Distinctive molecular features of regenerative stem cells in the damaged male germline

Abstract

Maintenance of male fertility requires spermatogonial stem cells (SSCs) that self-renew and generate differentiating germ cells for production of spermatozoa. Germline cells are sensitive to genotoxic drugs and patients receiving chemotherapy can become infertile. SSCs surviving treatment mediate germline recovery but pathways driving SSC regenerative responses remain poorly understood. Using models of chemotherapy-induced germline damage and recovery, here we identify unique molecular features of regenerative SSCs and characterise changes in composition of the undifferentiated spermatogonial pool during germline recovery by single-cell analysis. Increased mitotic activity of SSCs mediating regeneration is accompanied by alterations in growth factor signalling including PI3K/AKT and mTORC1 pathways. While sustained mTORC1 signalling is detrimental for SSC maintenance, transient mTORC1 activation is critical for the regenerative response. Concerted inhibition of growth factor signalling disrupts core features of the regenerative state and limits germline recovery. We also demonstrate that the FOXM1 transcription factor is a target of growth factor signalling in undifferentiated spermatogonia and provide evidence for a role in regeneration. Our data confirm dynamic changes in SSC functional properties following damage and support an essential role for microenvironmental growth factors in promoting a regenerative state.

Proteomic characterization of gastric cancer response to chemotherapy and targeted therapy reveals potential therapeutic strategies

“…To validate the hypothesis, we performed further in vitro validation experiment to confirm the synergistic effects of the combination of anti-HER2 and the PI3K-AKT inhibitors. As reported in the previous studies, buparlisib (BKM120) is a commonly used potent, pan-class I PI3K inhibitor approved for clinical trials [48][49][50] . We treated NCI-N87 cells (HER2-positive cell line) with trastuzumab (TRA), buparlisib (BUP), and combination of trastuzumab and buparlisib (BUP + TRA) with a ratio of 1:1, respectively.…”

Germline stem cells in human

“…For example, in a mouse model, mTORC1 and FOXO1 signaling have been shown to be key regulators for regenerative undifferentiated spermatogonia. 361 The hepatic stellate cell activation pathway is upregulated in SSCs, suggesting its role in the specification and maintenance of SSC fate. 343 The SSC niche is another regulatory layer for SSC development.…”

“…Some parts of the figure were drawn by Figdraw SSC transplantation for fertility preservation in cancers and gene therapies. Spermatogonial stem cell transplantation is a promising approach to restore fertility for patients who need chemotherapy and radiation treatment, such as in cancer therapies, because these treatments often lead to damage to gonadal cells, thus infertility, 361,378,379 although some antioxidants can reduce the damage to germ cells. 380 Prepubertal boys who suffer from gonadotoxic treatment under pediatric cancer circumstances, e.g., acute lymphoblastic leukemia and testicular cancer, might cause sterile for the rest of their life.…”

Quantitative association between gene expression and blood cell production of individual hematopoietic stem cells in mice

“…S11). Moreover, a previous study has shown that six of the seven genes are significantly up-regulated in spermatogonial stem cells during regeneration as compared to a homeostatic state ( 68 ). Our analyses further reveal that these seven genes also share common regulatory motifs at their promoter regions in mice and humans (Fig.…”