Cited by 302Pancreatic function and diabetesPluripotent Stem Cells ResearchDiabetes and associated disorders

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Differentiated human stem cells resemble fetal, not adult, β cells

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Hrvatin, Sinisa, O’Donnell, Charles W., Deng, Francis, Millman, Jeffrey R., Pagliuca, Felicia Walton, DiIorio, Philip, Rezania, Alireza, Gifford, David K., Melton, Douglas A.·2014·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1400709111PMC PMC3939927

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Abstract

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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Background
How to build a human
Mellough, C. B., & Lako, M. (2016) · eLife · doi:10.7554/elife.19826 · Cited by 1
“However, these approaches have their limitations (Hrvatin et al., 2014; Patterson et al., 2012), and it is challenging to ensure that stem cells differentiate into completely mature tissues in vitro.”
Background
Stem cells and the pancreas: from discovery to clinical approach
Dessì, A., Marras, S., Locci, G., Magistris, A. D., Fanos, V., & Faa, G. (2016) · doi:10.7363/050130 · Cited by 1
“Dessì • Marras • Locci • De Magistris • Fanos • Faa To that end, a study conducted in 2013 [9] compared the transcriptome of HPSC-derived pancreatic cells produced in vitro with that of human fetal and adult beta cells.”
Result
Pluripotent Stem Cell-Derived Pancreatic β Cells: From In Vitro Maturation to Clinical Application
Abdelalim, E. M., & Emara, M. M. (2016) · Stem cell biology and regenerative medicine · doi:10.1007/978-3-319-33270-3_6 · Cited by 1
Protective IFIH1 variant reduces islet stress and dysfunction in a type 1 diabetes genetic background
Veronese-Paniagua, D., Banks, C. E., Bradley, K., Mukherjee, N., Gale, S. E., Hinshaw, K. E., Meacham, A. M., Iwaloye, O. F., Tse, H. M., Mathews, C. E., et al. (2026) · iScience · doi:10.1016/j.isci.2026.117560
“89, 92 future studies utilizing longitudinal”
Self-citation
The comparative cell physiology of stem cell-derived and primary human β cells
Maghera, J., Chu, C. M. J., Schaaf, C., Bruin, J. E., Johnson, J. D., Lynn, F. C., & MacDonald, P. E. (2026) · Nature Reviews Endocrinology · doi:10.1038/s41574-026-01295-0 · Cited by 1
Physical and Biochemical Determinants of Endocrine Fate in 3D Suspension Culture Based Stem Cell-Derived β-Cell Differentiation
Castro-Gutiérrez, R., Shilleh, A. H., Barra, J. M., Williams, S. P. M., Nedumaran, B., Triolo, T. M., Hebrok, M., & Russ, H. A. (2026) · Cells · doi:10.3390/cells15171600
“Despite these successes, current differentiation protocols remain limited by incomplete β -cell generation and the frequent emergence of off-target cell types [7,10–12].”
Immune cell development from human pluripotent stem cells
Cruz, L. S., Castañeda, A. R., Srisantitham, J., & Kaufman, D. S. (2026) · Stem Cells · doi:10.1093/stmcls/sxag048
MAFB in Pancreatic β-Cell Development and Dysfunction: Implications for Diabetes and Translational Applications
Mu-u-min, R., Diané, A., & Al-Siddiqi, H. (2026) · Biomolecules · doi:10.3390/biom16081076
“In addition to the differences in rodent vs. human expression of MafA/MafB, it is also important to note that immortalized cell lines and stem-cell-derived β -like cells may not fully recapitulate the functional and transcriptional complexity of mature human islets [35,36].”
Development and trend of stem cell therapy for diabetes: a comprehensive review based on knowledge visualization
Huang, X., chen, Q., & Lü, H. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1856373
Mitochondrial development and remodeling occur at pancreatic progenitor stage during induction of stem cell-derived islet organoids
