Combined inhibition of DYRK1A, SMAD, and trithorax pathways synergizes to induce robust replication in adult human beta cells
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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.
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Combined pharmacological inhibition of human β-cell DYRK1A and the TGF-β superfamily did not lead to a dedifferentiated phenotype.
“By contrast, combined pharmacological inhibition of human β-cell DYRK1A and the TGF-β superfamily did not lead to a dedifferentiated phenotype [48].”
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“Interestingly, DYRK1A complex is involved in the regulation of G0-G1 transition 32 and Harmine has been shown to induce human beta cells to enter cell cycle 33,34 , suggesting a similar effect on quiescent cancer cells.”
Metabolic Diseases and Down Syndrome: How Are They Linked Together?
Moreau, M., Benhaddou, S., Dard, R., Tolu, S., Hamzé, R., Vialard, F., Movassat, J., & Janel, N. (2021) · Biomedicines · doi:10.3390/biomedicines9020221 · Cited by 75 · see citing works
DYRK1A Inhibitors as Potential Therapeutics for β-Cell Regeneration for Diabetes
Kumar, K., Suebsuwong, C., Wang, P., Garcı́a-Ocaña, A., Stewart, A. F., & DeVita, R. J. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c02050 · Cited by 73 · see citing works
Self-citationRole of TGF-Beta Signaling in Beta Cell Proliferation and Function in Diabetes
Wang, H., Wang, L., Zhao, C.-Y., & Lan, H. Y. (2022) · Biomolecules · doi:10.3390/biom12030373 · Cited by 65 · see citing works
“Surprisingly, knockdown of TGFBR1 decreases the proliferation of these long-term cultured human β cells with increased expression of cell cycle inhibitors p21 and p27 [47], which is contrary to the findings in vivo and in short-term cultured human β cells [49,51].”
BackgroundResultGenetic and pharmacologic inhibition of ALDH1A3 as a treatment of β-cell failure
Son, J., Du, W. J., Esposito, M., Shariati, K., Ding, H., Kang, Y., & Accili, D. (2023) · Nature Communications · doi:10.1038/s41467-023-36315-4 · Cited by 66 · see citing works
Tacrolimus- and sirolimus-induced human β cell dysfunction is reversible and preventable
Dai, C., Walker, J. T., Shostak, A., Padgett, A., Spears, E., Wisniewski, S., Poffenberger, G., Aramandla, R., Dean, E. D., Prasad, N., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.130770 · Cited by 64 · see citing works
Glucose-dependent partitioning of arginine to the urea cycle protects β-cells from inflammation
Fu, A., Álvarez-Pérez, J. C., Avizonis, D. Z., Kin, T., Ficarro, S. B., Choi, D. W., Karaköse, E., Badur, M. G., Evans, L., Rosselot, C., et al. (2020) · Nature Metabolism · doi:10.1038/s42255-020-0199-4 · Cited by 65 · see citing works
Self-citationLong-term culture of human pancreatic slices as a model to study real-time islet regeneration
Qadir, M. M. F., Álvarez-Cubela, S., Weitz, J., Panzer, J. K., Klein, D., Moreno-Hernández, Y., Cechin, S. R., Tamayo, A., Almaça, J., Hiller, H., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-17040-8 · Cited by 62 · see citing works
Kang, R. B., Li, Y., Rosselot, C., Zhang, T., Siddiq, M. M., Rajbhandari, P., Stewart, A. F., Scott, D. K., Garcı́a-Ocaña, A., & Lu, G. (2023) · Genome Medicine · doi:10.1186/s13073-023-01179-2 · Cited by 59 · see citing works
“Transcriptional deregulation leading to cellular immaturity, reorganization of β-cell transcription factor networks, and reduced glucose-stimulated insulin release in different β-cell subtypes occurs during β-cell aging [72].”
BackgroundSelf-citationLan, C., Chen, C., Qu, S., Cao, N., Luo, H., Yu, C. C., Wang, N., Xue, Y., Xia, X., Fan, C., et al. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.104139 · Cited by 63 · see citing works
The Natural Metabolite 4-Cresol Improves Glucose Homeostasis and Enhances β-Cell Function
Brial, F., Alzaïd, F., Sonomura, K., Meneyrol, K., Lay, A. L., Pean, N., Neves, A., Chilloux, J., Hedjazi, L., Sato, T.-A., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.01.066 · Cited by 58 · see citing works
“There is compelling evidence supporting causal relations between DYRK1a inhibition and the induction of b-cell proliferation, the stimulation of glucose-induced insulin secretion, and the increase in b-cell mass and insulin content (Dirice et al., 2016; Shen et al., 2015; Wang et al., 2019).”
