Diabetes Remission Using Glucose-Responsive Insulin-Producing Human alpha-Cells

Natural and stable cell identity switches, where terminally-differentiated cells convert into different cell-types when stressed, represent a widespread regenerative strategy in animals, yet they are poorly documented in mammals. In mice, some glucagon-producing pancreatic a-cells become insulin expressers upon ablation of insulin-secreting ß-cells, promoting diabetes recovery. Whether human islets also display this plasticity for reconstituting ß-like cells, especially in diabetic conditions, remains unknown. Here we show that two different islet non-ß-cell types, a- and ?–cells, obtained from deceased non-diabetic or diabetic human donors can be lineage-traced and induced to produce insulin and secrete it in response to glucose. When transplanted into diabetic mice, converted human a-cells reverse diabetes and remain producing insulin even after 6 months. Insulin-producing a-cells maintain a-cell markers, as seen by deep transcriptomic and proteomic characterization, and display hypo-immunogenic features when exposed to T-cells derived from diabetic patients. These observations provide conceptual evidence and a molecular framework for a mechanistic understanding of in situ cell plasticity in islet cells, as well as in other organs, as a therapy for degenerative diseases by fostering the highly-regulated intrinsic cell regeneration. Overall design: Single-cell transcriptomic profiles of human pancreatic ?-cells that convert into insulin-producing cells were generated by deep sequencing using Illumina Hi-seq 4000.