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DOI：
10.5694/j.1326-5377.1969.tb107150.x
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发表时间：
1969-08
影响因子：
11.4
通讯作者：
J. Loewenthal
中科院分区：
文献类型：
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作者：
J. Loewenthal
1. 摘要 哺乳动物的精子发生是一个复杂但协调良好的过程，其中睾丸的精原干细胞（SSC）发育形成精子。在睾丸稳态期间，精原干细胞自我更新以维持干细胞库或分化形成生殖细胞的后代，随后转化为精子。来自临床数据和不同模型生物体的积累证据表明，精原干细胞自我更新或分化的命运是由细胞内的内在信号和来自 SSC 生态位的细胞外信号控制的。在这里，我们回顾了了解小鼠精原干细胞的性质及其稳态调节的过去和最新进展。我们还回顾了精原干细胞在男性不育以及生殖细胞修饰中的潜在临床应用，通过基因校正和将体细胞转化为具有生物活性的男性生殖细胞。由体细胞和生殖细胞分别分泌的近分泌和旁分泌因子贡献。源自支持细胞、睾丸间质细胞、脉管系统睾丸内皮细胞 (TEC) 和淋巴内皮细胞 (LEC) 的旁分泌因子，如 GDNF、FGF、CSF1、IGF1 和 CXCL12，通过上调 Etv5、Lhx1、Cxcr4、Nanos2 等基因的表达，通过其同源受体维持 SSC 的自我更新状态。 Shisa6 和 Id4 SSC 的 PLZF、SHISA6、EOMES、LHX1、PDX1 和 ID4 表达。自我更新因子通过抑制分化途径发挥作用，例如SHISA6是WNT抑制剂，Nanos2隔离并抑制mTORC1途径的活性。源自脉管系统的卵泡刺激素 (FSH) 和源自管周肌样细胞 (PMC) 的睾酮 (T) 通过上调 GDNF 表达间接发挥作用。分化启动的 A 型未分化祖细胞（与 SSC 相比，未分化的精原细胞池表达一组独有的基因。祖细胞表达 NGN3、MIWI2 和 RARG。祖细胞的主要特征是对视黄酸 (RA) 的反应性，视黄酸 (RA) 由减数分裂前和减数分裂后的生殖细胞（如精母细胞）通过 RARG 受体合成，导致 Stra8 上调、Kit、Sohlh1 和 Plzf 和 kit 降解 miR221 的下调使细胞容易分化为分化的精原细胞，祖细胞还确保通过 RA 和 NOTCH 信号介导的 GDNF 表达抑制来关闭自我更新途径，而 CYP26B1 是通过 PMC 去除管外来源的管周巨噬细胞样本而分泌的。在第一种方法中，可以从睾丸活检样本中分离出SSC并进行体外扩增以供将来使用。在第二种方法中，可以将从睾丸活检中获得的小管直接冷冻保存以供将来使用。冷冻保存的样品可以通过 2D、3D 或器官培养中的体外成熟 (IVM) 进行复活，从而形成成熟的精子，可应用于辅助生殖技术 (ART)，例如基于组织的精子注射，其优点是可以保留生精上皮的结构完整性，从而实现有效的恢复。在该方法中，可以使用来自青春期前或成年男性皮肤活检的体细胞。在体外被重新编程为多能细胞（诱导多能干细胞，iPSC）。这些 iPSC 可以在体外转分化为原始生殖细胞样细胞（PGCLC），这些细胞可以自体移植到成年男性体内以恢复自然生育能力。
1. ABSTRACT Mammalian spermatogenesis is a complex but well-coordinated process in which spermatogonial stem cells (SSC) of the testis develop to form spermatozoa. During testicular homeostasis, the spermatogonial stem cells self-renew to maintain the stem cell pool or differentiate to form a progeny of germ cells which sequentially transform to spermatozoa. Accumulating evidence from clinical data and diverse model organisms suggest that the fate of spermatogonial stem cells towards self-renewal or differentiation is governed by intrinsic signals within the cells and by extracellular signals from the SSC niche. Here, we review the past and the most recent developments in understanding the nature of spermatogonial stem cells and the regulation of their homeostasis in mice. We also review the potential clinical applications of spermatogonial stem cells in male infertility as well as in germline modification, by virtue of gene correction and conversion of somatic cells to biologically competent male germline cells. is contributed by juxtacrine and paracrine factors secreted by the somatic cells and germ cells respectively. Paracrine factors such as GDNF, FGF, CSF1, IGF1 and CXCL12 derived from Sertoli cells, Leydig cells, testicular endothelial cells (TECs) of the vasculature and lymphatic endothelial cells (LECs) maintain the self- renewal state of SSC via their cognate receptors by upregulating the expression of genes including Etv5 , Lhx1 , Cxcr4 , Nanos2 , Shisa6 and Id4 SSCs by expression of PLZF, SHISA6, EOMES, LHX1, PDX1, and ID4. self-renewal factors function by inhibiting differentiation pathway, for example, SHISA6 is a WNT inhibitor and Nanos2 sequesters and inhibits activity of mTORC1 pathway. Follicle stimulating hormone (FSH), derived from vasculature, and testosterone (T), derived from peritubular myoid cells (PMCs), act indirectly by upregulating GDNF expression. Differentiation primed progenitor cells of A type undifferentiated (A undiff spermatogonia pool express an exclusive set of genes compared to SSCs. The progenitor cells by the expression of NGN3, MIWI2, and RARG. The major characteristic of progenitor cells is the responsiveness to retinoic acid (RA), synthesized by pre-meiotic and post-meiotic germ cells such as spermatocytes, through RARG receptor resulting in upregulation of Stra8 , Kit , Sohlh1 and downregulation of Plzf and kit -degrading miR221 making the cells vulnerable to differentiation into differentiating spermatogonia. The progenitor cells also ensure the shutting down of self-renewal pathway by RA and NOTCH signaling mediated inhibition of GDNF expression. RA degrading enzyme, CYP26B1, secreted by PMC removal of RA extratubular sources peritubular macrophages. samples as prepubertal cancer patients and Klinefelter patients. In the first method, SSCs can be isolated from testis biopsy samples and expanded in vitro. The expanded SSC-derived germ-line clusters can be cryopreserved for future application. In the second method, the tubules obtained from testis biopsy can be directly cryopreserved for future applications. In the adult stage of the male, the cryopreserved samples can be transplanted back into the testis to restore spermatogenesis and fertility. Alternatively, the cryopreserved samples can be revived by in vitro maturation (IVM) in 2D, 3D or organ culture, resulting in the formation of mature sperms that can be applied in assisted reproductive techniques (ART) such as intracytoplasmic sperm injection. Tissue-based approaches have the advantage of preserving the structural integrity of the seminiferous epithelium resulting in efficient restoration. In the method, somatic cells such as fibroblast cells, derived from skin biopsy from prepubertal or adult male, can be reprogrammed in vitro to pluripotent cells (induced pluripotent stem cells, iPSCs). These iPSCs can be transdifferentiated in vitro into primordial germ cell like cells (PGCLCs) that can be autotransplanted into the adult male to restore natural fertility.