BackgroundKumar, K., Wang, P., Wilson, J., Zlatanic, V., Berrouet, C. C., Khamrui, S., Secor, C., Swartz, E., Lazarus, M. B., Sánchez, R., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01379 · Cited by 60 · see citing works
Self-citationAckeifi, C. A., Swartz, E., Kumar, K., Liu, H., Suebsuwong, C., Karaköse, E., Scott, D. K., Garcı́a-Ocaña, A., Sánchez, R., DeVita, R. J., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.132594 · Cited by 54 · see citing works
“6 Ki67 co-immunolabeling in dispersed human islets confirmed, as reported previously (5-7), that silencing DYRK1A does induce human beta cells to proliferate (Fig 2D).”
BackgroundMethodResultInfluentialSelf-citationHuman Beta Cell Regenerative Drug Therapy for Diabetes: Past Achievements and Future Challenges
Wang, P., Karaköse, E., Choleva, L., Kumar, K., DeVita, R. J., Garcı́a-Ocaña, A., & Stewart, A. F. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.671946 · Cited by 53 · see citing works
Self-citationSpears, E., Serafimidis, I., Powers, A. C., & Gavalas, A. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.722250 · Cited by 46 · see citing works
“Combined inhibition of the Calcineurin/NFAT/DYRK1A pathway with the DYRK1A inhibitor, Harmine, and the TGFb signaling pathway, with inhibitors such as ALK5, resulted in a synergistic increase in b cell proliferation in primary cultures and human islet xenografts (16).”
BackgroundFunction and inhibition of DYRK1A: Emerging roles of treating multiple human diseases
Yang, Y., Fan, X., Liu, Y., Ye, D., Liu, C., Yang, H., Su, Z., Zhang, Y., & Liu, Y. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115521 · Cited by 43 · see citing works
How, When, and Where Do Human β-Cells Regenerate?
Basile, G., Kulkarni, R. N., & Morgan, N. G. (2019) · Current Diabetes Reports · doi:10.1007/s11892-019-1176-8 · Cited by 42 · see citing works
Functional loss of pancreatic islets in type 2 diabetes: How can we halt it?
Marrano, N., Biondi, G., Cignarelli, A., Perrini, S., Laviola, L., Giorgino, F., & Natalicchio, A. (2020) · Metabolism · doi:10.1016/j.metabol.2020.154304 · Cited by 42 · see citing works
In vivo screen identifies a SIK inhibitor that induces β cell proliferation through a transient UPR
Charbord, J., Ren, L., Sharma, R. B., Johansson, A., Ågren, R., Chu, L., Tworus, D., Schulz, N., Charbord, P., Stewart, A. F., et al. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00391-x · Cited by 39 · see citing works
Self-citationDeau, E., Lindberg, M. F., Miege, F., Roche, D., George, N. S., George, P. G., Krämer, A., Knapp, S., & Meijer, L. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00884 · Cited by 42 · see citing works
González, B. J., Zhao, H., Niu, J., Williams, D. J., Lee, J., Goulbourne, C. N., Xing, Y., Wang, Y., Oberholzer, J., Blumenkrantz, M., et al. (2022) · Communications Biology · doi:10.1038/s42003-022-03696-z · Cited by 39 · see citing works
“All protein concentrations were measured by ELISA. n represents the number of biological replicates.”
MethodInfluentialSelf-citationDisrupting the DREAM complex enables proliferation of adult human pancreatic β cells
Wang, P., Karaköse, E., Argmann, C., Wang, H., Balev, M., Brody, R., Rivas, H. G., Liu, X., Wood, O., Liu, H., et al. (2022) · Journal of Clinical Investigation · doi:10.1172/jci157086 · Cited by 35 · see citing works
“Even higher rates of proliferation can be achieved by combining DYRK1A inhibitors with peptide agonists of the GLP1 receptor such the GLP1 7–36 peptide, or more stable synthetic analogs, such as exendin-4, liraglutide, semaglutide, and others, all in current widespread use in T2D (10, 12).”
