Combined Inhibition of DYRK1A, SMAD, and Trithorax Pathways Synergizes to Induce Robust Replication in Adult Human Beta Cells

Cell Metab. 2019 Mar 5;29(3):638-652.e5. doi: 10.1016/j.cmet.2018.12.005. Epub 2018 Dec 20.

Abstract

Small-molecule inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) induce human beta cells to proliferate, generating a labeling index of 1.5%-3%. Here, we demonstrate that combined pharmacologic inhibition of DYRK1A and transforming growth factor beta superfamily (TGFβSF)/SMAD signaling generates remarkable further synergistic increases in human beta cell proliferation (average labeling index, 5%-8%, and as high as 15%-18%), and increases in both mouse and human beta cell numbers. This synergy reflects activation of cyclins and cdks by DYRK1A inhibition, accompanied by simultaneous reductions in key cell-cycle inhibitors (CDKN1C and CDKN1A). The latter results from interference with the basal Trithorax- and SMAD-mediated transactivation of CDKN1C and CDKN1A. Notably, combined DYRK1A and TGFβ inhibition allows preservation of beta cell differentiated function. These beneficial effects extend from normal human beta cells and stem cell-derived human beta cells to those from people with type 2 diabetes, and occur both in vitro and in vivo.

Keywords: DYRK1A; SMAD; TGFbeta; beta cell; diabetes; harmine; proliferation; regeneration.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Animals
  • Cell Line
  • Cell Proliferation
  • Diabetes Mellitus, Type 2* / drug therapy
  • Diabetes Mellitus, Type 2* / metabolism
  • Female
  • Harmine / pharmacology*
  • Histone-Lysine N-Methyltransferase / antagonists & inhibitors
  • Humans
  • Insulin-Secreting Cells* / drug effects
  • Insulin-Secreting Cells* / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Monoamine Oxidase Inhibitors / pharmacology*
  • Myeloid-Lymphoid Leukemia Protein / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Smad Proteins / antagonists & inhibitors
  • Stem Cells
  • Transforming Growth Factor beta / antagonists & inhibitors*
  • Young Adult

Substances

  • KMT2A protein, human
  • Monoamine Oxidase Inhibitors
  • Smad Proteins
  • Transforming Growth Factor beta
  • Myeloid-Lymphoid Leukemia Protein
  • Harmine
  • Histone-Lysine N-Methyltransferase
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases