Abstract
Maintenance of adult tissues depends on stem cell self-renewal in local niches. Spermatogonial stem cells (SSC) are germline adult stem cells necessary for spermatogenesis and fertility. We show that testicular endothelial cells (TECs) are part of the SSC niche producing glial cell line-derived neurotrophic factor (GDNF) and other factors to support human and mouse SSCs in long-term culture. We demonstrate that FGF-2 binding to FGFR1 on TECs activates the calcineurin pathway to produce GDNF. Comparison of the TEC secretome to lung and liver endothelial cells identified 5 factors sufficient for long-term maintenance of human and mouse SSC colonies in feeder-free cultures. Male cancer survivors after chemotherapy are often infertile since SSCs are highly susceptible to cytotoxic injury. Transplantation of TECs alone restores spermatogenesis in mice after chemotherapy-induced depletion of SSCs. Identifying TECs as a niche population necessary for SSC self-renewal may facilitate fertility preservation for prepubertal boys diagnosed with cancer.
Highlights
Maintenance of adult tissues depends on stem cell self-renewal in local niches
We show that injection of testicular endothelial cells (TECs) alone is sufficient to restore spermatogenesis in mice after chemotherapy-induced depletion of Spermatogonial stem cells (SSC) and that TECs, but not other organ endothelium, express growth factors that are sufficient for the maintenance of SSCs in culture and include glial cell line-derived neurotrophic factor (GDNF), fibroblast growth factor-2 (FGF-2), stromal cell-derived factor-1 (SDF-1), macrophage inflammatory protein 2 (MIP-2) and insulin-like growth factor binding protein 2 (IGFBP-2)
Since GDNF is necessary for the long-term culture of SSCs and Sertoli and peritubuluar myoid (PTM) cells produce GDNF, we investigated whether Sertoli cells and PTMs could maintain Thy1+SSCs in culture
Summary
Maintenance of adult tissues depends on stem cell self-renewal in local niches. Spermatogonial stem cells (SSC) are germline adult stem cells necessary for spermatogenesis and fertility. Transplantation of TECs alone restores spermatogenesis in mice after chemotherapy-induced depletion of SSCs. Identifying TECs as a niche population necessary for SSC self-renewal may facilitate fertility preservation for prepubertal boys diagnosed with cancer. We show that TECs are a key population in the male germline stem cell niche providing necessary growth factors for self-renewal and expansion of human and mouse SSCs in culture. Our data support the conclusion that the SSC niche is created in part by TECs providing the necessary factors for SSC self-renewal and we identify the CaN–NFAT pathway in TECs as regulating the expression of GDNF, the most critical factor for the maintenance of spermatogenesis
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