Circadian Entrainment Triggers Maturation of Human In Vitro Islets
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Abstract
Stem-cell-derived tissues could transform disease research and therapy, yet most methods generate functionally immature products. We investigate how human pluripotent stem cells (hPSCs) differentiate into pancreatic islets in vitro by profiling DNA methylation, chromatin accessibility, and histone modification changes. We find that enhancer potential is reset upon lineage commitment and show how pervasive epigenetic priming steers endocrine cell fates. Modeling islet differentiation and maturation regulatory circuits reveals genes critical for generating endocrine cells and identifies circadian control as limiting for in vitro islet function. Entrainment to circadian feeding/fasting cycles triggers islet metabolic maturation by inducing cyclic synthesis of energy metabolism and insulin secretion effectors, including antiphasic insulin and glucagon pulses. Following entrainment, hPSC-derived islets gain persistent chromatin changes and rhythmic insulin responses with a raised glucose threshold, a hallmark of functional maturity, and function within days of transplantation. Thus, hPSC-derived tissues are amenable to functional improvement by circadian modulation.
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Significant progress has been made at improving the function of SC-islets when compared to the original protocols.
“To this end, significant progress has been made at improving the function of SC-islets when compared to the original protocols,39,40,44,48,49”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [48]
The supplied passage and the indexed passages have no substantive discussion of SC-islet function or comparisons with original protocols; they consist largely of links. Searches for insulin secretion, maturation, and original protocols did not retrieve a passage that establishes the claimed improvement. (LLM, conf=0.72)
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Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · see citing works
Integrative analysis of 111 reference human epigenomes
Roadmap Epigenomics Consortium, Kundaje, A., Meuleman, W., Ernst, J., Bilenky, M., Yen, A., Heravi-Moussavi, A., Kheradpour, P., Zhang, Z., Wang, J., et al. (2015) · Nature · doi:10.1038/nature14248 · Cited by 6,368 · see citing works
Self-citationOptimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9
Doench, J. G., Fusi, N., Sullender, M., Hegde, M., Vaimberg, E. W., Donovan, K. F., Smith, I., Tothova, Z., Wilen, C., Orchard, R., et al. (2016) · Nature Biotechnology · doi:10.1038/nbt.3437 · Cited by 4,637 · see citing works
GREAT improves functional interpretation of cis-regulatory regions
McLean, C. Y., Bristor, D., Hiller, M., Clarke, S. L., Schaar, B. T., Lowe, C. B., Wenger, A. M., & Bejerano, G. (2010) · Nature Biotechnology · doi:10.1038/nbt.1630 · Cited by 4,502 · see citing works
Histone modifications at human enhancers reflect global cell-type-specific gene expression
Heintzman, N. D., Hon, G. C., Hawkins, R. D., Kheradpour, P., Stark, A., Harp, L. F., Ye, Z., Lee, L. K., Stuart, R. K., Ching, C. W., et al. (2009) · Nature · doi:10.1038/nature07829 · Cited by 2,533 · see citing works
A unique chromatin signature uncovers early developmental enhancers in humans
Rada-Iglesias, A., Bajpai, R., Swigut, T., Brugmann, S. A., Flynn, R. A., & Wysocka, J. (2011) · Nature · doi:10.1038/nature09692 · Cited by 2,233 · see citing works
Generation of Functional Human Pancreatic β Cells In Vitro
Pagliuca, F. W., Millman, J. R., Gürtler, M., Segel, M., Van Dervort, A., Ryu, J. H., Peterson, Q. P., Greiner, D., & Melton, D. A. (2014) · Cell · doi:10.1016/j.cell.2014.09.040 · Cited by 2,025 · see citing works
Self-citationTranscriptional architecture and chromatin landscape of the core circadian clock in mammals
Koike, N., Yoo, S.-H., Huang, H.-C., Kumar, V., Lee, C., Kim, T.-K., & Takahashi, J. S. (2012) · Science · doi:10.1126/science.1226339 · Cited by 1,464 · see citing works
Charting a dynamic DNA methylation landscape of the human genome
Ziller, M. J., Gu, H., Müller, F., Donaghey, J., Tsai, L. T.-Y., Kohlbacher, O., De Jager, P. L., Rosen, E. D., Bennett, D. A., Bernstein, B. E., et al. (2013) · Nature · doi:10.1038/nature12433 · Cited by 1,357 · see citing works
Self-citationEngineering Adolescence: Maturation of Human Pluripotent Stem Cell–Derived Cardiomyocytes
Yang, X., Pabon, L., & Murry, C. E. (2014) · Circulation Research · doi:10.1161/circresaha.114.300558 · Cited by 939 · see citing works
Transcriptional and Epigenetic Dynamics during Specification of Human Embryonic Stem Cells
Gifford, C. A., Ziller, M. J., Gu, H., Trapnell, C., Donaghey, J., Tsankov, A., Shalek, A. K., Kelley, D. R., Shishkin, A. A., Issner, R., et al. (2013) · Cell · doi:10.1016/j.cell.2013.04.037 · Cited by 435 · see citing works
Self-citationZhang, J. A., Mortazavi, A., Williams, B. A., Wold, B. J., & Rothenberg, E. V. (2012) · Cell · doi:10.1016/j.cell.2012.01.056 · Cited by 337 · see citing works
Epigenomic annotation of enhancers predicts transcriptional regulators of human neural crest
Rada-Iglesias, A., Bajpai, R., Prescott, S., Brugmann, S. A., Swigut, T., & Wysocka, J. (2012) · Cell stem cell · doi:10.1016/j.stem.2012.07.006 · Cited by 314 · see citing works
The α-cell in diabetes mellitus
Gromada, J., Chabosseau, P., & Rutter, G. A. (2018) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0097-y · Cited by 143 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Balboa, D., Barsby, T., Lithovius, V., Saarimäki-Vire, J., Omar-Hmeadi, M., Dyachok, O., Montaser, H., Lund, P.-E., Yang, M., Ibrahim, H., et al. (2022) · Nature Biotechnology · doi:10.1038/s41587-022-01219-z · Cited by 433 · see citing works
Multi-lineage human iPSC-derived platforms for disease modeling and drug discovery
Sharma, A., Sances, S., Workman, M. J., & Svendsen, C. N. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2020.02.011 · Cited by 296 · see citing works
“Other unique methods to induce hiPSC-derivative maturation have recently been illustrated, such as training human PSC-derived pancreatic islets according to a circadian rhythm (Alvarez-Dominguez et al., 2020).”
