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Transplantation of testosterone-producing cells is a promising treatment for male hypogonadism. However, getting a cell source with the characteristics of Leydig cells (LCs) is still a challenge. Here, a high-efficiency reprogramming of skin-derived fibroblasts into functional Leydig-like cells (LLCs) based on epigenetic mechanism was described. By performing an integrated analysis of genome-wide DNA methylation and transcriptome profiling in LCs and fibroblasts, the potentially epigenetic-regulating steroidogenic genes and signaling pathways were identified. Then by using CRISPR\/dCas9 activation system and signaling pathway regulators, the male- or female-derived fibroblasts were reprogrammed into LLCs with main LC-specific traits. Transcriptomic analysis further indicated that the correlation coefficients of global genes and transcription factors between LLCs and LCs were higher than 0.81 and 0.96, respectively. After transplantation in the testes of hypogonadal rodent models, LLCs increased serum testosterone concentration significantly. In type 2 diabetic rats model, LLCs which were transplanted in armpit, have the capability to restore the serum testosterone level and improve the hyperglycemia status. In conclusion, our approach enables skin-derived fibroblasts reprogramming into LLCs with high fidelity, providing a potential cell source for the therapeutics of male hypogonadism and metabolic-related comorbidities.<\/jats:p>","DOI":"10.1093\/pnasnexus\/pgac179","type":"journal-article","created":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T15:41:08Z","timestamp":1662478868000},"source":"Crossref","is-referenced-by-count":2,"title":["High-fidelity reprogramming into Leydig-like cells by CRISPR activation and paracrine factors"],"prefix":"10.1093","volume":"1","author":[{"given":"Zhaohui","family":"Li","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Bioengineering Medicine, Department of Cell Biology, Jinan University , Guangzhou 510632, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuxiao","family":"Fan","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Bioengineering Medicine, 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