InfluentialSelf-citationBasile, G., Kahraman, S., Dirice, E., Pan, H., Dreyfuss, J. M., & Kulkarni, R. N. (2021) · Genome Medicine · doi:10.1186/s13073-021-00941-8 · Cited by 33 · see citing works
“We used the immunodeficient NSG mouse model which is a widely utilized in vivo model for βcell regeneration studies [6, 8, 10, 65].”
MethodLong Non-Coding RNAs as Key Modulators of Pancreatic β-Cell Mass and Function
López–Noriega, L., & Rutter, G. A. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.610213 · Cited by 35 · see citing works
“Of note, recent findings point to inhibition of the protein kinase DYRK1A as a possible target for the activation of b-cell growth (71), though no evidence exists at present of a role for lncRNAs in the control of this enzyme.”
ResultPancreatic β-cell failure, clinical implications, and therapeutic strategies in type 2 diabetes
Cui, D., Feng, X., Lei, S., Zhang, H., Hu, W., Yang, S., Yu, X., & Su, Z. (2024) · Chinese Medical Journal · doi:10.1097/cm9.0000000000003034 · Cited by 36 · see citing works
“[72,73] Moreover, the combination of DYRK1A inhibitors, such as harmine, with other compounds, such as exendin-4 and liraglutide, that are GLP1R agonists, [75] as well as ALK5 that is a TGF β -pathway inhibitor [76] induces a synergistic increase in human β -cell proliferation.”
BackgroundInhibition of DYRK1a Enhances Cardiomyocyte Cycling After Myocardial Infarction
Young, A., Bradley, L. A., Farrar, E., Bilcheck, H. O., Tkachenko, S., Saucerman, J. J., Bekiranov, S., & Wolf, M. J. (2022) · Circulation Research · doi:10.1161/circresaha.121.320005 · Cited by 35 · see citing works
Davies, M. J., Lim, S. K., Slater, T., Goldney, J., Philis‐Tsimikas, A., Franco, D. R., Lamptey, R., Yates, T. E., Tankova, T. I., & Lingvay, I. (2026) · Nature Reviews Disease Primers · doi:10.1038/s41572-026-00687-w · Cited by 36 · see citing works
Rosselot, C., Li, Y., Wang, P., Alvarsson, A., Beliard, K., Lu, G., Kang, R. B., Li, R., Liu, H., Gillespie, V., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.adg3456 · Cited by 30 · see citing works
Self-citationWang, H., Wei, B., He, H., et al. (2021) · Theranostics · doi:10.7150/thno.67034 · Cited by 29 · see citing works
“ANOVA: analysis of variance; BrdU: 5-bromo-2'-deoxyuridine; CDKs: cyclin-dependent kinases; CDKIs: cyclin-dependent kinase inhibitors; ChIP: chromatin immunoprecipitation; DAB: 3,3’-diaminobenzidine; DEG: differentially expressed gene; E2F3: E2F transcription factor 3; FBG: fasting blood glucose; HA1c: hemoglobin A1c;…”
BackgroundMethodInfluentialCobo‐Vuilleumier, N., & Gauthier, B. R. (2020) · Metabolism · doi:10.1016/j.metabol.2020.154137 · Cited by 28 · see citing works
Basile, G., Vetere, A., Hu, J., Ijaduola, O., Zhang, Y., Liu, K., Eltony, A. M., Jesus, D. F. D., Fukuda, K., Doherty, G., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.05.007 · Cited by 27 · see citing works
Identification of a LIF-Responsive, Replication-Competent Subpopulation of Human β Cells
Rosado-Olivieri, E. A., Aigha, I. I., Kenty, J. H.-R., & Melton, D. A. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2019.12.009 · Cited by 28 · see citing works
The many lives of Myc in the pancreatic β-cell
Rosselot, C., Baumel-Alterzon, S., Li, Y., Brill, G., Lambertini, L., Katz, L. S., Lu, G., Garcı́a-Ocaña, A., & Scott, D. K. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.rev120.011149 · Cited by 30 · see citing works
“agonists has been shown to induce a striking increase in human β-cell proliferation (5–8%), suggesting that combination therapies affecting several signaling pathways could further enhance human β-cell regeneration for diabetes treatment (135, 136).”
