Differentiation of human induced pluripotent stem cells into Leydig-like cells with molecular compounds
Differentiation of human induced pluripotent stem cells into Leydig-like cells with molecular compounds
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用分子化合物将人诱导多能干细胞分化为 Leydig 样细胞
DOI：
10.1038/s41419-019-1461-0
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发表时间：
2019-03-04
影响因子：
9
通讯作者：
Guo, Xiaoling
中科院分区：
文献类型：
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作者：
Chen, Xianwu;Li, Chao;Guo, Xiaoling
睾丸间质细胞 (LC) 在产生睾酮方面发挥着至关重要的作用，而睾酮对于男性生殖和发育的调节至关重要。睾酮水平低会导致男性性腺功能减退症。 LC移植是治疗男性性腺功能减退症的一种有前途的替代疗法。然而，LC的来源限制了这种策略的临床应用。迄今为止，已有报道可以通过基因转染的方式从干细胞中衍生LC，但安全有效的诱导方法尚未见报道。在这里，我们报告使用基于分子化合物的新型分化方案可以从人类诱导多能干细胞（iPSC）中衍生出Leydig样细胞。 iPSC 衍生的 Leydig 样细胞 (iPSC-LC) 获得了睾酮合成能力，具有与 LC 相似的基因表达谱，并阳性表达 Leydig 细胞谱系特异性蛋白标记物 LHCGR、STAR、SCARB1、SF-1、CYP11A1、HSD3B1 和 HSD17B3 以及负表达 iPSC 特异性标记物 NANOG、OCT4 和硫氧化物2。当将亲脂性红色染料（PKH26）标记的iPSC-LC移植到使用EDS（75mg/kg）选择性消除内源性LC的大鼠睾丸中时，移植的iPSC-LC可以在睾丸间质中存活并发挥作用，并加速血清睾酮水平和睾丸重量的恢复。总的来说，这些研究结果表明，iPSC 能够通过少数确定的分子化合物分化为 Leydig 样细胞，这可能为 iPSC-LC 治疗性腺功能减退症的进一步临床应用奠定更安全的基础。
Leydig cells (LCs) play crucial roles in producing testosterone, which is critical in the regulation of male reproduction and development. Low levels of testosterone will lead to male hypogonadism. LC transplantation is a promising alternative therapy for male hypogonadism. However, the source of LCs limits this strategy for clinical applications. Thus far, others have reported that LCs can be derived from stem cells by gene transfection, but the safe and effective induction method has not yet been reported. Here, we report that Leydig-like cells can be derived from human induced pluripotent stem cells (iPSCs) using a novel differentiation protocol based on molecular compounds. The iPSCs-derived Leydig-like cells (iPSC-LCs) acquired testosterone synthesis capabilities, had the similar gene expression profiles with LCs, and positively expressed Leydig cell lineage-specific protein markers LHCGR, STAR, SCARB1, SF-1, CYP11A1, HSD3B1, and HSD17B3 as well as negatively expressed iPSC-specific markers NANOG, OCT4, and SOX2. When iPSC-LCs labeled with lipophilic red dye (PKH26) were transplanted into rat testes that were selectively eliminated endogenous LCs using EDS (75 mg/kg), the transplanted iPSC-LCs could survive and function in the interstitium of testes, and accelerate the recovery of serum testosterone levels and testis weights. Collectively, these findings demonstrated that the iPSCs were able to be differentiated into Leydig-like cells by few defined molecular compounds, which may lay the safer groundwork for further clinical application of iPSC-LCs for hypogonadism.