301 Comprehensive analyses on melanocytes differentiated from induced pruripotent stem cells originated from xeroderma pigmentosum complementation group A

Abstract

Xeroderma Pigmentosum (XP) is a rare, autosomal recessive, hereditary DNA repair disorder characterized by extreme hypersensitivity to ultraviolet radiation (UVR). XP complementation group A (XP-A) is the most frequent type in Japan, and patients with XP-A present most severe cutaneous and neurological symptoms due to nucleotide excision repair deficiency. Here, we succeeded in generating melanocytes from induced pruripotent stem cells (iPSCs) derived from XP-A patients via melanocyte precursor cells (MPCs), and performed comprehensive analyses of gene expression to investigate the underlying molecular mechanisms of the disease. XP-A-iPSC- derived melanocytes (XP-A-iMCs) appeared morphologically similar to normal human epidermal melanocytes and expressed similarly melanocyte markers. We analyzed difference of the microarray data between XP-A-iMCs and healthy-control-iPSC-derived melanocytes (HC-iMCs) at 12 hours after high dose (150 J/m2) UV-B irradiation. Consequently we found that the major GO term categories for genes specifically upregulated in XP-A-iMCs were cell proliferation and death, and that for genes specifically downregulated in XP-A-iMCs was cell cycle regulation. These results suggest that XP-A-iMCs have increased apoptosis and cell proliferation compared to HC-iMCs. This phenotype of XP-A-iMCs may be responsible for the pigmented and depigmented maculae characteristic of XP-A patients.