Directing differentiation of human induced pluripotent stem cells toward androgen-producing Leydig cells rather than adrenal cells
Directing differentiation of human induced pluripotent stem cells toward androgen-producing Leydig cells rather than adrenal cells
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DOI：
10.1073/pnas.1908207116
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发表时间：
2019-11-12
影响因子：
11.1
通讯作者：
Papadopoulos, Vassilios
中科院分区：
文献类型：
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作者：
Li, Lu;Li, Yuchang;Papadopoulos, Vassilios
血清睾酮(T)降低，或性腺功能减退，影响数百万男性，并与许多病理有关，包括不孕不育、心血管疾病、代谢综合征以及性欲和性功能下降。实施T替代疗法(TRT)可以逆转许多与低T水平相关的症状。然而，TRT与不孕不育、前列腺癌和心血管疾病风险增加等副作用有关。因此，有必要通过移植和在体内重建产生T细胞谱系来获得可用于治疗性腺功能减退症的T产生细胞。T是由间质细胞(LCS)合成的，被认为来源于中肾来源的间充质细胞。虽然间充质细胞已被成功地诱导分化为LCS，但来源有限且可能对供者造成创伤阻碍了其在临床治疗中的应用。或者，人类诱导多能干细胞(HiPSCs)在培养中可扩增，并具有分化为所有体细胞类型的潜力，已成为自体细胞治疗的新兴来源。我们利用化学方法成功地诱导hPSCs分化为人间质样细胞(HLLCs)或肾上腺样细胞(HALCs)。在两种培养体系中都加入了对LCS的发育至关重要的因素。HLLCs表达所有对T生物合成重要的类固醇激素基因和蛋白，合成T而不是皮质醇，分泌对二丁酰cAMP和22(R)-羟基胆固醇反应的类固醇激素，并表现出与LCS相似的超微结构特征。相反，hALCs合成的是皮质醇，而不是T。成功地生成了具有广泛人类LC(HLC)特征的hPSC来源的hLLC，支持了基于hPSC的hLLC再生的潜力。
Reduced serum testosterone (T), or hypogonadism, affects millions of men and is associated with many pathologies, including infertility, cardiovascular diseases, metabolic syndrome, and decreased libido and sexual function. Administering T-replacement therapy (TRT) reverses many of the symptoms associated with low T levels. However, TRT is linked to side effects such as infertility and increased risk of prostate cancer and cardiovascular diseases. Thus, there is a need to obtain T-producing cells that could be used to treat hypogonadism via transplantation and reestablishment of T-producing cell lineages in the body. T is synthesized by Leydig cells (LCs), proposed to derive from mesenchymal cells of mesonephric origin. Although mesenchymal cells have been successfully induced into LCs, the limited source and possible trauma to donors hinders their application to clinical therapies. Alternatively, human induced pluripotent stem cells (hiPSCs), which are expandable in culture and have the potential to differentiate into all somatic cell types, have become the emerging source of autologous cell therapies. We have successfully induced the differentiation of hiPSCs into either human Leydig-like (hLLCs) or adrenal-like cells (hALCs) using chemically defined culture conditions. Factors critical for the development of LCs were added to both culture systems. hLLCs expressed all steroidogenic genes and proteins important for T biosynthesis, synthesized T rather than cortisol, secreted steroid hormones in response to dibutyryl-cAMP and 22(R)-hydroxy-cholesterol, and displayed ultrastructural features resembling LCs. By contrast, hALCs synthesized cortisol rather than T. The success in generating hiPSC-derived hLLCs with broad human LC (hLC) features supports the potential for hiPSC-based hLC regeneration.