BackgroundSelf-citationIslet Regeneration: Endogenous and Exogenous Approaches
Docherty, F. M., & Sussel, L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073306 · Cited by 28 · see citing works
“More recently, the combinatorial inhibition of DRYK1A and Transforming Growth Factor beta (TGFβ) signaling was shown to synergistically promote human beta cell proliferation, without causing adverse functional affects [125].”
BackgroundDYRK1A Kinase Inhibitors Promote β-Cell Survival and Insulin Homeostasis
Barzowska, A., Pucelik, B., Pustelny, K., Matsuda, A., Martyniak, A., Stępniewski, J., Maksymiuk, A., Dawidowski, M., Rothweiler, U., Dulak, J., et al. (2021) · Cells · doi:10.3390/cells10092263 · Cited by 27 · see citing works
“These results are consistent with the recent reports that DYRK1A inhibition induces human β-cell proliferation [14,34,35].”
BackgroundResultStructure–Activity Relationship in the Leucettine Family of Kinase Inhibitors
Tahtouh, T., Durieu, É., Villiers, B., Bruyère, C., Nguyen, T. L., Fant, X., Ahn, K. H., Khurana, L., Deau, E., Lindberg, M. F., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01141 · Cited by 31 · see citing works
Mohammad, S. A., Metkari, S., & Bhartiya, D. (2019) · Stem Cell Reviews and Reports · doi:10.1007/s12015-019-09919-x · Cited by 27 · see citing works
“[44] showed significant increase in proliferation of beta cells when exposed to harmine and inhibitor of TGFb SF receptors inmice after PP and also in human islets transplanted in Stem Cell Rev and Rep”
BackgroundPancreatic β cell regeneration induced by clinical and preclinical agents
Wang, K., Tao, M., Wei, T., & Wei, R. (2021) · World Journal of Stem Cells · doi:10.4252/wjsc.v13.i1.64 · Cited by 25 · see citing works
Allegretti, P. A., Horton, T. M., Abdolazimi, Y., Moeller, H. P., Yeh, B. T., Caffet, M., Michel, G., Smith, M. A., & Annes, J. P. (2019) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2019.115193 · Cited by 24 · see citing works
Interactions between islets and regulatory immune cells in health and type 1 diabetes
Budd, M. A., Monajemi, M., Colpitts, S. J., Crome, S. Q., Verchere, C. B., & Levings, M. K. (2021) · Diabetologia · doi:10.1007/s00125-021-05565-6 · Cited by 23 · see citing works
“For example, enhancement of beta cell proliferation and regeneration has been achieved through pharmacological targeting of pathways such as the glucagon-like peptide-1 receptor (GLP1R) and TGF-β family members [27].”
BackgroundMaladaptive positive feedback production of ChREBPβ underlies glucotoxic β-cell failure
Katz, L. S., Brill, G., Zhang, P., Kumar, A., Baumel-Alterzon, S., Honig, L. B., Gómez-Banoy, N., Karaköse, E., Tanase, M., Doridot, L., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-32162-x · Cited by 23 · see citing works
Self-citationDiabetic Kinome Inhibitors—A New Opportunity for β-Cells Restoration
Pucelik, B., Barzowska, A., Dąbrowski, J. M., & Czarna, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22169083 · Cited by 23 · see citing works
“These effects were proved in healthy human- and stem cell-derived β-cells as well as patients with T2D both in in vitro and in vivo investigations [181].”
BackgroundHarnessing beta cell regeneration biology for diabetes therapy
Bourgeois, S., Coenen, S., Degroote, L., Willems, L., Mulders, A. V., Pierreux, J., Heremans, Y., Leu, N. D., & Staels, W. (2024) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2024.03.006 · Cited by 25 · see citing works
“A higher human β -cell replication rate is observed when DYRK1A andTGF β /SMADinhibitioniscombinedorwhenaGLP-1RagonistispairedwithaDYRK1Ainhibitor[106,114].”
BackgroundPancreatic β cell regeneration: to β or not to β
Guney, M. A., Lorberbaum, D. S., & Sussel, L. (2019) · Current Opinion in Physiology · doi:10.1016/j.cophys.2019.10.019 · Cited by 23 · see citing works
Novel Strategies to Protect and Visualize Pancreatic β Cells in Diabetes
Gurzov, E. N., Ke, P. C., Ahlgren, U., Ribeiro, R. S. G., & Gotthardt, M. (2020) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2020.10.002 · Cited by 23 · see citing works
“The combination induced a synergistic increase in replication of mature human β cells [31].”