Wang, S., Du, Y., Zhang, B., Meng, G., Liu, Z., Liew, S. Y., Liang, R., Zhang, Z., Cai, X., Wu, S., et al. (2024) · Cell · doi:10.1016/j.cell.2024.09.004 · Cited by 281 · see citing works
Generation of insulin-producing pancreatic β cells from multiple human stem cell lines
Hogrebe, N. J., Maxwell, K. G., Augsornworawat, P., & Millman, J. R. (2021) · Nature Protocols · doi:10.1038/s41596-021-00560-y · Cited by 211 · see citing works
Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes
Hogrebe, N. J., Ishahak, M., & Millman, J. R. (2023) · Cell Stem Cell · doi:10.1016/j.stem.2023.04.002 · Cited by 210 · see citing works
Engineering islets from stem cells for advanced therapies of diabetes
Siehler, J., Blöchinger, A. K., Meier, M., & Lickert, H. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00262-w · Cited by 125 · see citing works
Single cell transcriptomic and spatial landscapes of the developing human pancreas
Olaniru, O., Kadolsky, U., Kannambath, S., Vaikkinen, H., Fung, K., Dhami, P., & Persaud, S. (2022) · bioRxiv · doi:10.1101/2022.02.04.478971 · Cited by 124
TETs compete with DNMT3 activity in pluripotent cells at thousands of methylated somatic enhancers
Charlton, J., Jung, E. J., Mattei, A. L., Bailly, N., Liao, J., Martin, E. J., Gießelmann, P., Brändl, B., Stamenova, E. K., Müller, F.-J., et al. (2020) · Nature Genetics · doi:10.1038/s41588-020-0639-9 · Cited by 107 · see citing works
Self-citationThe promise of stem cell-derived islet replacement therapy
Melton, D. (2021) · Diabetologia · doi:10.1007/s00125-020-05367-2 · Cited by 96 · see citing works
“There are also differences in epigenetic modifications, including DNA methylation and histone modifications [29, 30].”
BackgroundSelf-citationModelling metabolic diseases and drug response using stem cells and organoids
Hu, W., & Lazar, M. A. (2022) · Nature Reviews Endocrinology · doi:10.1038/s41574-022-00733-z · Cited by 98 · see citing works
Circadian Regulation of Adult Stem Cell Homeostasis and Aging.
Benitah, S., & Welz, P. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2020.05.002 · Cited by 80 · see citing works
Cell Maturation: Hallmarks, Triggers, and Manipulation
Alvarez-Dominguez, J., & Melton, D. (2021) · Cell · doi:10.1016/j.cell.2021.12.012 · Cited by 78 · see citing works
Self-citationA method for the generation of human stem cell-derived alpha cells
Peterson, Q. P., Veres, A., Chen, L., Slama, M. Q., Kenty, J. H.-R., Hassoun, S., Brown, M., Dou, H., Duffy, C. D., Zhou, Q., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16049-3 · Cited by 93 · see citing works
Self-citationAugsornworawat, P., Hogrebe, N. J., Ishahak, M., Schmidt, M. D., Marquez, E., Maestas, M. M., Veronese-Paniagua, D., Gale, S. E., Miller, J. R., Velazco-Cruz, L., et al. (2023) · Nature Cell Biology · doi:10.1038/s41556-023-01150-8 · Cited by 85 · see citing works
Zhu, H., Wang, G., Nguyen-Ngoc, K.-V., Kim, D., Miller, M., Goss, G., Kovsky, J., Harrington, A. R., Saunders, D. C., Hopkirk, A. L., et al. (2023) · Developmental Cell · doi:10.1016/j.devcel.2023.03.011 · Cited by 85 · see citing works
The Human Islet: Mini-Organ With Mega-Impact
Walker, J. T., Saunders, D. C., Briššová, M., & Powers, A. C. (2021) · Endocrine Reviews · doi:10.1210/endrev/bnab010 · Cited by 80 · see citing works
Weng, C., Xi, J., Li, H., Cui, J., Gu, A., Lai, S., Leskov, K., Ke, L., Jin, F., & Li, Y. (2020) · Nature Metabolism · doi:10.1038/s42255-020-00314-2 · Cited by 65 · see citing works
“Interestingly, cell cycle genes (TOP2A, CENPE, MKI67, AURKB and CDK1) were not expressed in the entire endocrine lineage branch, indicating cell cycle exit during the fate choice to differentiate into pancreatic endocrine cells (module 57; Extended Data Fig.”
