| 论文作者 |
You, X; Peng, Q; Qian, WJ; Xie, ZQ; Lin, YJ; Gai, YK; Ye, JR; Feng, Y |
| 摘要 |
Background: beta-Cell proliferation is vital for adapting to metabolic stress. Failure to expand beta-cell mass during insulin resistance and aging contributes to dysfunction and diabetes. Understanding the mechanisms behind beta-cell proliferation issues and dysfunction is crucial. SRSF1 is a central regulator of cell proliferation and survival, but its influence on beta-cell proliferation and glucose control remains unclear. This study aims to investigate the role of SRSF1 in beta-cell proliferation and its impact on glucose regulation. By examining the consequences of SRSF1 deficiency in pancreatic beta-cells, we seek to elucidate the mechanisms linking SRSF1 to beta-cell maintenance and function. Methods: Mice with pancreatic beta-cell-specific deletion of SRSF1 and a Rosa26-tdT lineage reporter were generated. Pancreatic sections were analyzed using immunostaining for insulin, glucagon, somatostatin, Ki67, tdT, proinsulin, TUNEL, and ER stress markers, as well as HE staining. Glucose tolerance tests, glucose and insulin measurements were performed in knockout and control mice. RNA-seq analyzed gene expression changes in 4month-old islets, while scRNA-seq assessed cellular heterogeneity and gene expression profiles in 10-month-old mice islets. Knockdown assays and puromycin labeling experiments measured new protein synthesis. Results: SRSF1 deficiency resulted in glucose intolerance and impaired insulin secretion, worsening with age. At early stages, knockout islets exhibited reduced beta-cell proliferation accompanied by compensatory a-cell expansion. By 4 months, RNA-seq analysis showed downregulation of ribosome biogenesis and cell cycle genes, along with upregulation of alpha-cell determinants and progenitor-associated factors. Histological examination further revealed a decreased beta-cell fraction, an increased a-cell fraction, and a small subset of a-cells co-expressing somatostatin, indicative of transient, stress-associated phenotypic plasticity. scRNA-seq identified ER stress and altered beta-cell fate in knockout beta-cells from 10-month-old mice. Notably, these changes were absent in 4month-old knockout islets, indicating ER stress as a secondary response to proliferative defects from SRSF1 deficiency. Mechanistically, SRSF1 employs mechanisms similar to MYC to promote beta-cell proliferation, with its effects on beta-cells through the regulation of MYC expression. Conclusions: SRSF1 is essential for beta-cell proliferation and function through MYC-mediated pathways. Its deficiency disrupts beta-cell homeostasis and contributes to metabolic dysfunction in mice, underscoring its importance in preserving functional beta-cells and maintaining glucose balance. |
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