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
Assessment of different strategies for scalable production and proliferation of human myoblasts
Min‐Wen, J. C., Yildirim, E. D., Jun‐Hao, E. T., Chua, B. Y.-J., Low, S. M. C., Ding, S. L. S., Li, C., Jiang, Z., Teh, B. T., Yu, K., et al. (2019) · Cell Proliferation · doi:10.1111/cpr.12602 · Cited by 16
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β‐Cell replacement as a treatment for type 1 diabetes: an overview of possible cell sources and current axes of research
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Statistical approaches and software for clustering islet cell functional heterogeneity
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Regenerative Medicine in Diabetes
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Islets in the body are never flat: transitioning from two-dimensional (2D) monolayer culture to three-dimensional (3D) spheroid for better efficiency in the generation of functional hPSC-derived pancreatic β cells in vitro
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“recapitulate the complexity of the pancreas niche in vivo [28, 29] when compared to the three-dimensional culture (3D).”
Background
Developmentally-Inspired Biomimetic Culture Models to Produce Functional Islet-Like Cells From Pluripotent Precursors
Tran, R., Moraes, C., & Hoesli, C. A. (2020) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2020.583970 · Cited by 19
“The average diameter of human islets is around 100–400 µm (Hellman, 1959; Suszynski et al., 2014; Ionescu-Tirgoviste et al., 2015).”
Background
Preferential gene expression and epigenetic memory of induced pluripotent stem cells derived from mouse pancreas
Nukaya, D., Minami, K., Hoshikawa, R., Yokoi, N., & Seino, S. (2015) · Genes to Cells · doi:10.1111/gtc.12227 · Cited by 14
Non-coding genome functions in diabetes
Cebola, I., & Pasquali, L. (2015) · Journal of Molecular Endocrinology · doi:10.1530/jme-15-0197 · Cited by 25
“Similarly to many other human diseases, it is now possible to generate iPSC from diabetic patients (Maehr et al. 2009, Kudva et al. 2012, Hua et al. 2013, Teo et al. 2013, Thatava et al. 2013).”
Background
Two decades of induced pluripotent stem cell research: From discovery to diverse applications
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Advances in Understanding the Mechanism of Transitional Neonatal Hypoglycemia and Implications for Management
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Temporal Transcriptome Analysis Reveals Dynamic Gene Expression Patterns Driving β-Cell Maturation
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Airway and Alveoli Organoids as Valuable Research Tools in COVID-19
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In Vivo and In Vitro Models of Diabetes: A Focus on Pregnancy
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“To try and counteract this problem, cell sorting is typically performed [79]; however, this relies on a suitable marker being available.”
Background
Association of expression levels of pluripotency/stem cell markers with the differentiation outcome of Wharton's jelly mesenchymal stem cells into insulin producing cells.
Kassem, D., Kamal, M. M., El-Kholy, A., & El-Mesallamy, H. (2016) · Biochimie · doi:10.1016/j.biochi.2016.05.019 · Cited by 12
“properly secrete insulin in response to glucose, and the reason for such anomalies, together 82 with the mechanisms through which differentiation occurs are far from complete 83 elucidation [24].”
Background
V-Maf Musculoaponeurotic Fibrosarcoma Oncogene Homolog A Synthetic Modified mRNA Drives Reprogramming of Human Pancreatic Duct-Derived Cells Into Insulin-Secreting Cells
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Han, J., Lim, D., & Yang, K. (2025) · Journal of Tissue Engineering · doi:10.1177/20417314251373039 · Cited by 8
“28,29”
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Movasat, H., Giacopino, E., Shahdoost, A., Nokoorani, Y. D., Abrbekouh, A. H., Tahamtani, Y., & Shakiba, N. (2025) · Cell Systems · doi:10.1016/j.cels.2025.101300 · Cited by 15
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Chen, J., Lu, J., Wang, S., & Miao, C. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1366417 · Cited by 12
Permanent neonatal diabetes-causing insulin mutations have dominant negative effects on beta cell identity
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“However, some transcriptional similarities have been identified between PSC-derived β-cells and human foetal β-cells, which may explain a relative immaturity of PSC-derived β-cells [165].”
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Cell Therapy for Type 1 Diabetes: From Islet Transplantation to Stem Cells
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“Current protocols for hESC and hiPSC differentiation are widely acknowledged to yield cells of fetal phenotype (e.g. Hrvatina et al., 2014; van den Heuvel et al., 2014) which may not provide optimal cells for therapy in adult tissue.”
Background
Genome-edited human stem cell-derived beta cells: a powerful tool for drilling down on type 2 diabetes GWAS biology
Beer, N. L., & Gloyn, A. L. (2016) · F1000Research · doi:10.12688/f1000research.8682.1 · Cited by 11
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In Vitro Disease Models of the Endocrine Pancreas
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Background
Transcriptional profiling and functional network analyses of islet-like clusters (ILCs) generated from pancreatic stem cells in vitro
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Reprogramming of Human Pancreatic Organoid Cells into Insulin-Producing β-Like Cells by Small Molecules and in Vitro Transcribed Modified mRNA Encoding Neurogenin 3 Transcription Factor
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“These cells also had a limited insulin expression capacity in comparison with adult human islets, were polyhormonal, glucose unresponsive and displayed reduced expression of some of the key β-cell transcription factors (Rezania et al., 2012; Bruin et al., 2014; Hrvatin et al., 2014).”
Background
The Nexus of Stem Cell-Derived Beta-Cells and Genome Engineering
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Background
A ONECUT1 regulatory, non-coding region in pancreatic development and diabetes
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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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