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Circulation,2020,141(19):1554–1569
2020年02月26日
Background: In mammals, regenerative therapy after myocardial infarction is hampered by the limited regenerative capacity of adult heart, whereas a transient regenerative capacity is maintained in the neonatal heart. Systemic phosphorylation signaling analysis on ischemic neonatal myocardium might be helpful to identify key pathways involved in heart regeneration. Our aim was to define the kinase-substrate network in ischemic neonatal myocardium and to identify key pathways involved in heart regeneration after ischemic insult. Methods: Quantitative phosphoproteomics profiling was performed on infarct border zone of neonatal myocardium, and kinase-substrate network analysis revealed 11 kinases with enriched substrates and upregulated phosphorylation levels, including checkpoint kinase 1 (CHK1) kinase. The effect of CHK1 on cardiac regeneration was tested on Institute of Cancer Research CD1 neonatal and adult mice that underwent apical resection or myocardial infarction. Results: In vitro, CHK1 overexpression promoted whereas CHK1 knockdown blunted cardiomyocyte proliferation. In vivo, inhibition of CHK1 hindered myocardial regeneration on resection border zone in neonatal mice. In adult myocardial infarction mice, CHK1 overexpression on infarct border zone upregulated mammalian target of rapamycin C1/ribosomal protein S6 kinase b-1 pathway, promoted cardiomyocyte proliferation, and improved cardiac function. Inhibiting mammalian target of rapamycin activity by rapamycin blunted the neonatal cardiomyocyte proliferation induced by CHK1 overexpression in vitro. Conclusions: Our study indicates that phosphoproteome of neonatal regenerative myocardium could help identify important signaling pathways involved in myocardial regeneration. CHK1 is found to be a key signaling responsible for neonatal regeneration. Myocardial overexpression of CHK1 could improve cardiac regeneration in adult hearts by activating the mammalian target of rapamycin C1/ribosomal protein S6 kinase b-1 pathway. Thus, CHK1 might serve as a potential novel target in myocardial repair after myocardial infarction.
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Cell Research volume,2020,30():pages244–2
2020年02月21日
Unlike most organs that mature during the fetal period, the male reproductive system reaches maturity only at puberty with the commencement of spermatogenesis. Robust modelling of human testicular organogenesis in vitro would facilitate research into mechanisms of and factors affecting human spermatogenic failure and male fertility preservation in prepubertal tumor patients. Here, we report successful recapitulation of human testicular organogenesis in vitro from fetal gonadal ridge. Our model displayed the formation of mature seminiferous epithelium and self-renewing spermatogonia. Remarkably, in vitro-derived haploid spermatids have undergone meiotic recombination, and showed increased genetic diversity as indicated by genetic analysis. Moreover, these spermatids were able to fertilize oocytes and support subsequent blastocyst formation. The in vitro testicular organogenesis system described here will play an important role in elucidating the regulation of human testis development and maintaining male fertility in prepubertal cancer patients.
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