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Differentiated human stem cells resemble fetal, not adult, β cells
Open accessAbstract
Significance: Human pluripotent stem cells (hPSCs) can be produced from any person and have the potential to differentiate into any cell type in the body. This study focuses on the generation of insulin-expressing cells from hPSCs and compares their gene expression, as assayed by transcriptional gene products, to that of insulin-expressing β cells from human fetal and adult samples. We employ a new method to isolate and profile insulin-expressing cells and conclude that several different hPSC lines generate very similar insulin-expressing cells, cells whose transcripts resemble fetal rather than adult β cells. This study advances the possibility of directing the differentiation of stem cells into functional β cells by comparing and cataloging differences between hPSC-derived insulin-expressing cells and human β cells.
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“SC-islets generated in vitro remain transcriptionally and functionally immature compared to adult human islets.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [77]
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“This is a valid concern as fully reprogrammed iPSCs can be difficult to differentiate into mature adult cells and instead these differentiated cells often resemble their fetal counterparts (Hrvatin et al., 2014).”
From Multi-omic rejuvenation of human cells by maturation phase transient reprogramming (2022) · cites this paper as Hrvatin et al., 2014
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“The PluriTest assay may prove to be valuable for this purpose.(306,307) Ultimately, a fully terminally differentiated purified cell population may have an extremely low teratoma risk profile, but determining this preclinically for a given cell population would have merit.”
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LIM domain–binding 1 maintains the terminally differentiated state of pancreatic β cells
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“On the contrary, currently available pancreatic b cell differentiation protocols are often unable to generate functional 202 iScience 16, 192–205, June 28, 2019 b cells in vitro and require transplantation into mice for in vivo maturation (Hrvatin et al., 2014; Loo et al., 2018).”
BackgroundThe Importance of Proper Oxygenation in 3D Culture
Tse, H., Gardner, G., Domínguez-Bendala, J., & Fraker, C. (2021) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2021.634403 · Cited by 54
Ramond, C., Glaser, N., Berthault, C., Ameri, J., Kirkegaard, J. S., Hansson, M., Honoré, C., Semb, H., & Scharfmann, R. (2017) · eLife · doi:10.7554/elife.27564 · Cited by 54
“This is the case for hepatocytes (Baxter et al., 2015), cardiomyocytes (Karakikes et al., 2015), neurons (Playne and Connor, 2017) and pancreatic beta cells (Hrvatin et al., 2014).”
BackgroundJohnson, J. D. (2016) · Diabetologia · doi:10.1007/s00125-016-4059-4 · Cited by 56
Oshima, M., Pechberty, S., Bellini, L., Göpel, S., Campaña, M. B., Rouch, C., Dairou, J., Cosentino, C., Fantuzzi, F., Toivonen, S., et al. (2019) · Diabetologia · doi:10.1007/s00125-019-05046-x · Cited by 56
Pancreatic islet cell development and regeneration
Romer, A. I., & Sussel, L. (2015) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000174 · Cited by 57
Protecting Stem Cell Derived Pancreatic Beta-Like Cells From Diabetogenic T Cell Recognition
Castro-Gutiérrez, R., Alkanani, A. K., Mathews, C. E., Michels, A. W., & Russ, H. A. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.707881 · Cited by 60
“It is intriguing to speculate that sBC, which have been proposed to closer resemble fetal rather than adult beta cells (31), might display an immature immune profile when challenged.”
