Inhibition of TGF-β Signaling Promotes Human Pancreatic β-Cell Replication.
Inhibition of TGF-β Signaling Promotes Human Pancreatic β-Cell Replication.
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作者：
Dhawan S;Dirice E;Kulkarni RN;Bhushan A
糖尿病与功能性胰腺β细胞的丧失相关，并且β细胞的恢复是再生疗法的主要目标。通过β细胞复制的β细胞内源性再生具有恢复细胞质量的潜力;然而，促进内源性β细胞再生或扩增的药理学试剂一直难以捉摸。由于p16 INK 4a的积累，β细胞的再生能力随着年龄的增长而迅速下降，导致成人内分泌胰腺再生的能力有限。在这里，我们表明，通过Smad 3的转化生长因子-β（TGF-β）信号转导与三胸复合体整合，以激活和维持Ink 4a表达，从而阻止β细胞复制。重要的是，TGF-β信号传导的抑制可导致Ink 4a/Arf基因座的抑制，导致成年小鼠中β细胞复制增加。此外，TGF-β途径的小分子抑制剂促进移植到NOD-scid IL-2 Rgnull小鼠中的人胰岛中的β细胞复制。这些数据揭示了TGF-β信号传导在Ink 4a/Arf基因座调节中的新作用，并强调了使用TGF-β信号传导的小分子抑制剂促进人β细胞复制的潜力。
Diabetes is associated with loss of functional pancreatic β-cells, and restoration of β-cells is a major goal for regenerative therapies. Endogenous regeneration of β-cells via β-cell replication has the potential to restore cellular mass; however, pharmacological agents that promote regeneration or expansion of endogenous β-cells have been elusive. The regenerative capacity of β-cells declines rapidly with age, due to accumulation of p16INK4a, resulting in limited capacity for adult endocrine pancreas regeneration. Here, we show that transforming growth factor-β (TGF-β) signaling via Smad3 integrates with the trithorax complex to activate and maintain Ink4a expression to prevent β-cell replication. Importantly, inhibition of TGF-β signaling can result in repression of the Ink4a/Arf locus, resulting in increased β-cell replication in adult mice. Furthermore, small molecule inhibitors of the TGF-β pathway promote β-cell replication in human islets transplanted into NOD-scid IL-2Rgnull mice. These data reveal a novel role for TGF-β signaling in the regulation of the Ink4a/Arf locus and highlight the potential of using small molecule inhibitors of TGF-β signaling to promote human β-cell replication.