Koltzov Institute of Developmental Biology of Russian Academy of Sciences, ul. Vavilova, 26, Moscow, 119334, Russia.
Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, ul.Ostrovityanova, 1, Moscow, 117997, Russia.
Histochem Cell Biol. 2022 Jan;157(1):83-91. doi: 10.1007/s00418-021-02040-6. Epub 2021 Oct 15.
Human infertility is a complex disorder at the genetic, molecular, cellular, organ, and hormonal levels. New developing technology based on the generation of human primordial germ cell-like cells (hPGCLCs) from induced pluripotent stem cells (hiPSCs) might improve understanding of early germ cell development (specification, migration, gametogenesis, and epigenetic reconstitutions), as well as offering a solution for infertility and hereditary disorders. In this study, we differentiated hiPSCs with trisomy 21 into hPGCLCs. In vitro-derived germ cells from hiPSCs with Down syndrome (DS) express hPGCLC core circuitry, EOMES, SOX17, and PRDM14 at relatively low levels. TFAP2C and PRDM1 were expressed and remained elevated, whereas NANOS3 and NANOG were downregulated in BMP4-induced hiPSCs with DS. The low level of NANOG and NANOS3 expression might negatively influence hPGCLC generation in DS hiPSCs. We suggest that DS hPGCLCs could be a suitable model for studying human early germ cell development, the epigenetic and molecular mechanisms of PGC specification and formation, as well as related infertility disorders, such as azoospermia and teratozoospermia.
人类不孕不育是一种涉及基因、分子、细胞、器官和激素等多个层面的复杂疾病。基于诱导多能干细胞（hiPSCs）生成人类原始生殖细胞样细胞（hPGCLCs）的新技术的发展，可能有助于深入理解早期生殖细胞的发育（特化、迁移、配子发生和表观遗传重建），并为不孕不育和遗传性疾病提供解决方案。在这项研究中，我们将 21 三体 hiPSCs 分化为 hPGCLCs。来自唐氏综合征（DS）hiPSCs 的体外衍生生殖细胞相对低水平表达 hPGCLC 核心电路、EOMES、SOX17 和 PRDM14。TFAP2C 和 PRDM1 表达并保持升高，而 BMP4 诱导的 DS hiPSCs 中 NANOS3 和 NANOG 下调。NANOG 和 NANOS3 表达水平较低可能会对 DS hiPSCs 中 hPGCLC 的生成产生负面影响。我们提出，DS hPGCLCs 可以作为研究人类早期生殖细胞发育、PGC 特化和形成的表观遗传和分子机制，以及相关不孕不育疾病（如无精子症和畸形精子症）的合适模型。
