Acinar to β-like cell conversion through inhibition of focal adhesion kinase

Insufficient functional β-cell mass causes diabetes; however, an effective cell replacement therapy for curing diabetes is currently not available. Reprogramming of acinar cells toward functional insulin-producing cells would offer an abundant and autologous source of insulin-producing cells. Our lineage tracing studies along with transcriptomic characterization demonstrate that treatment of adult mice with a small molecule that specifically inhibits kinase activity of focal adhesion kinase results in trans-differentiation of acinar cells into insulin producing β-like cells. The acinar-derived insulin-producing cells infiltrate the pre-existing endocrine islets, partially restore β-cell mass, and significantly improve glucose homeostasis in diabetic mice. Importantly, this treatment can substantially reduce the exogenous insulin requirements in streptozotocin-induced diabetic non-human primates. These findings provide evidence that inhibition of the kinase activity of focal adhesion kinase can convert acinar cells into insulin-producing cells and could offer a promising strategy for treating diabetes. To better characterize these newly formed insulin-producing cells, we conducted single cell RNA sequencing (scRNA-seq) analysis on islets isolated from wild type mice ten days after cessation of vehicle- or FAKi treatment. Approximately 8500 cells were sequenced at 225,000 reads per cell.

功能性β细胞质量不足可诱发糖尿病，但目前尚无成熟有效的细胞替代疗法用于治愈该疾病。将腺泡细胞重编程为功能性产胰岛素细胞，可获得充足的自体产胰岛素细胞来源。我们的谱系示踪研究结合转录组表征结果显示，采用可特异性抑制黏着斑激酶（focal adhesion kinase, FAK）激酶活性的小分子化合物处理成年小鼠，可诱导腺泡细胞向产胰岛素样β细胞发生转分化。此类腺泡来源的产胰岛素细胞可浸润已存在的内分泌胰岛，部分恢复β细胞质量，并显著改善糖尿病小鼠的葡萄糖稳态。尤为重要的是，该处理方案可大幅降低链脲佐菌素诱导的糖尿病非人灵长类动物的外源性胰岛素需求量。上述研究结果证实，抑制黏着斑激酶的激酶活性可将腺泡细胞转化为产胰岛素细胞，有望为糖尿病治疗提供极具前景的策略。为更好地表征这些新生成的产胰岛素细胞，我们对溶媒对照或FAK抑制剂（FAKi）处理停止10天后的野生型小鼠所分离的胰岛开展了单细胞RNA测序（scRNA-seq）分析。本次测序每细胞获取约225000条读数，共完成约8500个细胞的测序。