating diseases and restore nerve function is enticing and may represent one of the most innovative solutions to these problems faced by Veterans. VA has an interest in treating Veterans with demyelinating diseases through its support of centers such as the Multiple Sclerosis Centers of Excellence. Rehabilitation and restoration of function following neurotrauma has consistently been a strong interest in VA healthcare. Seemingly unrelated, but nonetheless linked to the ability of melanocytes and McSCs to transition between discrete differentiation states, is the relevance of CD34+ McSCs to melanoma therapeutic resistance. The less differentiated CD34+ McSC subtype has been correlated with relative resistance to immunotherapy in murine melanoma models. Understanding the molecular and cellular basis of McSC dedifferentiation could inform strategies designed to block melanoma cell dedifferentiation as a novel strategy to maintain therapeutic responsiveness. Scientific efforts in this direction are synergistic with VA’s interest in Precision Oncology, both with the new Precision Oncology Actively-Managed Research Portfolio and with its clinical support of precision oncology programs. Significance and Impact to Veterans Healthcare: The proposed work is relevant to Veteran healthcare and disease as follows: (1) Developing stem cells easily accessible from autologous skin that have the potential to undergo glial differentiation represents a potential cellular therapy solution to diseases that affect Veterans. These include demyelinating diseases such as multiple sclerosis and recovery from neurotrauma, since stem cells with glial differentiation properties introduced into a neural injury environment facilitate recovery of nerve function. Both multiple sclerosis and recovery from neurotrauma are priorities for Veteran health care. (2) Dedifferentiation enables melanoma cells to escape as targets for immunotherapy. Understanding the mechanistic underpinnings of McSC dedifferentiation, which are likely to share a molecular basis with melanoma cells, may illuminate strategies designed to block dedifferentiation in cancer and enhance therapeutic responsiveness. Novel strategies to treat cancer are relevant to VA health priorities, given the recent emphasis on developing Precision Oncology clinical care pathways and research initiatives within the Veterans Health Administration. Path to translation/implementation: We need to refine the identification of the CD34+ McSC subtype in murine skin to maximize the opportunity to identify a similar cell in human skin. Optimizing techniques to expand CD34+ McSCs that have glial differentiation potential will be important for obtaining sufficient cells that maintain the glial differentiation phenotype to evaluate for cellular therapy. Identifying the master regulators of melanocyte dedifferentiation will be important. Those regulators, or critical effector genes of those regulators, could represent therapeutic targets to be tested in clinical trials of advanced melanoma refractory to standard therapy, as part of VA’s Precision Oncology initiative.