Improving stem cell-derived pancreatic islets using single-cell multiome-inferred regulomes
Open accessAbstract
Pancreatic islet cells derived from human pluripotent stem cells hold great promise for modeling and treating diabetes. Differences between stem cell-derived and primary islets remain, but molecular insights to inform improvements are limited. Here, we acquire single-cell transcriptomes and accessible chromatin profiles during in vitro islet differentiation and pancreas from childhood and adult donors for comparison. We delineate major cell types, define their regulomes, and describe spatiotemporal gene regulatory relationships between transcription factors. CDX2 emerged as a regulator of enterochromaffin-like cells, which we show resemble a transient, previously unrecognized, CDX2 + pre-β-cell population in fetal pancreas, arguing against a proposed non-pancreatic origin. Furthermore, we observe insufficient activation of signal-dependent transcriptional programs during in vitro β-cell maturation and identify sex hormones as drivers of β-cell proliferation in childhood. Altogether, our analysis provides a comprehensive understanding of cell fate acquisition in stem cell-derived islets and a framework for manipulating cell identities and maturity.
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Both multiomic studies indicated that epigenetic regulators are important drivers of cell identity, particularly in the cell fate choice between SC-EC and SC-β cells.
“Importantly, both studies indicated that epigenetic regulators are important drivers of cell identity, particularly in the cell fate choice between SC-EC and SC-β cells.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [74]
In “Chromatin accessibility and gene expression during SC-islet differentiation” (page unavailable), the paper analyzes the SC-β/SC-EC lineage branch and identifies candidate transcription factors for each fate. The Discussion (page unavailable) describes these as predicted regulators, not demonstrated drivers, and the passages do not establish that epigenetic regulators specifically drive the fate choice. This source also cannot substantiate the statement about both studies on its own. (LLM, conf=0.82)
Experimental — accuracy not yet measuredBoth multiomic studies identified distinct populations representing SC-β, SC-α, SC-δ, and SC-EC cells using canonical gene markers of islet cell types.
“Using canonical gene markers of islet cell types, both multiomic studies identified distinct populations representing SC-β, SC-α, SC-δ, and SC-EC cells.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [74]
SC-β cells were less similar to their primary counterparts than other stem cell-derived endocrine cell types.
“The multiomic studies described here further demonstrated that SC-β cells were less similar to their primary counterparts than other stem cell-derived endocrine cell types.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [74]
Both multiomic studies provided greater resolution of cellular heterogeneity by describing specific subpopulations of expected cell types.
“Notably, both studies also provided greater resolution of cellular heterogeneity by describing specific subpopulations of expected cell types.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [74]
CDX2 was identified as the earliest transcription factor expressed during SC-EC lineage specification.
“Additionally, the other study identified CDX2 as the earliest transcription factor expressed during SC-EC lineage specification.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [74]
A novel CDX2+ β-cell precursor-like population in the human fetal pancreas resembled SC-EC cells.
“Interestingly, they also reported a novel CDX2+ β-cell precursor-like population in the human fetal pancreas that resembled SC-EC cells,”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [74]
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Cites
chromVAR: inferring transcription-factor-associated accessibility from single-cell epigenomic data
Schep, A. N., Wu, B., Buenrostro, J. D., & Greenleaf, W. J. (2017) · Nature Methods · doi:10.1038/nmeth.4401 · Cited by 1,680 · see citing works
Satpathy, A. T., Granja, J. M., Yost, K. E., Qi, Y., Meschi, F., McDermott, G. P., Olsen, B. N., Mumbach, M. R., Pierce, S. E., Corces, M. R., et al. (2019) · Nature Biotechnology · doi:10.1038/s41587-019-0206-z · Cited by 980 · see citing works
Purhonen, J., Banerjee, R., McDonald, A. E., Fellman, V., & Kallijärvi, J. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa516 · Cited by 657 · see citing works
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
Acquisition of Dynamic Function in Human Stem Cell-Derived β Cells
Velazco-Cruz, L., Song, J., Maxwell, K. G., Goedegebuure, M. M., Augsornworawat, P., Hogrebe, N. J., & Millman, J. R. (2019) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.12.012 · Cited by 399 · see citing works
Age-Dependent Pancreatic Gene Regulation Reveals Mechanisms Governing Human β Cell Function
Arda, H. E., Li, L., Tsai, J., Torre, E. A., Rosli, Y., Peiris, H., Spitale, R. C., Dai, C., Gu, X., Qu, K., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.04.002 · Cited by 222 · see citing works
Self-citationAugsornworawat, P., Maxwell, K. G., Velazco-Cruz, L., & Millman, J. R. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108067 · Cited by 200 · see citing works
Circadian Entrainment Triggers Maturation of Human In Vitro Islets
Alvarez-Dominguez, J. R., Donaghey, J., Rasouli, N., Kenty, J. H. R., Helman, A., Charlton, J., Straubhaar, J. R., Meissner, A., & Melton, D. A. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2019.11.011 · Cited by 189 · cited 5× · 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.”