Diané, A., Mu-u-min, R., Al-Shukri, N. A., Nour‐Eldine, W., & Al-Siddiqi, H. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1795738 · Cited by 1
“…ef ﬁ ciency of differentiation protocols, hPSC-derived b -like cells generated in vitro exhibit suboptimal glucose-stimulated insulin secretion (GSIS) when compared with primary human islets (9), suggesting the generation of immature organoids that may resemble fetal, not adult b -cells (42, 43).”
Metabolic Maturation and Clinical Translation of Stem Cell-Derived β-Cells in Diabetes Therapy
Serdah, R., & Gallicchio, V. S. (2026) · Journal of Regenerative Medicine and Biology Research · doi:10.46889/jrmbr.2026.7108
DBSOMA: A Machine Learning Method that Identifies Chemical Modulators of Transcriptional States Uncovers Effectors of Beta-Cell MaturationPreprint
Kunz, T. R., & Rivera-Feliciano, J. (2026) · bioRxiv · doi:10.64898/2026.01.30.701818
Endocrine-disrupting chemical exposure during differentiation alters the proliferation–maturation balance in stem-cell islets
Gudmestad, J. H., Unger, L., Paulo, J. A., Ghila, L., & Legøy, T. A. (2025) · Toxicological Sciences · doi:10.1093/toxsci/kfaf163
“2E), like insulin ( INS ) and glucose-6-phosohatase catalytic subunit 2 ( G6PC2 ), or maturation like HOP Homeobox ( HOPX ) (Hrvatin et al. 2014; Balboa et al. 2022).”
Crosstalk between the aryl hydrocarbon receptor and hypoxia-inducible factor 1α pathways in human islet models
Gang, N., van Allen, K. A., Willmore, W. G., Lynn, F. C., & Bruin, J. E. (2025) · Islets · doi:10.1080/19382014.2025.2526871 · Cited by 3
Mechanism of trypsin-mediated differentiation of pancreatic progenitor cells into functional islet-like clusters
Gao, L., Lai, J.-S., Chen, H., Qian, L.-X., Hong, W.-J., & Li, L.-C. (2025) · World Journal of Diabetes · doi:10.4239/wjd.v16.i6.102727
“Although they secrete insulin, they do not have the function to respond to glucose stimulation, and complete endocrine function can be exerted only when they further mature to single-hormone-expressing cells[30].”
Diabetes current and future translatable therapies
Gonzalez-Sanchez, F. A., Sanchez-Huerta, T. M., Huerta-Gonzalez, A., Sepúlveda-Villegas, M., Altamirano, J., Aguilar-Aleman, J. P., & García‐Varela, R. (2024) · Endocrine · doi:10.1007/s12020-024-03944-8 · Cited by 1
“Furthermore, characteristics of the resulting cells resemble more those of fetal pancreatic stem cells than adult mature β -cells [98].”
De la biologie du développement à la thérapie cellulaire du diabète
Schreiber, V., & Gradwohl, G. (2023) · Médecine des Maladies Métaboliques · doi:10.1016/j.mmm.2023.05.009
“Les cellules bêta générées in vitro ont des caractéristiques de cellules embryonnaires ou néonatales (Hrvatin et al., 2014).”
Micro-RNA-124-5p promotes insulin producing cell differentiation through regulating transcriptional factor NKX6.1
Zhang, X., Shao, S.-J., Zhao, X., Zhang, M., & Wang, J.-B. (2022) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2022.101273
Direct reprogramming of human fibroblasts into insulin-producing cells by transcription factors
Fontcuberta-PiSunyer, M., García-Alamán, A., Prades, È., Téllez, N., Figueiredo, H., Fernández-Ruiz, R., Cervantes, S., Enrich, C., Clua, L., Ramón-Azcón, J., et al. (2021) · bioRxiv · doi:10.1101/2021.08.05.455196
Modelling late-onset diseases with induced pluripotent stem cells: a matter of time management
Cossins, C., & Fairchild, P. J. (2021) · Cell and Gene Therapy Insights · doi:10.18609/cgti.2021.015
“90 Subsequent studies have reported similar findings in cell types as diverse as pancreatic beta 91 cells and hepatocytes [20,21], suggesting that the progeny of hiPSC may perform functions 92 essential to the foetus rather than the adult.”
Background
The prolyl hydroxylase PHD3 maintains β-cell glucose metabolism during fatty acid excessPreprint
