Abstract
Recently published article by Pieri’s group suggested that follicle-stimulating hormone (FSH) activates canine testicular spermatogonial stem cells (SSCs) and results in increased expression of pluripotent markers and formation of germ cell clumps possibly via indirect paracrine effect of Sertoli cells. We disagree with their interpretations and herewith provide a better explanation to their findings. We have earlier reported the presence of pluripotent, very small embryonic-like stem cells (VSELs) as a sub-group among the SSCs in human and mouse testes and that both VSELs and SSCs express FSH receptors. Thus, FSH exerts a direct stimulatory action on the testicular stem/progenitor cells whereby VSELs undergo asymmetrical cell divisions to self-renew (result in upregulation of pluripotent markers) and give rise to slightly bigger SSCs which undergo symmetrical cell divisions and “clonal expansion” (rapid proliferation with incomplete cytokinesis) which was noted by the authors as “clump” formation. This action of FSH is mediated via alternately spliced FSHR3 rather than the canonical FSHR1 receptor isoform, and FSH exerts similar action on ovarian and uterine stem/progenitor cells also. Being quiescent by nature, VSELs survive chemotherapy. Transplanted germ cells colonize chemoablated tubules but do not differentiate into sperm since the testicular stem cell niche comprising Sertoli cells gets functionally compromised by chemotherapy. Transplanting healthy niche cells (Sertoli or bone marrow-derived mesenchymal cells) can restore spermatogenesis in chemoablated testes.
Highlights
Published article by Pieri’s group suggested that follicle-stimulating hormone (FSH) activates canine testicular spermatogonial stem cells (SSCs) and results in increased expression of pluripotent markers and formation of germ cell clumps possibly via indirect paracrine effect of Sertoli cells
Testis harbors OCT-4-positive pluripotent stem cells in addition to SSCs: We have reported that both adult human and mouse testicular stem cells include a sub-group of pluripotent stem cells termed very small embryonic-like stem cells (VSELs) along with SSCs [2,3,4]
Two distinct populations of stem cells exist in adult tissues including pluripotent VSELs and slightly bigger tissue-specific progenitor ovarian stem cells (OSCs) in the ovary [6] and endometrial stem cells (EnSCs) in the uterus [7] similar to SSCs in the testis [4]. 2
Summary
Published article by Pieri’s group suggested that follicle-stimulating hormone (FSH) activates canine testicular spermatogonial stem cells (SSCs) and results in increased expression of pluripotent markers and formation of germ cell clumps possibly via indirect paracrine effect of Sertoli cells. FSH treatment resulted in increased expression of early pluripotency marker OCT-4 and later germ cell markers PLZF, DAZL, c-Kit, and GFRA. On transplanting in chemoablated mouse testis, cSSCs were found to colonize and proliferate in the presence of FSH but there was no evidence of differentiation and increase in numbers of germ cells/sperm.
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