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

• Published in: Cell metabolism Vol. 29; no. 3; pp. 638 - 652.e5
• Main Authors: Wang, Peng, Karakose, Esra, Liu, Hongtao, Swartz, Ethan, Ackeifi, Courtney, Zlatanic, Viktor, Wilson, Jessica, González, Bryan J., Bender, Aaron, Takane, Karen K., Ye, Lillian, Harb, George, Pagliuca, Felicia, Homann, Dirk, Egli, Dieter, Argmann, Carmen, Scott, Donald K., Garcia-Ocaña, Adolfo, Stewart, Andrew F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.03.2019
• Subjects: Adolescent; Adult; Aged; Animals; beta cell; Cell Line; Cell Proliferation; diabetes; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Dyrk Kinases; DYRK1A; Female; harmine; 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; proliferation; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - antagonists & inhibitors; regeneration; SMAD; Smad Proteins - antagonists & inhibitors; Stem Cells; TGFbeta; Transforming Growth Factor beta - antagonists & inhibitors; Young Adult; beta cell; proliferation; regeneration; DYRK1A; harmine; SMAD; diabetes; TGFbeta
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2018.12.005

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. [Display omitted] •Adult human pancreatic beta cells can be induced to proliferate at high rates•Driven by synergy between DYRK1A inhibitors and TGFβ superfamily inhibitors•Reflects activation of cyclins and CDKs accompanied by CDK inhibitor suppression•Proliferation occurs in type 2 diabetic beta cells, with enhanced differentiation 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.