Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei 400715 Chongqing, China.
Development. 2023 Mar 15;150(6). doi: 10.1242/dev.201306. Epub 2023 Mar 27.
Pancreatic ε-cells producing ghrelin are one type of endocrine cell found in islets, which have been shown to influence other intra-islet cells, especially in regulating the function of β cells. However, the role of such cells during β-cell regeneration is currently unknown. Here, using a zebrafish nitroreductase (NTR)-mediated β-cell ablation model, we reveal that ghrelin-positive ε-cells in the pancreas act as contributors to neogenic β-cells after extreme β-cell loss. Further studies show that the overexpression of ghrelin or the expansion of ε-cells potentiates β-cell regeneration. Lineage tracing confirms that a proportion of embryonic ε-cells can transdifferentiate to β-cells, and that the deletion of Pax4 enhances this transdifferentiation of ε-cells to β-cells. Mechanistically, Pax4 binds to the ghrelin regulatory region and represses its transcription. Thus, deletion of Pax4 derepresses ghrelin expression and causes producing more ghrelin-positive cells, enhancing the transdifferentiation of ε-cells to β-cells and consequently potentiating β-cell regeneration. Our findings reveal a previously unreported role for ε-cells during zebrafish β-cell regeneration, indicating that Pax4 regulates ghrelin transcription and mediates the conversion of embryonic ε-cells to β-cells after extreme β-cell loss.
胰腺中产生 ghrelin 的 ε 细胞是胰岛中发现的一种内分泌细胞类型，已被证明可以影响其他胰岛内细胞，尤其是调节β细胞的功能。然而，在β细胞再生过程中，这些细胞的作用目前尚不清楚。在这里，我们使用斑马鱼硝基还原酶（NTR）介导的β细胞消融模型，揭示了胰腺中 ghrelin 阳性的 ε 细胞在β细胞大量丢失后可作为新生β细胞的贡献者。进一步的研究表明，ghrelin 的过表达或 ε 细胞的扩增可增强β细胞再生。谱系追踪证实，一部分胚胎期的 ε 细胞可以转分化为β细胞，而 Pax4 的缺失增强了这种 ε 细胞向β细胞的转分化。从机制上讲，Pax4 结合 ghrelin 的调控区并抑制其转录。因此，Pax4 的缺失使 ghrelin 表达去抑制，并导致产生更多的 ghrelin 阳性细胞，增强了 ε 细胞向β细胞的转分化，从而增强了β细胞的再生。我们的研究结果揭示了 ε 细胞在斑马鱼β细胞再生过程中的一个以前未被报道的作用，表明 Pax4 调节 ghrelin 转录，并介导在β细胞大量丢失后胚胎期 ε 细胞向β细胞的转化。
