Molecular signatures of Sertoli cells

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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.