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

Peng Wang, Esra Karakose, Hongtao Liu, Ethan Swartz, Courtney Ackeifi, Viktor Zlatanic, Jessica Wilson, Bryan J. González, Aaron Bender, Karen K. Takane, Lillian Ye, George Harb, Felicia Pagliuca, Dirk Homann, Dieter Egli, Carmen Argmann, Donald K. Scott, Adolfo Garcia-Ocaña, Andrew F. Stewart

Research output: Contribution to journalArticlepeer-review

90 Scopus citations


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. Adult human pancreatic beta cells are notoriously resistant to replication. Wang et al. find that the combination of the DYRK1A inhibitor harmine with an inhibitor of the TGFβ superfamily of receptors induces synergistic increases in human beta cell cells in vitro and in vivo associated with enhanced differentiation.

Original languageEnglish
Pages (from-to)638-652.e5
JournalCell Metabolism
Issue number3
StatePublished - 5 Mar 2019


  • DYRK1A
  • SMAD
  • TGFbeta
  • beta cell
  • diabetes
  • harmine
  • proliferation
  • regeneration


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