BackgroundHuman Islet Isolation and Distribution Efforts for Clinical and Basic Research
Ng, N. H. J., Tan, W. X., Koh, Y. X., & Teo, A. K. K. (2019) · OBM Transplantation · doi:10.21926/obm.transplant.1902068 · Cited by 21 · see citing works
Kumar, K., Wang, P., Swartz, E., Khamrui, S., Secor, C., Lazarus, M. B., Sánchez, R., Stewart, A. F., & DeVita, R. J. (2020) · Molecules · doi:10.3390/molecules25081983 · Cited by 21 · see citing works
Self-citationTian, S., Jia, W., Lü, M., Zhao, J., & Sun, X. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.010809 · Cited by 22 · see citing works
Movassat, J., Delangre, E., Liu, J., Gu, Y., & Janel, N. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.00649 · Cited by 21 · see citing works
DNA Damage Does Not Cause BrdU Labeling of Mouse or Human β-Cells
Sharma, R. B., Darko, C., Zheng, X., Gablaski, B., & Alonso, L. C. (2019) · Diabetes · doi:10.2337/db18-0761 · Cited by 19 · see citing works
“Evidence supporting the conclusion that some BrdU-labeled b-cells do successfully complete cell division include the many studies showing that BrdU labeling correlates with other proliferation markers such as Ki67, PCNA (proliferating cell nuclear antigen), and pHH3 (17,34,35), the documented increase in b-cell number…”
BackgroundKimani, C. N., Reuter, H., Kotzé, S. H., & Muller, C. J. F. (2023) · Current Issues in Molecular Biology · doi:10.3390/cimb45080392 · Cited by 21 · see citing works
Title, A. C., Karsai, M., Mir-Coll, J., Grining, Ö. Y., Rufer, C., Sonntag, S., Forschler, F., Jawurek, S., Klein, T., & Yesildag, B. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.854094 · Cited by 19 · see citing works
“Harmine, an orally bioavailable, naturally occurring compound, is the best studied and a highly potent DYRK1A-inhibitor (36), and has been found to induce human b-cell-proliferation up to 3% (10, 37).”
BackgroundResultInfluentialIbrahim, S., Johnson, M., Stephens, C. H., Xu, J., Moore, R., Mariani, A., Contreras, C., Syed, F., Mirmira, R. G., Anderson, R. M., et al. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101289 · Cited by 18 · see citing works
Karaköse, E., Wang, X., Wang, P., Carcamo, S., Demircioğlu, D., Lambertini, L., Wood, O., Kang, R. B., Lu, G., Scott, D. K., et al. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101832 · Cited by 18 · see citing works
“10, 38, 39 For example , the DYRK1A inhibitor inhibitor , increases beta cell mass in human islets transplanted Here, we report single-cell transcriptomics data for regenerative drug-treated human islets.”
Self-citationA Dual Inhibitor of DYRK1A and GSK3β for β‐Cell Proliferation: Aminopyrazine Derivative GNF4877
Liu, Y. A., Jin, Q., Ding, Q., Hao, X., Mo, T., Yan, S., Zou, Y., Huang, Z., Zhang, X., Gao, W., et al. (2020) · ChemMedChem · doi:10.1002/cmdc.202000183 · Cited by 19 · see citing works
Self-citationGlobal Deletion of the Prolactin Receptor Aggravates Streptozotocin-Induced Diabetes in Mice
Ramírez‐Hernández, G., Adán‐Castro, E., Díaz‐Lezama, N., Ruíz‐Herrera, X., de la Escalera, G. M., Macotela, Y., & Clapp, C. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.619696 · Cited by 17 · see citing works
“Moreover, the mRNA expression of the gene (Tgfb) encoding transforming growth factor b, an inhibitor of b-cell proliferation and differentiation (35), was higher in the pancreas of diabetic Prlr mice relative to diabetic Prlr mice (Figure 6B).”
BackgroundMitogen Synergy: An Emerging Route to Boosting Human Beta Cell Proliferation
Shcheglova, E. G., Błaszczyk, K., & Borowiak, M. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.734597 · Cited by 16 · see citing works
SMAD7 enhances adult β-cell proliferation without significantly affecting β-cell function in mice
Sehrawat, A., Shiota, C., Mohamed, N., et al. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.011011 · Cited by 17 · see citing works
“(18) reported that glucose physiology and GSIS could remain intact despite the induction of proliferation in islets.”