InfluentialThe hidden link between circadian entropy and mental health disorders
Alachkar, A., Lee, J., Asthana, K., Monfared, R. V., Chen, J., Alhassen, S., Samad, M., Wood, M., Mayer, E., & Baldi, P. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02028-3 · Cited by 65 · see citing works
Pancreatic islet transplantation: current advances and challenges
Wang, Q., Huang, Y.-X., Liu, L., Zhao, X.-H., Sun, Y., Mao, X.-L., & Li, S.-W. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1391504 · Cited by 63 · see citing works
3D chromatin maps of the human pancreas reveal lineage-specific regulatory architecture of T2D risk
Su, C., Gao, L., May, C. L., Pippin, J. A., Boehm, K. D., Lee, M., Liu, C., Pahl, M. C., Golson, M. L., Naji, A., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.08.014 · Cited by 78 · see citing works
Advances Toward Engineering Functionally Mature Human Pluripotent Stem Cell-Derived β Cells
Velazco-Cruz, L., Goedegebuure, M. M., & Millman, J. (2020) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2020.00786 · Cited by 62 · see citing works
Human pluripotent stem cell-derived insulin-producing cells: A regenerative medicine perspective
Migliorini, A., Nostro, M. C., & Sneddon, J. B. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.03.021 · Cited by 61 · see citing works
Human expandable pancreatic progenitor–derived β cells ameliorate diabetes
Ma, X., Lu, Y., Zhou, Z., Li, Q., Chen, X., Wang, W., Jin, Y., Hu, Z., Chen, G., Deng, Q., et al. (2022) · Science Advances · doi:10.1126/sciadv.abk1826 · Cited by 60 · see citing works
“…the transcriptional profile of ePP- cells, we compared the transcriptomes of ePP- cells, early-and late-passage ePPs (ePP-P9 and ePP-P21), hPSCs, DE, and PP2 by RNA-seq and also with the RNA-seq dataset (hPSCs, DE, PP2, SC- , and cells) from the recent work by Melton laboratory ( 10 ).”
Maturation of beta cells: lessons from in vivo and in vitro models
Barsby, T., & Otonkoski, T. (2022) · Diabetologia · doi:10.1007/s00125-022-05672-y · Cited by 66 · see citing works
Islet organoid as a promising model for diabetes
Zhang, X., Ma, Z., Song, E., & Xu, T. (2021) · Protein & Cell · doi:10.1007/s13238-021-00831-0 · Cited by 52 · see citing works
“Although significant glucose stimulated insulin secretion (GSIS) was not observed, the β-like cells slowly accumulated insulin upon glucose responsiveness (Rezania et al., 2014).”
BackgroundInfluentialEpigenome editing for targeted DNA (de)methylation: a new perspective in modulating gene expression
Seem, K., Kaur, S., Kumar, S., & Mohapatra, T. (2024) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2024.2320659 · Cited by 58 · see citing works
“Pluripotency genes undergo DNA hypermethylation during in vitro differentiation of human pluripotent stem cells (hPScs) into pancreatic islets (Alvarez-Dominguez et al. 2020).”