BackgroundIslet 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 58
“However, in these previous studies, the immaturity of sc-β cells, as demonstrated by the poor glucose responsiveness, polyhormonal signatures, and preferential commitment of the polyhormonal cells to α instead of β cells, has been reported (Kelly et al., 2011; Basford et al., 2012; Rezania et al., 2013; Bruin et al.,…”
BackgroundResultShaping Pancreatic β-Cell Differentiation and Functioning: The Influence of Mechanotransduction
Galli, A., Marku, A., Marciani, P., Schulte, C., Lenardi, C., Paolo, M., Maffioli, E., Tedeschi, G., & Perego, C. (2020) · Cells · doi:10.3390/cells9020413 · Cited by 51
Beamish, C. A., Strutt, B. J., Arany, E. J., & Hill, D. J. (2016) · Islets · doi:10.1080/19382014.2016.1162367 · Cited by 48
A Stem Cell Approach to Cure Type 1 DiabetesPreprint
Helman, A., & Melton, D. A. (2020) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a035741 · Cited by 56
Self-citationConcise Review: Human Pluripotent Stem Cells for the Modeling of Pancreatic β‐Cell Pathology
Balboa, D., Saarimäki-Vire, J., & Otonkoski, T. (2018) · Stem Cells · doi:10.1002/stem.2913 · Cited by 48
Aguayo-Mazzucato, C., DiIenno, A. R., Hollister-Lock, J., Cahill, C., Sharma, A. J., Weir, G., Colton, C., & Bonner-Weir, S. (2015) · Journal of Clinical Endocrinology and Metabolism · doi:10.1210/jc.2015-2632 · Cited by 47
Advances and challenges in the differentiation of pluripotent stem cells into pancreatic β cells.
Abdelalim, E. M., & Emara, M. (2015) · World Journal of Stem Cells · doi:10.4252/wjsc.v7.i1.174 · Cited by 47
ENTPD3 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 70
“Furthermore, we confirm the existence of previously described fetal-like sBC and sBC with cohormone transcript expression (37) and a small subpopulation of proliferating sBC (38).”
BackgroundMutations and variants of ONECUT1 in diabetes
Philippi, A., Heller, S., Costa, I. G., Senée, V., Breunig, M., Li, Z., Kwon, G., Russell, R., Illing, A., Lin, Q., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01502-7 · Cited by 57
Higuchi, A., Kumar, S. S., Ling, Q., Alarfaj, A. A., Munusamy, M. A., Murugan, K., Hsu, S.-T., Benelli, G., & Umezawa, A. (2016) · Progress in Polymer Science · doi:10.1016/j.progpolymsci.2016.09.002 · Cited by 57
Chmielowiec, J., Szlachcic, W. J., Yang, D., Scavuzzo, M. A., Wamble, K., Sarrion-Perdigones, A., Sabek, O., Venken, K., & Borowiak, M. (2022) · Nature Communications · doi:10.1038/s41467-022-29646-1 · Cited by 43
(Re)generating Human Beta Cells: Status, Pitfalls, and Perspectives
Baeyens, L., Lemper, M., Staels, W., Groef, S. D., Leu, N. D., Heremans, Y., German, M. S., & Heimberg, H. (2018) · Physiological Reviews · doi:10.1152/physrev.00034.2016 · Cited by 52
Kassem, D., Kamal, M. M., El-Kholy, A., & El-Mesallamy, H. (2016) · Stem cell research & therapeutics · doi:10.1186/s13287-016-0374-4 · Cited by 43
“Nevertheless, despite all of the vigorous efforts to generate mature functioning β cells from MSCs or even other types of stem cells, the majority of the obtained IPCs mostly fail to properly secrete insulin in response to glucose, and the reason for such anomalies together with the mechanisms through which differenti…”
BackgroundBlanchi, B., Taurand, M., Sauty-Colace, C., Thomaidou, S., Audeoud, C., Fantuzzi, F., Sawatani, T., Gheibi, S., Sabadell‐Basallote, J., Boot, F., et al. (2023) · Molecular Metabolism · doi:10.1016/j.molmet.2023.101772 · Cited by 55
“We next focused on 54 transcripts encoding proteins important for beta cell function (Figure 2D) [5,14,15].”
Characterization of stem-cell-derived islets during differentiation and after implantation
Cuesta-Gomez, N., Verhoeff, K., Jasra, I. T., Pawlick, R., Dadheech, N., & Shapiro, A. M. J. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111238 · Cited by 41
Coronnello, C., & Francipane, M. G. (2021) · Stem Cell Reviews and Reports · doi:10.1007/s12015-021-10302-y · Cited by 54
“In many cases, the progeny of iPSCs are comparable to an immature fetal stage [9–11].”