Nasteska, D., Cuozzo, F., Thakker, A., Bakar, R. B., Westbrook, R. L., Akerman, I., Cantley, J., Tennant, D., & Hodson, D. (2020) · bioRxiv · doi:10.1101/2020.04.30.068106
“(B) The ACACB promoter is regulated by multiple β-cell 824 transcription factors, with the presence of an antisense transcribed long non-coding RNA ( 825 detected data were also obtained from (35, 47, 48)).”
BackgroundMethod
Subcutaneous DL Technique Has Proven To Be an Adequate Host for Human Embryonic Stem Cells
Srinivas, A., Kumar, K. P., & Garrepally, P. (2019) · Stem cell Research and Therapeutics International · doi:10.31579/2643-1912/004
“In particular, research using insulin-producing cells derived from human embryonic stem cells (hESC) has shown very promising results in maturation yield and ultimately, in insulin secretion in response to adequate stimuli [3-6].”
Background
Gene Editing of Stem Cells to Model and Treat Disease
Hollywood, J. A., Sanz, D. J., Davidson, A. J., & Harrison, P. T. (2018) · Current Stem Cell Reports · doi:10.1007/s40778-018-0140-x
The role of transcription factor GATA6 in the development of the human pancreas
Chia, C. Y. (2018) · doi:10.17863/cam.18840
“…studies were succeeded by numerous modified variations of pancreatic differentiation protocols (Jiang et al., 2007a, Kroon et al., 2008, Zhang et al., 2009, Cai et al., 2010, Nostro et al., 2011, Loh et al., 2014, Pagliuca et al., 2014, Rezania et al., 2014, Russ et al., 2015, Cho et al., 2012).”
Background
Forcing alpha-cell-mediated beta-cell regeneration
Ben-Othman, N. (2015) · theses.fr (ABES) · doi:10.70675/376c5af0zd161z4a1ez92aez1b3746176067
“Besides, safety concerns due to inherent risks of teratoma formation originating from residual stem cells remain a major hurdle (Borowiak and Melton, 2009; Bruin et al., 2014; Hrvatin et al., 2014; McKnight et al., 2010; Pagliuca et al., 2014; Ricordi and Edlund, 2008; Van Hoof et al., 2009).”
Background
多能性幹細胞を用いた膵 β 細胞分化誘導研究の最新動向
髙橋, 禎., 武部, 貴., & 谷口, 英. (2014) · doi:10.11378/organbio.21.228
A demanding path from iPSCs toward pancreatic β- and α-cells
Marques, J. M., Nunes, R., Florindo, H. F., Ferreira, D., & Sarmento, B. F. C. C. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-822230-0.00002-8
Investigating the differentiation and functional maturation of stem cell-derived β cells
Velazco-Cruz, L. (2021) · Open Scholarship Institutional Repository (Washington University in St. Louis) · doi:10.7936/8q4b-x232
Stem Cell Applications in Metabolic Disorders: Diabetes Mellitus
Ahmed, S. M., Elshaboury, S. S., & El‐Badri, N. (2020) · Learning materials in biosciences · doi:10.1007/978-3-030-55359-3_6 · Cited by 1
Engraftment of Reprogrammed Human Bile Duct Cells Transiently Rescues Diabetes in Mice
Banga, A., Dutton, J., Mysz, M. A., Norris, B. J., Ogle, B., Tolar, J., Schumacher, R., & Flory, C. (2018) · Journal of Stem Cell Research & Therapy · doi:10.4172/2157-7633.1000432
Regenerative Medicine for Diabetes Treatment: New β-Cell Sources
Gasa, R., & Rovira, M. (2018) · Springer eBooks · doi:10.1007/978-3-319-90695-9_9
The Elusive Pancreatic Stem Cell
Braitsch, C. M., & Cleaver, O. B. (2015) · Stem cell biology and regenerative medicine · doi:10.1007/978-3-319-21705-5_6
A Perspective of Sensor-Augmented Insulin Pump Therapy in The Treatment of Type 1 Diabetes
Rayfield, E. J. (2014) · Endocrine Practice · doi:10.4158/ep14443.co

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)
ORCID: Deng, Francis
Millman, Jeffrey R.
Pagliuca, Felicia Walton
Gifford, David K.
Melton, Douglas A.
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
DOI: 10.1073/pnas.1400709111
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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Differentiated human stem cells resemble fetal, not adult, β cells

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