BackgroundDissecting the complexities of Alzheimer disease with in vitro models of the human brain
Blanchard, J., Victor, M. B., & Tsai, L. (2021) · Nature Reviews Neurology · doi:10.1038/s41582-021-00578-6 · Cited by 65 · see citing works
Engineering multiscale structural orders for high-fidelity embryoids and organoids
Shao, Y., & Fu, J. (2022) · Cell stem cell · doi:10.1016/j.stem.2022.04.003 · Cited by 56 · see citing works
Emerging diabetes therapies: Bringing back the β-cells
Basile, G., Qadir, F., Mauvais-Jarvis, F., Vetere, A., Shoba, V., Modell, A. E., Pastori, R., Russ, H., Wagner, B., & Domínguez-Bendala, J. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101477 · Cited by 47 · see citing works
“Over the last few years, many studies have further enhanced the in vitro generation of functional sBCs by synchronizing cultures [18], changing signaling pathway modulation [19,20], altering available energy sources in culture media [21], facilitating coalescence of sBCs into islet-like structures [22], and recreating…”
BackgroundENTPD3 Marks Mature Stem Cell–Derived β-Cells Formed by Self-Aggregation In Vitro
Docherty, F. M., Riemondy, K. A., Castro-Gutiérrez, R., Dwulet, J. M., Shilleh, A. H., Hansen, M. S., Williams, S. P. M., Armitage, L. H., Santostefano, K. E., Wallet, M. A., et al. (2021) · Diabetes · doi:10.2337/db20-0873 · Cited by 69 · see citing works
“For generation of more mature sBC in vitro, several approaches, including sorting of putative progenitor cells during direct differentiation (6), optimization of culture conditions (7), modeling the nutrient-sensing transition occurring at birth (8), entrainment of circadian cycles (9), and manipulation of transcripti…”
BackgroundA human pancreatic ECM hydrogel optimized for 3-D modeling of the islet microenvironment
Tremmel, D. M., Sackett, S., Feeney, A. K., Mitchell, S. A., Schaid, M. D., Polyák, E., Chlebeck, P., Gupta, S., Kimple, M. E., Fernandez, L. A., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-11085-z · Cited by 45 · see citing works
Transcriptional mechanisms of pancreatic β-cell maturation and functional adaptation
Wortham, M., & Sander, M. (2021) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2021.04.011 · Cited by 56 · see citing works
Jun, Y., Nguyen-Ngoc, K.-V., Sai, S., Bender, R., Gong, W., Kravets, V., Zhu, H., Hatch, C. J., Schlichting, M., Gaetani, R., et al. (2022) · bioRxiv · doi:10.1101/2022.10.28.513298 · Cited by 42 · see citing works
dos Santos, C., Cambraia, A., Shrestha, S., Cutler, M., Cottam, M. A., Perkins, G. A., Lev‐Ram, V., Roy, B., Acree, C., Keun-young Kim, A., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-53127-2 · Cited by 47 · see citing works
“This approach revealed the expected and positive correlation in the activation of beta cell TFs ( Pdx1 , Mafa , and Foxa2 , (Fig.”
BackgroundInfluentialOrganoid-guided precision hepatology for metabolic liver disease
Osonoi, S., & Takebe, T. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.01.002 · Cited by 40 · see citing works
The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A
Beucher, A., Miguel-Escalada, I., Balboa, D., Vas, M. G. D., Maestro, M. A., García-Hurtado, J., Bernal, A., Gonzalez-Franco, R., Vargiu, P., Heyn, H., et al. (2022) · Nature Cell Biology · doi:10.1038/s41556-022-00996-8 · Cited by 41 · see citing works
Human Pluripotent Stem Cells to Model Islet Defects in Diabetes
Balboa, D., Iworima, D. G., & Kieffer, T. J. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.642152 · Cited by 47 · see citing works
Immune Protection of Stem Cell-Derived Islet Cell Therapy for Treating Diabetes
Tahbaz, M., & Yoshihara, E. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.716625 · Cited by 42 · see citing works
DNA Methylation Patterning and the Regulation of Beta Cell Homeostasis
Parveen, N., & Dhawan, S. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.651258 · Cited by 48 · see citing works
Maternal circadian rhythms during pregnancy dictate metabolic plasticity in offspring
Yao, N., Kinouchi, K., Katoh, M., Ashtiani, K. C., Abdelkarim, S., Morimoto, H., Torimitsu, T., Kozuma, T., Iwahara, A., Kosugi, S., et al. (2025) · Cell Metabolism · doi:10.1016/j.cmet.2024.12.002 · Cited by 38 · see citing works
“46 Conversely, the absence of Bmal1 during development adversely impacts lifespan and relates to an aging-like phenotype, based on the fact that inducible BKO as late as 3 months of age produces little abnormality, which is appreciated in conventional BKO mice.”
Extensive NEUROG3 occupancy in the human pancreatic endocrine gene regulatory network
Schreiber, V., Mercier, R., Jiménez, S., Ye, T., García-Sánchez, E., Klein, A.-C., Meunier, A., Ghimire, S., Birck, C., Jost, B., et al. (2021) · bioRxiv · doi:10.1016/j.molmet.2021.101313 · Cited by 34 · see citing works
Delás, M., Kalaitzis, C. M., Fawzi, T., Demuth, M., Zhang, I., Stuart, H., Costantini, E., Ivanovitch, K., Tanaka, E. M., & Briscoe, J. (2022) · Developmental Cell · doi:10.1016/j.devcel.2022.11.016 · Cited by 31 · see citing works
A role for alternative splicing in circadian control of exocytosis and glucose homeostasisPreprint
Marcheva, B., Perelis, M., Weidemann, B. J., Taguchi, A., Lin, H.-P., Omura, C., Kobayashi, Y., Newman, M., Wyatt, E. J., McNally, E., et al. (2020) · Genes & Development · doi:10.1101/gad.338178.120 · Cited by 31 · see citing works
“…(Bark et al. 1995; Johansson et al. 2008; Song et al. 2017) and (2) the emergence of circadian rhythms during human β -cell maturation coincides with metabolic maturation (Alvarez-Dominguez et al. 2020), raise the possibility that the circadian control of AS may participate in β -cell maturation.”
Zhang, W.-B., Ross, P., Ellis, J., & Salter, M. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02010-z · Cited by 30 · see citing works
“Some of these sensory stimuli naturally fluctuate in daily cycles, and circadian entrainment has been shown to promote functional maturation of human embryonic stem cell-derived beta cells [146].”