BackgroundMolecular and genetic regulation of pig pancreatic islet cell development
Kim, S., Whitener, R. L., Peiris, H. S., Gu, X., Chang, C., Lam, J. Y., Camuñas-Soler, J., Park, I., Bevacqua, R. J., Tellez, K., et al. (2020) · Development · doi:10.1242/dev.186213 · Cited by 41
“Transcriptome analysis described here provides evidence of genetic regulatory mechanisms and cell development in pigs that are also conserved in other mammals, including (1) cell typespecific expression of transcription factors (PDX1, MAFA, ARX, IRX, HHEX) and functional regulators (PCSK1, PCSK2, SLC2A2, SLC30A8, GLP1…”
BackgroundDye, B. R., Miller, A. J., & Spence, J. R. (2016) · Current Pathobiology Reports · doi:10.1007/s40139-016-0102-x · Cited by 46
Pancreatic Stem Cells Remain Unresolved
Jiang, F., & Morahan, G. (2014) · Stem Cells and Development · doi:10.1089/scd.2014.0214 · Cited by 40
The Vascularised Chamber as an In Vivo Bioreactor
Yap, K. K., Yeoh, G. C., Morrison, W. A., & Mitchell, G. M. (2018) · Trends in biotechnology · doi:10.1016/j.tibtech.2018.05.009 · Cited by 42
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 49
Khatib, M. E. E., Ohmine, S., Jacobus, E. J., Tonne, J. M., Morsy, S. G., Holditch, S., Schreiber, C. A., Uetsuka, K., Fusaki, N., Wigle, D., et al. (2016) · Stem Cells Translational Medicine · doi:10.5966/sctm.2015-0017 · Cited by 38
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 43
Modeling rare diseases with induced pluripotent stem cell technology
Anderson, R. H., & Francis, K. R. (2018) · Molecular and Cellular Probes · doi:10.1016/j.mcp.2018.01.001 · Cited by 46
Pancreas-on-a-Chip Technology for Transplantation Applications
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hPSC-derived organoids: models of human development and disease
Frum, T., & Spence, J. R. (2020) · Journal of Molecular Medicine · doi:10.1007/s00109-020-01969-w · Cited by 43
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From Genetic Association to Molecular Mechanisms for Islet-cell Dysfunction in Type 2 Diabetes
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Recent Advances in Cell Replacement Therapies for the Treatment of Type 1 Diabetes
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Human stem cell-based disease modeling: prospects and challenges
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Stem cells to restore insulin production and cure diabetes
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Transcriptional changes and the role of ONECUT1 in hPSC pancreatic differentiation
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Metadata
- Authors
- Hrvatin, S., O’Donnell, C. W., Deng, F., Millman, J. R., Pagliuca, F. W., DiIorio, P., Rezania, A., Gifford, D. K., & Melton, D. A.
- Affiliations
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute and
- Harvard University (US)
- University of Massachusetts Chan Medical School (US)
- Janssen Research & Development (United States) (US)
- MIT Computer Science and Artificial Intelligence Laboratory (US)
- Howard Hughes Medical Institute (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-02-10
- Volume
- 111
- Issue
- 8
- Pages
- 3038-3043
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3939927
- OpenAlex
- W2055001415
- Cited by
- 302
- References
- 0
- Citations by year
- 2026: 13 · 2025: 12 · 2024: 19 · 2023: 30 · 2022: 25 · 2021: 33 · 2020: 42 · 2019: 15 · 2018: 18 · 2017: 15 · 2016: 47 · 2015: 25 · 2014: 8
- FWCI
- 31.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (U01HL100408, 1U01HL10040804)
- National Institute of Diabetes and Digestive and Kidney Diseases (RL1DK081184, 2U01DK07247307, U01DK072473)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › 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
- human pluripotent stem cells, pancreatic beta cells, fetal pancreas, gene expression profiling, stem cell differentiation, beta cell maturation, islet transplantation, gene expression signatures
- MeSH terms
- Adult, Cell Differentiation, Fetus, Flow Cytometry, Humans, Pancreas, Gene Expression Profiling, Pluripotent Stem Cells, Microarray Analysis, Insulin-Secreting Cells
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