Cycling Alpha Cells in Regenerative Drug-Treated Human Pancreatic Islets Serve As Key Beta Cell Progenitors

Diabetes results from an inadequate number of insulin-producing human beta cells. There is currently no effective means to restore beta cell mass in millions of people with diabetes. Although the DYRK1A inhibitors, either alone or in combination with GLP1 receptor agonists (GLP1) or TGF superfamily inhibitors (LY), induce beta cell replication and increase beta cell mass, the precise mechanisms of action remain elusive. We performed single cell RNA sequencing on human pancreatic islets treated with a DYRK1A inhibitor, either alone, or with GLP1 or LY. We identify Cycling Alpha Cells as the most responsive cells to DYRK1A inhibition. Lineage trajectory analyses suggest that Cycling Alpha Cells may serve as precursor cells that transdifferentiate into beta cells. In addition to shedding light onto the mechanisms of action of DYRK1A inhibitors, our findings suggest that the proper target for regenerative drugs in human islets may be Cycling Alpha Cells. Cadaveric human islets were subject to beta cell regenerative drug treatment for 96 hours which was followed by scRNA-seq experiments. DMSO (control), Harmine (10μM), Harmine + GLP1RA (GLP), and Harmine + LY364947 (LY) treatments.

糖尿病的发生源于能够产生胰岛素的人β细胞（human beta cell）数量匮乏。目前，全球数百万糖尿病患者仍缺乏能够有效恢复β细胞总量的治疗手段。尽管DYRK1A抑制剂（DYRK1A inhibitor）单独使用或与GLP1受体激动剂（GLP1 receptor agonist, GLP1）、转化生长因子β（TGF-β）超家族抑制剂（LY）联合使用时，可诱导β细胞增殖并提升β细胞总量，但其确切的作用机制仍未明确。本研究使用尸检来源的人胰腺胰岛，先施以β细胞再生药物处理96小时，随后开展单细胞RNA测序（single cell RNA sequencing, scRNA-seq）实验，处理组分别为二甲基亚砜（DMSO，对照组）、哈尔明（Harmine，10μM）、哈尔明联合GLP1受体激动剂（Harmine + GLP1RA, GLP）以及哈尔明联合LY364947（LY）。研究鉴定出增殖态α细胞（Cycling Alpha Cells）是对DYRK1A抑制响应最为显著的细胞群。谱系轨迹分析结果显示，增殖态α细胞可作为前体细胞转分化为β细胞。本研究不仅阐明了DYRK1A抑制剂的作用机制，同时还揭示：针对人胰腺胰岛的再生治疗药物，其潜在的理想靶点或为增殖态α细胞。