BackgroundTissue engineering and 3D printing of bioartificial pancreas for regenerative medicine in diabetes.
Soetedjo, A. A. P., Lee, J.-M., Lau, H. H., Goh, G.-L., An, J., Koh, Y., Yeong, W., & Teo, A. (2021) · Trends in endocrinology and metabolism · doi:10.1016/j.tem.2021.05.007 · Cited by 30 · see citing works
Maturing differentiated human pluripotent stem cells in vitro: methods and challenges.
Ottaviani, D., ter Huurne, M., Elliott, D., Bellin, M., & Mummery, C. (2023) · Development · doi:10.1242/dev.201103 · Cited by 29 · see citing works
Engineered Human Organoids for Biomedical Applications
Zhu, Y., Sun, L., Wu, X., Gu, Z., & Zhao, Y. (2023) · Advanced Functional Materials · doi:10.1002/adfm.202310961 · Cited by 27 · see citing works
Repression of Latent NF-κB Enhancers by PDX1 Regulates β-cell Functional Heterogeneity
Weidemann, B. J., Marcheva, B., Kobayashi, M., Omura, C., Newman, M., Kobayashi, Y., Waldeck, N. J., Perelis, M., Lantier, L., McGuinness, O. P., et al. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2023.11.018 · Cited by 27 · see citing works
Lin, Z.-W., Wang, W., Liu, R., Li, Q., Lee, J., Hirschler, C., & Liu, J. (2025) · Nature Protocols · doi:10.1038/s41596-025-01147-7 · Cited by 25 · see citing works
Regulation of CTCF loop formation during pancreatic cell differentiation
Lyu, X., Rowley, M. J., Kulik, M. J., Dalton, S., & Corces, V. G. (2023) · Nature Communications · doi:10.1038/s41467-023-41964-6 · Cited by 21 · see citing works
Stepwise differentiation of functional pancreatic β cells from human pluripotent stem cells
Jin, W., & Jiang, W. (2022) · Cell Regeneration · doi:10.1186/s13619-022-00125-8 · Cited by 25 · see citing works
“Functional maturation of β cells can be improved through controlling energy metabolism and GSIS function by circadian modulation (Alvarez-Dominguez et al., 2020) (Fig.”
BackgroundCircadian regulation of lung repair and regeneration
Naik, A., Forrest, K., Paul, O., Issah, Y., Valekunja, U., Tang, S., Reddy, A. B., Hennessy, E., Brooks, T. G., Chaudhry, F. N., et al. (2021) · bioRxiv · doi:10.1172/jci.insight.164720 · Cited by 25 · see citing works
“While many studies have demonstrated the presence of a cell-autonomous clock active in in vitro cultures, evidence of the same in organotypic cultures is limited, mainly restricted to rapidly proliferating, intestinal organoids (9, 10, 19) or metabolically active, β (islet) cell organoids (20).”
Spatial transcriptomics AI agent charts hPSC-pancreas maturation in vivoPreprint
Lin, Z.-W., Wang, W., Marin-Llobet, A., Li, Q., Pollock, S. D., Sui, X., Aljović, A., Lee, J., Baek, J., Liang, N., et al. (2025) · bioRxiv · doi:10.1101/2025.04.01.646731 · Cited by 22 · see citing works
“Although human pluripotent stem cell (hPSC)-derived pancreatic tissues hold promise for cell replacement therapies, in vitro -produced SC-pancreas generally lacks full transcriptional and functional maturity 25,26 .”