BackgroundInfluentialAn atlas of gene regulatory elements in adult mouse cerebrum
Li, Y. E., Preissl, S., Hou, X., Zhang, Z., Zhang, K., Qiu, Y., Poirion, O. B., Li, B., Chiou, J., Liu, H., et al. (2021) · Nature · doi:10.1038/s41586-021-03604-1 · Cited by 185 · cited 1× · see citing works
“To identify putative target genes of cCREs, we combined and modified previously published methods (Li et al., 2021).”
MethodSelf-citationVettorazzi, J. F., Ribeiro, R. A., Borck, P. C., Branco, R. C. S., Soriano, S., Merino, B., Boschero, A. C., Nadal, A., Quesada, I., & Carneiro, E. M. (2016) · Metabolism · doi:10.1016/j.metabol.2015.10.021 · Cited by 104 · see citing works
Lactation improves pancreatic β cell mass and function through serotonin production
Moon, J. H., Kim, H., Kim, H., Park, J., Choi, W., Choi, W., Hong, H. J., Ro, H.-J., Jun, S., Choi, S. H., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aay0455 · Cited by 67 · 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
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Research works printed but not linked: 4
- Castell, A.-L., Ethier, M., Fergusson, G., Tremblay, C., Goubault, C., Baltz, M., Soglio, D.D., Ghislain, J., and Poitout, V. (2022). Beta-cell mass expansion during puberty involves serotonin signaling and determines glucose homeostasis in adulthood. bioRxiv, 2022.2004.2006.487366.
- Fleck, J.S., Jansen, S.M.J., Wollny, D., Seimiya, M., Zenk, F., Santel, M., He, Z., Gray Camp, J., and Treutlein, B. (2021). Inferring and perturbing cell fate regulomes in human cerebral organoids. bioRxiv, 2021.2008.2024.457460.
- Moon, J.H., Kim, Y.G., Kim, K., Osonoi, S., Wang, S., Saunders, D.C., Wang, J., Yang, K., Kim, H., Lee, J., et al. (2020b). Serotonin Regulates Adult β-Cell Mass by Stimulating Perinatal β-Cell Proliferation. Diabetes 69, 205-214.
- Wortham, M., Liu, F., Fleischman, J.Y., Wallace, M., Mulas, F., Vinckier, N.K., Harrington, A.R., Cross, B.R., Chiou, J., Patel, N.A., et al. (2019). Nutrient regulation of the islet epigenome controls adaptive insulin secretion. bioRxiv, 742403.
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Sorted by citations
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
- Authors
- Zhu, H., Wang, G., Nguyen-Ngoc, K.-V., Kim, D., Miller, M., Goss, G., Kovsky, J., Harrington, A. R., Saunders, D., Melton, R., Powers, A. C., Preissl, S., Spagnoli, F. M., Gaulton, K. J., & Sander, M.
- Affiliations
- University of California San Diego (US)
- King's College London (GB)
- Vanderbilt University Medical Center (US)
- Vanderbilt University (US)
- Corresponding author
- Sander, Maike
- ORCID
- Venue
- Developmental Cell
- Publisher
- openRxiv
- Published
- 2022-09-26
- Volume
- 58
- Issue
- 9
- Pages
- 727-743.e11
- ISSN
- 1534-5807 (ISSN-L)
- PMC
- PMC10175223
- OpenAlex
- W4363677402
- Cited by
- 85
- References
- 12
- Citations by year
- 2026: 24 · 2025: 23 · 2024: 24 · 2023: 14
- FWCI
- 22.96
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- Developmental Cell (publishedVersion, other-oa)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, other-oa)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, other-oa)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion, other-oa)
- Funders
- California Institute for Regenerative Medicine (EDUC4-12804)
- Leona M. and Harry B. Helmsley Charitable Trust
- Juvenile Diabetes Research Foundation United States of America
- Diabetes Research Connection
- National Institutes of Health
- University of California, San Diego (P30 DK064391)
- National Institute of Diabetes and Digestive and Kidney Diseases (UH3DK122639, U01DK105541, UG3DK122639, R01DK064391, U01DK120429, R01DK068471, P30DK063491)
- School of Medicine, University of California, San Diego
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- pluripotent stem cell differentiation, islet differentiation, single-cell multiome, regulome, CDX2, enterochromaffin-like cells, fetal pancreas, beta cell maturation, sex hormones, beta-cell proliferation, diabetes modeling, transcription factors, chromatin accessibility
- MeSH terms
- Adult, Cell Differentiation, Humans, Islets of Langerhans, Pancreas, Pluripotent Stem Cells, Insulin-Secreting Cells
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