![]() Testicular endothelial cells express GDNF ( Bhang et al., 2018) and FGF5 ( Kitadate et al., 2019). Leydig cells express IGF1 ( Huang et al., 2009), CSF1 ( Oatley et al., 2009) and EGF ( Zhang et al., 1997). Other testicular somatic cells also express factors that regulate SSCs and/or spermatogenesis. Sertoli cells are thought to be the producer of many important growth factors that regulate spermatogenesis, including GDNF ( Meng et al., 2000), FGF2 ( Mullaney and Skinner, 1992), SCF ( Rossi et al., 1993), neuregulin 1 ( Zhang et al., 2011), WNT5A ( Yeh et al., 2011), activin A ( De Winter et al., 1993), BMP4 ( Pellegrini et al., 2003), EGF ( Radhakrishnan et al., 1992), PDGF ( Li et al., 1997 Loveland et al., 1995) and CXCL12 ( Yang et al., 2013). It is likely that deletion of these genes disrupts the normal properties of Sertoli cells, which indirectly affects spermatogenesis. However, there was no evidence that any of the above genes directly regulate spermatogonia. This is supported by findings that Sertoli cell-specific deletion of transcription factor-encoding genes, such as Rbpj ( Garcia et al., 2014), Sin3a ( Payne et al., 2010) and Gata4 ( Kyrönlahti et al., 2011), or hormone receptors, such as Ar ( De Gendt et al., 2004), Lifr ( Curley et al., 2018) and Pgrmc1 ( Broady et al., 2011), impaired spermatogenesis and male fertility. Sertoli cells have been regarded as a key component of the spermatogonial niche ( Oatley et al., 2011). Self-renewal and differentiation of SSCs are regulated by factors secreted from testicular somatic cells ( Chen et al., 2016 Kitadate et al., 2019 Oatley and Brinster, 2012 van Pelt and de Rooij, 1990). Mammalian spermatogenesis is a complex developmental process based on a robust spermatogonial stem cell (SSC) system. Our data reveal the importance of anatomical localization for Sertoli cells in regulating spermatogenesis and that SCF produced specifically by Sertoli cells is essential for spermatogenesis. Conditional overexpression of Scf in Sertoli cells, but not endothelial cells, significantly increased spermatogenesis. Conditional deletion of Scf from Sertoli cells, but not any other Scf-expressing cells, blocked the differentiation of spermatogonia, leading to complete male infertility. Both undifferentiated and differentiating spermatogonia were associated with Scf-expressing Sertoli cells in the seminiferous tubule. Here, using single-cell RNA sequencing and a series of fluorescent reporter mice, we found that stem cell factor ( Scf), one of the essential growth factors for spermatogenesis, was broadly expressed in testicular stromal cells, including Sertoli, endothelial, Leydig, smooth muscle and Tcf21-CreER + stromal cells. However, expression patterns of the key growth factors produced by these somatic cells have not been systematically studied and no such factor has been conditionally deleted from its primary source(s), raising the question of which cell type(s) are the physiological sources of these growth factors. Several cell types have been proposed to create the required microenvironment for spermatogenesis. ![]()
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