InfluentialSelf-citationBrown, M. R., Holmes, H. L., Rakshit, K., Javeed, N., Her, T. K., Stiller, A., Sen, S., Shull, G., Prakash, Y., Romero, M., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci142365 · Cited by 22 · see citing works
Gheibi, S., Singh, T., da Cunha, J. P. D., Fex, M., & Mulder, H. (2020) · Cells · doi:10.3390/cells9112465 · Cited by 22 · see citing works
Stem Cell Neurodevelopmental Solutions for Restorative Treatments of the Human Trunk and Spine
Olmsted, Z. T., & Paluh, J. L. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.667590 · Cited by 25 · see citing works
He, X., Di, R., Guo, X., Cao, X., Zhou, M., Li, X., Xia, Q., Wang, X., Zhang, J., Zhang, X., et al. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.848144 · Cited by 21 · see citing works
Pollock, S. D., Galicia-Silva, I. M., Liu, M., Gruskin, Z. L., & Alvarez‐Dominguez, J. R. (2023) · STAR Protocols · doi:10.1016/j.xpro.2023.102580 · Cited by 20 · see citing works
Self-citationModeling human liver organ development and diseases with pluripotent stem cell-derived organoids
Ouchi, R., & Koike, H. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1133534 · Cited by 17 · see citing works
“In human iPSC-derived intestinal organoids, circadian rhythms were observed upon differentiation and maturation and indeed, it has been suggested that in vitro introduction of circadian feeding and fasting cycles in pancreatic islets induces the cyclic synthesis and maturation of energy metabolism and insulin secretor…”
BackgroundMa, X.-J., Cao, J., Zhou, Z.-Y., Lu, Y.-K., Li, Q. H., Jin, Y., Chen, G., Wang, W.-Y., Ge, W., Chen, X., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-31698-2 · Cited by 18 · see citing works
A multimodal cross-species comparison of pancreas development
Yang, K., Spitzer, H., Sterr, M., Hrovatin, K., Sean de la, O., Zhang, X., Setyono, E. S. A., Ud‐Dean, M., Walzthoeni, T., Flisikowski, K., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-64774-4 · Cited by 15 · see citing works
NGN3 oscillatory expression controls the timing of human pancreatic endocrine differentiation
Miller, A., Biga, V., Rowntree, A., Chhatriwala, M., Woods, F., Noble, B., Marinopoulou, E., Kamath, A., Vallier, L., & Papalopulu, N. (2024) · bioRxiv · doi:10.1101/2024.01.10.574974 · Cited by 17
Pancreas agenesis mutations disrupt a lead enhancer controlling a developmental enhancer cluster
Miguel-Escalada, I., Maestro, M. Á., Balboa, D., Elek, A., Bernal, A., Bernardo, E., Grau, V., García-Hurtado, J., Sebé-Pedrós, A., & Ferrer, J. P. (2022) · Developmental Cell · doi:10.1016/j.devcel.2022.07.014 · Cited by 22 · see citing works
Engineered Biomaterials for Enhanced Function of Insulin‐Secreting β‐Cell Organoids
Hunckler, M. D., & García, A. J. (2020) · Advanced Functional Materials · doi:10.1002/adfm.202000134 · Cited by 17 · see citing works
Directed differentiation of pancreatic δ cells from human pluripotent stem cells
Chen, L., Wang, N., Zhang, T., Zhang, F., Zhang, W. K., Meng, H., Chen, J., Liao, Z., Xu, X., Ma, Z., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-50611-7 · Cited by 15 · see citing works
“Amongthesegenes, LMX1B functions downstream of NEUROG3 as a critical transcription factor for human islet endocrine cell generation 55,56 and CRABP1/2 functions in retinoic acid signaling 57 .”
Validating expression of beta cell maturation-associated genes in human pancreas development
Tremmel, D. M., Mikat, A. E., Gupta, S., Mitchell, S. A., Curran, A. M., Menadue, J. A., Odorico, J. S., & Sackett, S. D. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1103719 · Cited by 18 · see citing works
“The effects that some of these individual elements have on islet and SC-islet health and function have been explored in vitro through many different studies, and each have been shown to have influence on the identity and function of the cells (Alvarez-Dominguez et al., 2020; Singh et al., 2020; Nguyen-Ngoc et al., 202…”
Dynamic Ins2 gene activity defines β-cell maturity statesPreprint
Chu, C. M. J., Modi, H., Skovsø, S., Ellis, C., Krentz, N. A. J., Zhao, Y. B., Cen, H., Noursadeghi, N., Panzhinskiy, E., Hu, X., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/702589 · Cited by 8 · see citing works
Shilleh, A. H., Beard, S., & Russ, H. (2023) · Stem Cell Reports · doi:10.1016/j.stemcr.2023.05.010 · Cited by 14 · see citing works
“Manipulation of key signaling pathways (Velazco-Cruz et al., 2020; Zhu et al., 2016; Zhou et al., 2020), synchronization of cultures (Alvarez-Dominguez et al., 2020), alterations in medium composition, or extending in vitro culture (Velazco-Cruz et al., 2019; Docherty et al., 2021) has been shown…”
BackgroundThe circadian clock CRY1 regulates pluripotent stem cell identity and somatic cell reprogramming.
Sato, S., Hishida, T., Kinouchi, K., Hatanaka, F., Li, Y.-M., Nguyen, Q., Chen, Y.-M., Wang, P. H., Kessenbrock, K., Li, W., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112590 · Cited by 14 · see citing works
MYCL-mediated reprogramming expands pancreatic insulin-producing cells
Hirano, M., So, Y., Tsunekawa, S., Kabata, M., Ohta, S., Sagara, H., Sankoda, N., Taguchi, J., Yamada, Y., Ukai, T., et al. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00530-y · Cited by 14 · see citing works
Kimura, A., Toyoda, T., Iwasaki, M., Hirama, R., & Osafune, K. (2020) · Cell chemical biology · doi:10.1016/j.chembiol.2020.08.018 · Cited by 14 · see citing works
Liu, X.-R., Yang, J., Yan, Y., Li, Q.-F., & Huang, R.-L. (2024) · Theranostics · doi:10.7150/thno.93919 · Cited by 13 · see citing works
“Considering the intimate relationship between circadian rhythm and adipose tissue homeostasis [152], particularly BAT [153], core circadian clock activators should be further applied to adipose organoids [154].”