BackgroundStructure-activity relationship for the folding intermediate-selective inhibition of DYRK1A
Miyazaki, Y., Kikuchi, M., Umezawa, K., Descamps, A., Nakamura, D., Furuie, G., Sumida, T., Saito, K., Kimura, N., Niwa, T., et al. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113948 · Cited by 14 · see citing works
Stem Cell-Derived Islets for Type 2 Diabetes
Salib, A., Cayabyab, F., & Yoshihara, E. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23095099 · Cited by 16 · see citing works
“Inhibition of DYRK1A, SMAD and trithorax induce robust replication of hPSC-derived β-like cells and adult human pancreatic β-cells INS1 and βTC3 cell lines, validated in Mel1 hESC (MEL-1)-derived β like-cells 2300 compounds from MicroSource Discovery System and 100,000 compounds from Chembridge Luciferase-based high t…”
MethodMarshall, G. P., Cserny, J., Wang, C.-W., Looney, B. M., Posgai, A., Bacher, R. L., Keselowsky, B., & Brusko, T. (2022) · Journal of Biomedical Materials Research. Part A · doi:10.1002/jbm.a.37442 · Cited by 15 · see citing works
“The NP-Treg formulation was further optimized by dual loading of IL-2 with harmine, which stimulates insulin-producing β-cell replication.(70,71) IL-2/harmine NPs were coupled to BDC2.”
MethodEguchi, N., Toribio, A. J., Alexander, M., Xu, I., Whaley, D. L., Hernandez, L. F., Dafoe, D. C., & Ichii, H. (2022) · Biomedicines · doi:10.3390/biomedicines10020472 · Cited by 16 · see citing works
“First, harmine and TGFβ inhibitor combination resulted in increased Ki67 positive β-cells to 5–8% compared with the 1–3% in harmine alone in vitro [97].”
BackgroundAberrant methylation underlies insulin gene expression in human insulinoma
Karaköse, E., Wang, H., Inabnet, W. B., Thakker, R. V., Libutti, S. K., Fernandez-Ranvier, G. G., Suh, H., Stevenson, M., Kinoshita, Y., Donovan, M. J., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18839-1 · Cited by 15 · see citing works
Self-citationSdao, S. M., Ho, T., Poudel, C., Foster, H. R., Leon, E. R. D., Adams, M. T., Lee, J.-H., Blum, B., Rane, S. G., & Merrins, M. J. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.108690 · Cited by 14 · see citing works
“Diabetes is associated with loss of functional b cell mass, and there is growing interest in the therapeutic potential of re-initiating the b cell mitogenic program (Ackeifi et al., 2020; Wang et al., 2019), which is typically active only in the first few months of life in mice and a year or two in humans (Cozar-Caste…”
BackgroundShilleh, A. H., & Russ, H. (2023) · Cells · doi:10.3390/cells12050698 · Cited by 13 · see citing works
β-cell replenishment: Possible curative approaches for diabetes mellitus
RATHWA, N. N., Patel, R., Palit, S. P., PARMAR, N. R., Rana, S., Ansari, M. I., Ramachandran, A. V., & Begum, R. (2020) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2020.08.006 · Cited by 14 · see citing works
Cheng, Z., Gao, H., Shi, P., Zhang, A., Chen, X., Chen, Y., Gan, W., Zhao, K., Li, S., Cao, Y., et al. (2025) · Bone Research · doi:10.1038/s41413-025-00441-0 · Cited by 14 · see citing works
Regeneration of Pancreatic β-Cells for Diabetes Therapeutics by Natural DYRK1A Inhibitors
Guo, Y., Li, L., Yao, Y., & Li, H. (2022) · Metabolites · doi:10.3390/metabo13010051 · Cited by 14 · see citing works
“gene expression related to cell cycle [79].”
Obesity under the moonlight of c-MYC
Nevzorova, Y. A., & Cubero, F. J. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1293218 · Cited by 16 · see citing works
“…combined with GLP-1R agonists (Ackei fi et al., 2020) or TGFß inhibitors dramatically increases human β -cell proliferation (5% – 8%), indicating that combination treatments targeting multiple signalling pathways may be more effective for islet regeneration in T2DM patients (Wang et al., 2019).”
