Therapeutic Potential of Patient iPSC-Derived iMelanocytes in Autologous Transplantation

Abstract

Graphical Abstract Highlights d Suspensive system enhances efficiency of hiPSC differentiation into melanocytes d hiMelanocyte stem cells in bulge region provide long-term function maintenance d Mature hiMelanocytes integrate into the mouse hair bulb and produce melanin d Patient iMelanocytes reveal multiple vitiligo-associated signaling pathways SUMMARYInduced pluripotent stem cells (iPSCs) are a promising melanocyte source as they propagate indefinitely and can be established from patients. However, the in vivo functions of human iPSC-derived melanocytes (hiMels) remain unknown. Here, we generated hiMels from vitiligo patients using a three-dimensional system with enhanced differentiation efficiency, which showed characteristics of human epidermal melanocytes with high sequence similarity and involved in multiple vitiligo-associated signaling pathways. A modified hair follicle reconstitution assay in vivo showed that MITF + PAX3 + TYRP1 + hiMels were localized in the mouse hair bulb and epidermis and produced melanin up to 7 weeks after transplantation, whereas MITF + PAX3 + TYRP1 À hiMelanocyte stem cells integrated into the bulge-subbulge regions.Overall, these data demonstrate the long-term functions of hiMels in vivo to reconstitute pigmented hair follicles and to integrate into normal regions for both mature melanocytes and melanocyte stem cells, providing an alternative source of personalized cellular therapy for depigmentation.

Recent advances in the induced pluripotent stem cell‐based skin regeneration

“…The lack or absence of melanin can cause hypopigmentation disorders like albinism and vitiligo. 73 iPSC-derived melanocytes provide an important resource for in vitro studies on melanocyte development and diseases related to abnormal melanocyte differentiation. 74,75 Patient-specific iPSCs-derived melanocytes are being considered for potential use as an autologous melanocyte transplantation therapy in these disorders that needs further clinical research.…”

“…The differential gene expression analysis of human epidermal melanocytes and iPSC-derived melanocytes indicated similar transcriptome characteristics and comparable expression of melanocytic genes. 73 In addition to dermal fibroblasts, human adipose-derived stem cells were also used for the generation of iPSCs using SeV vectors which were later differentiated into melanocytes. 76…”

Practical choice for robust and efficient differentiation of human pluripotent stem cells

“…EB has been a very common model of in vitro hPSC differentiation for more than 50 years[ 7 ]. The EB-based method is widely used to differentiate majority of cell lineages from the three germ layers (Table 1 ) and has an obvious advantage in improving the differentiation efficiency of some cells[ 8 - 10 ], such as hematopoietic progenitors[ 11 ] and melanocytes[ 12 ]. Combined with suspension bioreactor technology, this advantage can be further amplified for large-scale production[ 13 ].…”

Axin, the classic scaffold protein of Wnt/β-catenin signalling as a potential drug-target for vitiligo

“…According to the regulatory networks underlying melanogenesis, upregulation of Wnt/β -catenin signalling promotes the expression of a critical melanogenic protein, melanocyte-inducing transcription factor (MITF), which subsequently activates TYRP (tyrosinase-related protein) 1 and 2 and TYR (tyrosinase) genes and finally increases melanogenesis (Fig. 1d) (Liu et al, 2019;Manga, Sheyn, Yang, Sarangarajan & Boissy, 2006). MITF controls the production of the pigment melanin, and TYRP1 and 2 are two transmembrane proteins.…”