BackgroundFunctional, metabolic and transcriptional maturation of stem cell derived beta cells
Balboa, D., Barsby, T., Lithovius, V., Saarimäki-Vire, J., Omar-Hmeadi, M., Dyachok, O., Montaser, H., Lund, P., Yang, M., Ibrahim, H., et al. (2021) · bioRxiv · doi:10.1101/2021.03.31.437748 · Cited by 13
Improving cellular fitness of human stem cell-derived islets under hypoxia
Wang, X., Brielle, S., Kenty, J. H.-R., Korover, N., Bavli, D., Pop, R., & Melton, D. A. (2025) · Nature Communications · doi:10.1038/s41467-025-59924-7 · Cited by 13 · see citing works
Self-citationMarcheva, B., Weidemann, B. J., Taguchi, A., Perelis, M., Ramsey, K., Newman, M., Kobayashi, Y., Omura, C., Fox, J. E. M., Lin, H.-P., et al. (2022) · eLife · doi:10.7554/elife.75132 · Cited by 12
Stem-cell-derived beta cells mature metabolically upon murine engraftment
Vähäkangas, E., Saarimäki‐Vire, J., Montaser, H., Lithovius, V., Eurola, S., Ibrahim, H., Kuuluvainen, E., Balboa, D., Katajisto, P., Barsby, T., et al. (2025) · Diabetologia · doi:10.1007/s00125-025-06474-8 · Cited by 13 · see citing works
“In addition, a multitude of factors in the bloodstream could trigger SC-islet maturation, including circadian cues and systemic hormones such as the thyroid hormone [41–43].”
TFEB and TFE3 control glucose homeostasis by regulating insulin gene expression
Pasquier, A., Pastore, N., D'Orsi, L., Colonna, R., Esposito, A., Maffia, V., Cegli, R. D., Mutarelli, M., Ambrosio, S., Tufano, G., et al. (2023) · EMBO Journal · doi:10.15252/embj.2023113928 · Cited by 11 · see citing works
The emergence of circadian timekeeping in the intestine
Parasram, K., Zuccato, A., Shin, M., Willms, R. J., DeVeale, B., Foley, E. A., & Karpowicz, P. (2023) · bioRxiv · doi:10.1038/s41467-024-45942-4 · Cited by 11 · see citing works
Mawla, A. M., van der Meulen, T., & Huising, M. O. (2023) · BMC Genomics · doi:10.1186/s12864-023-09293-6 · Cited by 14 · see citing works
Biohybrid-engineered tissue platforms: bridging the gap in tissue engineering.
Yong, U., Kim, J., & Jang, J. (2025) · Trends in Biotechnology · doi:10.1016/j.tibtech.2025.05.018 · Cited by 10 · see citing works
Stem cell-based multi-tissue platforms to model human autoimmune diabetes
Leavens, K. F., Alvarez‐Dominguez, J. R., Vo, L. T., Russ, H. A., & Parent, A. V. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101610 · Cited by 18 · see citing works
“Alternatively, modulating the circadian clock or cell cycle can also impact b cell functional maturation [33,43].”
BackgroundMethodSelf-citationGeorge, M. N., Leavens, K. F., & Gadue, P. J. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.682625 · Cited by 11 · see citing works
Han, T., Chen, Z., Chen, W.-D., Yuan, L., & Liu, B. (2021) · Cancer Gene Therapy · doi:10.1038/s41417-020-00270-9 · Cited by 10
Recent 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
Implanted flexible electronics reveal principles of human islet cell electrical maturation
Li, Q., Liu, R., Lin, Z., Zhang, X., Wang, W., Galicia-Silva, I. M., Liu, M., Gao, Z., Pollock, S. D., Alvarez‐Dominguez, J. R., et al. (2026) · Science · doi:10.1126/science.aeb3295 · Cited by 9 · see citing works
Self-citationWu, H., Liu, X., Jiang, W., Hu, C., Wang, X.-Y., Tian, Z., Gu, W.-B., Sun, C.-H., Han, T.-S., & Wei, W. (2023) · Diabetes, obesity and metabolism · doi:10.1111/dom.15236 · Cited by 9
Toren, E., Kepple, J., Coutinho, K., Poole, S. O., Deeba, I. M., Pierre, T. H., Liu, Y.-P., Bethea, M., & Hunter, C. S. (2023) · Molecular Metabolism · doi:10.1016/j.molmet.2023.101785 · Cited by 9 · see citing works
“Another LIM-HD TF, Lmx1b, was implicated in human endocrine progenitor fate in vitro [67] and may also be a component of islet SSBP3-mediated complexes, though its levels were not found to be altered in our transcriptome analysis.”
BackgroundCharacterization of cell-fate decision landscapes by estimating transcription factor dynamics
Jiménez, S., Schreiber, V., Mercier, R., Gradwohl, G., & Molina, N. (2022) · bioRxiv · doi:10.1016/j.crmeth.2023.100512 · Cited by 9 · see citing works
“Moreover, we are considering only interactions between TFs and promoters, and it is well known that some essential regulatory interactions occur at distal regulatory sites.(74) We have designed our pipeline such that the limitations mentioned above could be addressed by extending the binding-site matrix; indeed, with…”
Epigenome rewiring in human pluripotent stem cells
Yan, J., & Huangfu, D. (2021) · Trends in Cell Biology · doi:10.1016/j.tcb.2021.12.001 · Cited by 9 · see citing works
Zakaria, A., Berthault, C., Cosson, B., Jung, V., Guerrera, I., Rachdi, L., & Scharfmann, R. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100839 · Cited by 9 · see citing works
“This hypothesis correlates with recent results indicating that circadian glucose pulses induce β-cell differentiation and maturation of human-stem-cellderived islet (39).”
