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Metabolic Transitions Define the Spermatogonial Stem Cell Maturation [human]

ABSTRACT: Spermatogonial stem cells (SSCs) are the basis of spermatogenesis and therefore of male fertility. Transplantation of SSCs, isolated before treatment for cancer, and cultured in vitro, could be a potential treatment for infertility. Such clinical usage requires an understanding of the metabolic requirements during SSC development. Adult SSCs mainly use glycolysis for their maintenance in the mouse and human. However, SSCs embryonic precursors, primordial germ cells (PGCs), require a high mitochondrial metabolism in the mouse. Similarly, pig neonatal SSC precursors have been described to rely on oxidative phosphorylation (OXPHOS) for the first 2 months of development, when a transition to an adult SSC metabolic phenotype is initiated. When and if such a metabolic transition occurs in humans is ambiguous. We show here for the first time using single-cell RNA sequencing, that human PGCs and prepubertal human spermatogonia have an enrichment of oxidative phosphorylation associated genes, which is downregulated by 13 years of age. Furthermore, we show, that similar metabolic differences are detectable after birth also in mouse. The metabolic transition in humans with puberty was preceded by a drastic change of SSC shape. Using a pig model, we reveal that these metabolic changes could be regulated by IGF-1 dependent signaling via mTOR and proteasomic inhibition. Understanding the metabolic requirements of SSCs during development is crucial to establish a culture system and enable clinical use of SSCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196817 | GEO | 2022/07/20

REPOSITORIES: GEO

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Metabolic Transitions Define the Spermatogonial Stem Cell Maturation [mouse]

Project description:Spermatogonial stem cells (SSCs) are the basis of spermatogenesis and therefore of male fertility. Transplantation of SSCs, isolated before treatment for cancer, and cultured in vitro, could be a potential treatment for infertility. Such clinical usage requires an understanding of the metabolic requirements during SSC development. Adult SSCs mainly use glycolysis for their maintenance in the mouse and human. However, SSCs embryonic precursors, primordial germ cells (PGCs), require a high mitochondrial metabolism in the mouse. Similarly, pig neonatal SSC precursors have been described to rely on oxidative phosphorylation (OXPHOS) for the first 2 months of development, when a transition to an adult SSC metabolic phenotype is initiated. When and if such a metabolic transition occurs in humans is ambiguous. We show here for the first time using single-cell RNA sequencing, that human PGCs and prepubertal human spermatogonia have an enrichment of oxidative phosphorylation associated genes, which is downregulated by 13 years of age. Furthermore, we show, that similar metabolic differences are detectable after birth also in mouse. The metabolic transition in humans with puberty was preceded by a drastic change of SSC shape. Using a pig model, we reveal that these metabolic changes could be regulated by IGF-1 dependent signaling via mTOR and proteasomic inhibition. Understanding the metabolic requirements of SSCs during development is crucial to establish a culture system and enable clinical use of SSCs.

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