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Paracrine regulation of SSC self-renewal
Self-renewal of spermatogonial stem cells (SSCs) is regulated by local signals. Around 50% of the SSC population undergo self-renewal to maintain stem cell numbers, and the other 50% become committed progenitor cells that will differentiate into spermatozoa during spermatogenesis. Cells present in the testes express molecules that play key roles in the regulation of SSC self-renewal. In mice, Sertoli cells have been shown to secrete Glial cell line-derived neurotrophic factor (GDNF) which has a stimulatory effect on stem cell self-renewal. This factor is thought to be expressed in the peritubular cells in human testes. Fibroblast growth factor (FGF2) is another molecule crucial for the regulation of stem cell renewal and is expressed in Sertoli cells, Leydig cells and germ cells. FGF2 signalling interacts with GDNF to enhance proliferation rate. Chemokine (C-X-C motif) ligand 12 (CXCL12) signaling via its receptor C-X-C chemokine receptor type 4 (CXCR4) is also involved in regulation of SSC fate decisions.CXCL12 is found in Sertoli cells in the basement membrane of the seminiferous tubules in adult mouse testes, and its receptor is expressed in undifferentiated spermatogonial cells.

GDNF and FGF2 are both required to activate the phosphoinositide 3-kinase (PI3K)-Akt pathway, and the mitogen-activated protein kinase/ERK1 kinase1 (MEK) pathway, which potentiate SSC proliferation and survival. CXCL12, FGF2 and GDNF all communicate via a network to mediate SSC functions.