Cell-Based Methods to Identify Inducers of Human Pancreatic Beta-Cell Proliferation

Ackeifi, Courtney; Swartz, Ethan; Wang, Peng

doi:10.1007/978-1-4939-7847-2_7

Cited by 3 publications

(2 citation statements)

References 20 publications

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“…Immunocytochemistry was performed on coverslips fixed in fresh 4% paraformaldehyde. Accutase-dispersed human islet cells were plated on coverslips as previously described (35). Primary antisera were: C-peptide (DSHB GN-ID4); PDX1 (Ab47308, Abcam), NKX6.1 (DSHB, F55A10-c), ENTPD3 (provided by Dr. Alvin Powers, Vanderbilt University).…”

Section: Methodsmentioning

confidence: 99%

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Select DYRK1A Inhibitors Enhance Both Proliferation and Differentiation in Human Pancreatic Beta Cells

Wang,

Wood,

Choleva

et al. 2024

Preprint

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The small molecule DYRK1A inhibitor, harmine, induces human beta cell proliferation, expands beta cell mass, enhances expression of beta cell phenotypic genes, and improves human beta cell function in vitro and in vivo. It is unknown whether the pro-differentiation effect is a DYRK1A inhibitor class-wide effect. Here we compare multiple commonly studied DYRK1A inhibitors. Harmine, 2-2c and 5-IT increase expression of PDX1, MAFA, NKX6.1, SLC2A2, PCSK1, MAFB, SIX2, SLC2A2, SLC30A8, ENTPD3 in normal and T2D human islets. Unexpectedly, GNF4877, CC-401, INDY, CC-401 and Leucettine fail to induce expression of these essential beta cell molecules. Remarkably, the pro-differentiation effect is independent of DYRK1A inhibition: although silencing DYRK1A induces human beta cell proliferation, it has no effect on differentiation; conversely, harmine treatment enhances beta cell differentiation in DYRK1A-silenced islets. A careful screen of multiple DYRK1A inhibitor kinase candidate targets was unable to identify pro-differentiation pathways. Overall, harmine, 2-2c and 5-IT are unique among DYRK1A inhibitors in their ability to enhance both beta cell proliferation and differentiation. While beta cell proliferation is mediated by DYRK1A inhibition, the pro-differentiation effects of harmine, 2-2c and 5-IT are distinct, and unexplained in mechanistic terms. These considerations have important implications for DYRK1A inhibitor pharmaceutical development.

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Section: Methodsmentioning

confidence: 99%

“…Cells were cultured for 24-96 hr as described in the Figure Legends. Detailed protocols are provided in reference (35).…”

Section: Human Islet Dispersion and Virus Infectionmentioning

confidence: 99%

Select DYRK1A Inhibitors Enhance Both Proliferation and Differentiation in Human Pancreatic Beta Cells

Wang,

Wood,

Choleva

et al. 2024

Preprint

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Human umbilical cord mesenchymal stem cells pretreated with Angiotensin-II attenuate pancreas injury of rats with severe acute pancreatitis

Yang

et al. 2019

Biomedicine & Pharmacotherapy

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Disrupting the DREAM complex enables proliferation of adult human pancreatic β cells

Wang¹,

Karaköse²,

Argmann³

et al. 2022

Journal of Clinical Investigation

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Resistance to regeneration of insulin-producing pancreatic β cells is a fundamental challenge for type 1 and type 2 diabetes. Recently, small molecule inhibitors of the kinase DYRK1A have proven effective in inducing adult human β cells to proliferate, but their detailed mechanism of action is incompletely understood. We interrogated our human insulinoma and β cell transcriptomic databases seeking to understand why β cells in insulinomas proliferate, while normal β cells do not. This search reveals the DREAM complex as a central regulator of quiescence in human β cells. The DREAM complex consists of a module of transcriptionally repressive proteins that assemble in response to DYRK1A kinase activity, thereby inducing and maintaining cellular quiescence. In the absence of DYRK1A, DREAM subunits reassemble into the pro-proliferative MMB complex. Here, we demonstrate that small molecule DYRK1A inhibitors induce human β cells to replicate by converting the repressive DREAM complex to its pro-proliferative MMB conformation.

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Cell-Based Methods to Identify Inducers of Human Pancreatic Beta-Cell Proliferation

Cited by 3 publications

References 20 publications

Select DYRK1A Inhibitors Enhance Both Proliferation and Differentiation in Human Pancreatic Beta Cells

Select DYRK1A Inhibitors Enhance Both Proliferation and Differentiation in Human Pancreatic Beta Cells

Human umbilical cord mesenchymal stem cells pretreated with Angiotensin-II attenuate pancreas injury of rats with severe acute pancreatitis

Disrupting the DREAM complex enables proliferation of adult human pancreatic β cells

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