Enhanced Melanocyte Lineage Reprogramming from Human Fibroblasts via Small Molecule Combination

Abstract

Epidermal melanocytes play a crucial role in protecting the skin against ultraviolet radiation by producing a pigment called melanin. Current research highlights that the generation of melanocytes is essential for investigating melanocyte development, pigmentation diseases, and novel therapeutics. However, not only does isolation of melanocytes from adult skin encounter technical challenges, but also amplification of primary melanocyte culture systems. To overcome these limitations, differentiation of melanocytes from pluripotent stem cells (PSCs) has been established; however, safety issues, such as the risk of tumorigenesis, arise as another obstacle. Direct conversion offers a promising strategy for generating target cell types from somatic cells by ectopically overexpressing defined transcription factors. A previous study has demonstrated successful direct conversion of melanocytes, but with relatively low efficacy. In this study, we employ two transcription factors, SOX10 and MITF, with two small molecules and convert human fibroblasts into cells with a melanocyte-like phenotype. Induced melanocyte-like cells (iMeLs) adopt the molecular features of melanocytes, confirmed by morphology, gene expression, and functional profiles. Our findings demonstrate that direct melanocyte lineage conversion using two transcription factors and two small molecules has improved the efficiency and functionality of generating iMeLs. This provides an efficient and time-saving strategy for further studies of melanocyte differentiation mechanisms and potential clinical applications for pigmentation disorders.