ResultMetabolism as a central regulator of β‐cell chromatin state
Vanderkruk, B., & Hoffman, B. G. (2020) · FEBS Journal · doi:10.1111/febs.15562 · Cited by 10 · see citing works
Lithovius, V., & Otonkoski, T. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.837450 · Cited by 8 · see citing works
Sobel, J., Guay, C., Elhanani, O., Rodríguez-Trejo, A., Stoll, L., Menoud, V., Jacovetti, C., Walker, M., & Regazzi, R. (2021) · Scientific Reports · doi:10.1038/s41598-021-88003-2 · Cited by 8 · see citing works
Wei, Y., Hong, F., Xie, S., Luo, X., Li, X., Dao, F., Deng, K., Lin, H., & Lv, H. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262211005 · Cited by 8 · see citing works
Multiplexed CRISPR gene editing in primary human islet cells with Cas9 ribonucleoprotein
Bevacqua, R. J., Zhao, W., Merheb, E., Kim, S. H., Marson, A., Gloyn, A. L., & Kim, S. K. (2023) · iScience · doi:10.1016/j.isci.2023.108693 · Cited by 11 · see citing works
Human Pluripotent Stem Cells Go Diabetic: A Glimpse on Monogenic Variants
Heller, S., Melzer, M. K., Azoitei, N., Julier, C., & Kleger, A. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.648284 · Cited by 7 · see citing works
Hahm, J., Thirunavukarasu, B., Gadoo, R., Andrade, J. A. F., Dalton, T., Arany, E. J., & Hill, D. J. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252011152 · Cited by 8 · see citing works
dos Santos, C., Shrestha, S., Cottam, M., Perkins, G., Lev-Ram, V., Roy, B., Acree, C., Kim, K., Deerinck, T., Cutler, M., et al. (2023) · bioRxiv · doi:10.1101/2023.08.23.554369 · Cited by 6 · see citing works
“Immunohistochemistry (IHC) and confocal microscopy of islets from CR mice confirmed that ~80% of all CR beta cells have higher levels of Arntl/Bmal and Pdx1 in situ after 2 months on diet (Figure S4G).”
InfluentialClocking the circadian genes in human embryonic stem cells.
Thakur, S., Storewala, P., Basak, U., Jalan, N., & Pethe, P. (2020) · Stem Cell Investigation · doi:10.21037/sci-2020-014 · Cited by 6 · see citing works
“Recently, it was shown that by simply adjusting cells to regular feeding and fasting cycles, the in vitro generated islet cells get entrained and these cells become functionally mature islets cells in vitro (21).”
BackgroundImproving stem cell-derived pancreatic islets using single-cell multiome-inferred regulomes
Zhu, H., Wang, G., Nguyen-Ngoc, K.-V., Kim, D., Miller, M., Goss, G., Kovsky, J., Harrington, A. R., Saunders, D., Melton, R., et al. (2022) · doi:10.1101/2022.09.25.509355 · Cited by 85 · see citing works
“, 2017), the circadian clock-dependent TF ARNTL (Alvarez-Dominguez et al., 2020; Perelis et al., 2015; Rakshit et al., 2018; Vieira et al., 2012), and TFs activated by steroid hormones, such as the androgen receptor (AR) and thyroid hormone receptor (THRA) (Aguayo-Mazzucato et al.”
BackgroundInfluential
- Authors
- Alvarez-Dominguez, J. R., Donaghey, J., Rasouli, N., Kenty, J. H. R., Helman, A., Charlton, J., Straubhaar, J. R., Meissner, A., & Melton, D. A.
- Affiliations
- Harvard University (US)
- Corresponding author
- Melton, Douglas A.
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2020-01
- Volume
- 26
- Issue
- 1
- Pages
- 108-122.e10
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W2996224374
- Cited by
- 189
- References
- 123
- Citations by year
- 2026: 21 · 2025: 25 · 2024: 18 · 2023: 42 · 2022: 31 · 2021: 30 · 2020: 20 · 2019: 2
- FWCI
- 19.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- Leona M. and Harry B. Helmsley Charitable Trust
- Harvard Stem Cell Institute
- JPB Foundation
- Howard Hughes Medical Institute
- National Institutes of Health (P01GM099117, DP3K111898)
- Life Sciences Research Foundation
- Juvenile Diabetes Research Foundation International
- Max-Planck-Gesellschaft
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- circadian entrainment, pancreatic islets, epigenetic priming, DNA methylation, chromatin accessibility, histone modifications, insulin secretion, glucagon, islet transplantation, energy metabolism
- MeSH terms
- Insulin Secretion, Cell Differentiation, Circadian Rhythm, Glucagon, Humans, Insulin, Islets of Langerhans, Pluripotent Stem Cells
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