Zebrafish Development and Disease Models Laboratory, GIGA-Stem Cells, University of Liège, Liège, Belgium.
GIGA-Genomics Core Facility, GIGA, University of Lièg, Liège, Belgium.
Elife. 2024 Oct 9;12:RP88813. doi: 10.7554/eLife.88813.
Stimulation of pancreatic beta cell regeneration could be a therapeutic lead to treat diabetes. Unlike humans, the zebrafish can efficiently regenerate beta cells, notably from ductal pancreatic progenitors. To gain insight into the molecular pathways involved in this process, we established the transcriptomic profile of the ductal cells after beta cell ablation in the adult zebrafish. These data highlighted the protein phosphatase calcineurin (CaN) as a new potential modulator of beta cell regeneration. We showed that CaN overexpression abolished the regenerative response, leading to glycemia dysregulation. On the opposite, CaN inhibition increased ductal cell proliferation and subsequent beta cell regeneration. Interestingly, the enhanced proliferation of the progenitors was paradoxically coupled with their exhaustion. This suggests that the proliferating progenitors are next entering in differentiation. CaN appears as a guardian which prevents an excessive progenitor proliferation to preserve the pool of progenitors. Altogether, our findings reveal CaN as a key player in the balance between proliferation and differentiation to enable a proper beta cell regeneration.
刺激胰腺β细胞再生可能是治疗糖尿病的一种治疗方法。与人类不同，斑马鱼能够有效地再生β细胞，特别是从导管胰腺祖细胞中再生。为了深入了解这一过程中涉及的分子途径，我们在成年斑马鱼的β细胞消融后建立了导管细胞的转录组图谱。这些数据突出了钙调神经磷酸酶（CaN）作为β细胞再生的一个新的潜在调节剂。我们表明，CaN 的过表达消除了再生反应，导致血糖调节紊乱。相反，CaN 抑制增加了导管细胞的增殖和随后的β细胞再生。有趣的是，祖细胞的增殖增加与它们的耗竭同时发生。这表明增殖的祖细胞接下来进入分化。CaN 似乎是一个守护者，防止祖细胞过度增殖，以维持祖细胞库。总之，我们的研究结果表明 CaN 是增殖和分化之间平衡的关键参与者，以实现适当的β细胞再生。