BackgroundChernysheva, M. B., Ruchko, E. S., Karimova, M. V., Vorotelyak, E. A., & Vasiliev, А. V. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1424278 · Cited by 15 · see citing works
Wang, H., Bai, R., Wang, Y., Qu, M., Zhou, Y., Gao, Z., & Wang, Y. (2025) · Life Sciences · doi:10.1016/j.lfs.2025.123384 · Cited by 14 · see citing works
Maachi, H., Ghislain, J. J., Tremblay, C. C., & Poitout, V. (2021) · Scientific Reports · doi:10.1038/s41598-021-90643-3 · Cited by 14 · see citing works
Methylation of histone H3 lysine 4 is required for maintenance of beta cell function in adult mice
Vanderkruk, B., Maeshima, N., Pasula, D. J., An, M., McDonald, C. L., Suresh, P., Luciani, D. S., Lynn, F. C., & Hoffman, B. G. (2023) · Diabetologia · doi:10.1007/s00125-023-05896-6 · Cited by 15 · see citing works
“For example, inhibition of histone H3 lysine 4 (H3K4) methyltransferases has been suggested to prevent ectopic gene activation [4] or increase replication [10] in beta cells during type 2 diabetes; however, the consequences of such a strategy are unknown.”
BackgroundMoon, J. H., Choe, H. J., & Lim, S. K. (2024) · Journal of Diabetes Investigation · doi:10.1111/jdi.14221 · Cited by 13 · see citing works
“Somatomammotrophs, including prolactin, growth hormone, and placental lactogen, are implicated in b -cell proliferation during pregnancy and lactation 44,47,45 .”
BackgroundCui, G., Yuan, H., Jiang, Z., Zhang, J., Sun, Z., & Zhong, G. (2019) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2019.110134 · Cited by 13 · see citing works
A natural DYRK1A inhibitor as a potential stimulator for β‐cell proliferation in diabetes
Zheng, M., Zhang, Q., Zhang, C., et al. (2021) · Clinical and Translational Medicine · doi:10.1002/ctm2.494 · Cited by 12 · see citing works
DYRK1B phosphorylates FOXO1 to promote hepatic gluconeogenesis
Li, S., Huang, K., Chu, X., Zhang, H., Wang, X., Zhang, R., Lu, Y., Mohan, M., & Hu, C. H. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf319 · Cited by 12 · see citing works
Mass cytometry and type 1 diabetes research in the age of single-cell data science
Rahman, A. H., & Homann, D. (2020) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000549 · Cited by 11 · see citing works
“1 for representative transcription factor expression profiles in beta cells); we are seeking to broaden access to these analysis tools [39]; and we are developing ‘islet cell mass cytometry’ as a screening platform to monitor the consequences of mitogenic activation by combinations of harmine and inhibitors of SMAD si…”
BackgroundSelf-citationLessons from neonatal β-cell epigenomic for diabetes prevention and treatment
Abderrahmani, A., Jacovetti, C., & Regazzi, R. (2022) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2022.03.002 · Cited by 11 · see citing works
“Fetuin-A concentration declines from birth to weaning [48] while the islet concentration of TGF , a strong inducer of Smad pathway, increases [55], allowing H3K4 trimethylation of Cdkn2a, Cdkn1a and Cdkn1c, and causing cell cycle arrest [35,48].”
BackgroundRegeneration of the pancreas: proliferation and cellular conversion of surviving cells
Sever, D., & Grapin‐Botton, A. (2020) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2020.06.005 · Cited by 10 · see citing works
Katz, L. S., Argmann, C., Lambertini, L., & Scott, D. K. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101646 · Cited by 10 · see citing works
“The b-cell fraction was confirmed to be >92% pure by immunolabeling of sorted cells with insulin, and by qRT-PCR [72].”
MethodSelf-citationRecent advances and potential applications of human pluripotent stem cell-derived pancreatic β cells
Zhou, Z., Ma, X., & Zhu, S. (2020) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmaa047 · Cited by 11 · see citing works
Informing β-cell regeneration strategies using studies of heterogeneity
Nasteska, D., Viloria, K., Everett, L., & Hodson, D. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.06.004 · Cited by 9 · see citing works
“Current regeneration protocols successfully replicate b-cell-specific gene and protein signatures [12,15,16,19,25,38].”
