Molecular signatures of Sertoli cells

支持细胞（SCs）是精原干细胞生态位的一部分，对精子发生至关重要。它们直接与不同类型的生殖细胞相互作用，为精子发生提供形态、营养和旁分泌支持。功能生态位的形成和维持涉及大量的内分泌和其他因素，这些因素在生命的不同阶段对SCs有不同的影响。在青春期周围，SCs高度增殖，而它们在成年期进入有丝分裂静止期，随后在生命的后期阶段细胞衰老。最近有人提出，人类睾丸中存在不同的SC亚型。考虑到SCs在精子发生中的基本功能，令人惊讶的是，SCs及其对男性不育的影响仍未得到充分研究。特别是在SCO（男性不育的最严重形式）的情况下，很可能是生殖细胞生态位功能失调，导致SC基因突变或其他SC特性改变的可能性参与了这种病理。因此，在这个项目中，我们将解决SCs分子特征改变可能导致男性不育的假设。我们将研究正常精子发生患者和无精子患者仅支持细胞（SCO）的SCs。为了回答我们的假设，我们将通过scRNA-Seq和大量RNA-Seq实验生成健康和SCO患者SCs的转录组图谱。SCs建立生态位的能力将通过对细胞数量、形态、蛋白质生物合成和标记表达的详细分析来研究。最后，我们将通过对人类睾丸进行体外研究来深入了解SC的功能。生成的数据和研究参数将导致健康sc和来自SCO患者的sc的不同细胞和分子特征。这些参数将在SC评分系统中编制，该系统理想地描述了SC的功能状态和/或指示不同生理条件的SC亚型的存在。建立的SC评分将是表征SCO患者的工具，并可能破译潜在的病理生理机制。从角度来看，该项目将描述在何种程度上功能失调的SC功能有助于男性不育的难题。

Sertoli cells (SCs) are part of the spermatogonial stem cell niche, making them essential for spermatogenesis. They interact directly with the different germ cell types to provide morphological, nutritional, and paracrine support for spermatogenesis. The formation and maintenance of a functional niche involves a plethora of endocrine and other factors, which have different effects on SCs during different stages of life. During peripuberty SCs are highly proliferative, while they enter a mitotically quiescence phase during adulthood which is followed by cellular senescence during later stages of life. Recently the presence of different SC subtypes in the human testis was suggested. Given the essential function of SCs for spermatogenesis, it is surprising that SCs and their impact on male infertility remain grossly understudied. Especially in the case of SCO, the severest form of male infertility, it is very likely that the germ cell niche is dysfunctional, giving rise to the possibility that mutations in SC genes or other altered SCs properties are involved in this pathology.Within this project we will therefore address the hypothesis that altered molecular signatures of SCs can be causative for male infertility. We will study SCs from patients with normal spermatogenesis and azoospermic patients with Sertoli cell only (SCO). To answer our hypothesis we will generate a transcriptomic atlas of SCs from healthy and SCO patients by scRNA-Seq and bulk RNA-Seq experiments. The competence of SCs for establishing a niche will be studied by detailed analyses of cell number, morphology, protein biosynthesis, and marker expression. Finally, we will get insights into SC function by performing in-vitro studies on human testes.The generated data and studied parameters will result in distinct cellular and molecular signatures for healthy SCs and SCs from SCO patients. These parameters will be compiled in a SC scoring system, which ideally delineates the functional status of SCs and/or the presence of SC subtypes indicative for different physiological conditions. The established SC score will be tool for the characterization of SCO patients and might decipher underlying pathophysiological mechanisms. In perspective the project will delineate to which extent dysfunctional SC function contributes to the conundrum of male infertility.