Diabetes relief in mice by glucose-sensing insulin-secreting human α-cells

Nature. 2019 Mar;567(7746):43-48. doi: 10.1038/s41586-019-0942-8. Epub 2019 Feb 13.

Abstract

Cell-identity switches, in which terminally differentiated cells are converted 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 α-cells and somatostatin-producing δ-cells become insulin-expressing cells after the ablation of insulin-secreting β-cells, thus promoting diabetes recovery. Whether human islets also display this plasticity, especially in diabetic conditions, remains unknown. Here we show that islet non-β-cells, namely α-cells and pancreatic polypeptide (PPY)-producing γ-cells, obtained from deceased non-diabetic or diabetic human donors, can be lineage-traced and reprogrammed by the transcription factors PDX1 and MAFA to produce and secrete insulin in response to glucose. When transplanted into diabetic mice, converted human α-cells reverse diabetes and continue to produce insulin even after six months. Notably, insulin-producing α-cells maintain expression of α-cell markers, as seen by deep transcriptomic and proteomic characterization. These observations provide conceptual evidence and a molecular framework for a mechanistic understanding of in situ cell plasticity as a treatment for diabetes and other degenerative diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / analysis
  • Cell Lineage / drug effects
  • Cellular Reprogramming / drug effects
  • Diabetes Mellitus / immunology
  • Diabetes Mellitus / metabolism
  • Diabetes Mellitus / pathology*
  • Diabetes Mellitus / therapy*
  • Disease Models, Animal
  • Female
  • Glucagon / metabolism
  • Glucagon-Secreting Cells / cytology*
  • Glucagon-Secreting Cells / drug effects
  • Glucagon-Secreting Cells / metabolism*
  • Glucagon-Secreting Cells / transplantation
  • Glucose / metabolism*
  • Glucose / pharmacology
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Insulin / metabolism*
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / immunology
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology*
  • Maf Transcription Factors, Large / genetics
  • Maf Transcription Factors, Large / metabolism
  • Male
  • Mice
  • Organ Specificity / drug effects
  • Pancreatic Polypeptide / metabolism
  • Pancreatic Polypeptide-Secreting Cells / cytology
  • Pancreatic Polypeptide-Secreting Cells / drug effects
  • Pancreatic Polypeptide-Secreting Cells / metabolism
  • Proteomics
  • Sequence Analysis, RNA
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcriptome
  • Transduction, Genetic

Substances

  • Biomarkers
  • Homeodomain Proteins
  • Insulin
  • MAFA protein, human
  • Maf Transcription Factors, Large
  • Trans-Activators
  • pancreatic and duodenal homeobox 1 protein
  • Pancreatic Polypeptide
  • Glucagon
  • Glucose