BackgroundMechanistic insights and approaches for beta cell regeneration
Karampelias, C., Liu, K., Tengholm, A., & Andersson, O. (2025) · Nature Chemical Biology · doi:10.1038/s41589-024-01822-y · Cited by 9 · see citing works
“Importantly, a combination of harmine with inhibitors of TGFβ receptors has resulted in the highest percentage of human beta cell proliferation described so far 27 .”
Mishra, S., & Streeter, P. R. (2022) · Scientific Reports · doi:10.1038/s41598-022-19453-5 · Cited by 9 · see citing works
Saleh, M. W., Mohamed, N., Sehrawat, A., et al. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101235 · Cited by 9 · see citing works
“Our finding that blocking smad2 signaling is associated with improved β-cell function is consistent with previous studies using a global smad3 KO mouse model or treatment with TGF-β inhibitory molecules (15, 17).”
ResultHarmine suppresses collagen production in hepatic stellate cells by inhibiting DYRK1B
Yamaguchi, M., Ohbayashi, S., Ooka, A., Yamashita, H., Motohashi, N., Kaneko, Y. K., Kimura, T., Saito, S., & Ishikawa, T. (2022) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2022.02.054 · Cited by 9 · see citing works
Drug-induced regeneration of pancreatic beta cells: An approach to cellular therapeutic targets
Parsi, P., Saharkhiz, S., Farani, M. R., Bakhtiyari, S., & Alipourfard, I. (2025) · Cell Regeneration · doi:10.1186/s13619-025-00255-9 · Cited by 9 · see citing works
“Moreover, Inhibiting DYRK1A in tandem with inhibiting glycogen synthase kinase-3β18 or the SMAD and trithorax pathways 3, or with activating the glucagon-like peptide 1 receptor, has a deeper effect on proliferation (Wang et al. 2019; Ackeifi et al. 2020; Shen et al. 2015).”
Pahlavanneshan, S., Behmanesh, M., Oropeza, D., Furuyama, K., Tahamtani, Y., Basiri, M., Herrera, P. L., & Baharvand, H. (2020) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2020.151094 · Cited by 8 · see citing works
Oakie, A., & Nostro, M. C. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.636182 · Cited by 8 · see citing works
“In addition to using compound-based treatments previously mentioned, such as harmine (34, 35, 37), another method for inducing replication could be through viral delivery of controllable systems (70–72).”
Method
- Authors
- Wang, P., Karakose, E., Liu, H., Swartz, E., Ackeifi, C., Zlatanic, V., Wilson, J., González, B. J., Bender, A., Takane, K. K., Ye, L., Harb, G., Pagliuca, F., Homann, D., Egli, D., Argmann, C., Scott, D. K., Garcia-Ocaña, A., & Stewart, A. F.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Columbia University (US)
- Semma Therapeutics (United States) (US)
- Corresponding author
- Stewart, Andrew F.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2019-03
- Volume
- 29
- Issue
- 3
- Pages
- 638-652.e5
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC6402958
- OpenAlex
- W2906475498
- Semantic Scholar
- 3678aa03d63163b7942c5cf504b414ac29fd8de2
- Cited by
- 162
- References
- 70
- Citations by year
- 2026: 13 · 2025: 15 · 2024: 17 · 2023: 20 · 2022: 23 · 2021: 36 · 2020: 22 · 2019: 16
- FWCI
- 19.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Icahn School of Medicine
- NIDDK (R-01 DK 105015, R01 DK108905, UC4 DK104211, P-30 DK 020541, R-01 DK116873)
- JDRF (2-SRA-2017 514-S-B)
- ADA (1-16-ICTS-029)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- Smad signaling, beta-cell proliferation, TGF-beta superfamily, CDKN1C, p21, cyclin-dependent kinases, cell cycle regulation, stem cell-derived beta cells, type 2 diabetes, beta-cell mass, beta-cell function
- MeSH terms
- Dyrk Kinases, Adolescent, Adult, Aged, Animals, Cell Line, Diabetes Mellitus, Type 2, Female, Harmine, Humans, Male, Mice, Inbred C57BL, Middle Aged, Monoamine Oxidase Inhibitors, Histone-Lysine N-Methyltransferase, Protein-Tyrosine Kinases, Stem Cells, Transforming Growth Factor beta, Protein Serine-Threonine Kinases, Cell Proliferation, Insulin-Secreting Cells, Mice, Smad Proteins, Myeloid-Lymphoid Leukemia Protein, Young Adult
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