Charting cellular identity during human in vitro β-cell differentiation
Open accessAbstract
In vitro differentiation of human stem cells can produce pancreatic β-cells; the loss of this insulin-secreting cell type underlies type 1 diabetes. Here, as a step towards understanding this differentiation process, we report the transcriptional profiling of more than 100,000 human cells undergoing in vitro β-cell differentiation, and describe the cells that emerged. We resolve populations that correspond to β-cells, α-like poly-hormonal cells, non-endocrine cells that resemble pancreatic exocrine cells and a previously unreported population that resembles enterochromaffin cells. We show that endocrine cells maintain their identity in culture in the absence of exogenous growth factors, and that changes in gene expression associated with in vivo β-cell maturation are recapitulated in vitro. We implement a scalable re-aggregation technique to deplete non-endocrine cells and identify CD49a (also known as ITGA1) as a surface marker of the β-cell population, which allows magnetic sorting to a purity of 80%. Finally, we use a high-resolution sequencing time course to characterize gene-expression dynamics during the induction of human pancreatic endocrine cells, from which we develop a lineage model of in vitro β-cell differentiation. This study provides a perspective on human stem-cell differentiation, and will guide future endeavours that focus on the differentiation of pancreatic islet cells, and their applications in regenerative medicine.
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SC-EC cells were identified, are absent from primary human islets, and resemble an endocrine cell type normally found in the intestines.
“One of the most interesting findings from these scRNA-seq studies was the identification of SC-EC cells, which are absent from primary human islets and resemble an endocrine cell type normally found in the intestines.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [47]
The SC-islets and SC-EC cells sections identify SC-EC cells and describe their resemblance to gut enterochromaffin cells. The Discussion says enterochromaffin cells have not previously been observed in studies of human islets, but also notes rare evidence suggesting resident pancreatic enterochromaffin cells; it does not establish that they are categorically absent from primary human islets. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCurrent protocols also produce a significant percentage of stem cell-derived enterochromaffin cells (SC-ECs), which resemble a type of intestinal endocrine.
“Current protocols also produce a significant percentage of stem cell-derived enterochromaffin cells (SC-ECs), which resemble a type of intestinal endocrine.47”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [47]
The ‘SC-islets contain four major cell types’ section identifies SC-EC cells as a major population in both modified protocols and says they most resemble enterochromaffin cells. The ‘SC-EC cells’ section suggests their presence in other β-cell protocols, but does not establish that those protocols produce a significant percentage of them. (LLM, conf=0.82)
Experimental — accuracy not yet measuredSC-EC cells are characterized by the expression of enterochromaffin gene markers, such as TPH1 and LMX1A, as well as the secretion of serotonin rather than insulin.
“These cells are characterized by the expression of enterochromaffin gene markers, such as TPH1 and LMX1A, as well as the secretion of serotonin rather than insulin.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [47]
The “SC-EC cells” section reports TPH1 and LMX1A expression, serotonin content, and serotonin release from SC-islets; Extended Data Fig. 5 describes SC-EC cells as secreting serotonin. But the paper also reports low levels of insulin in SC-EC cells and does not establish that these cells secrete serotonin instead of insulin. (LLM, conf=0.86)
Experimental — accuracy not yet measuredHepatic, mesenchyme, and pancreatic exocrine cells are possible off-targets reported from SC-islet differentiations.
“Hepatic, mesenchyme, and pancreatic exocrine are also possible off-targets reported from SC-islet differentiations47,51,75”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [47]
The “Fates of non-endocrine cells” section (page unavailable) reports cells differentiating toward pancreatic exocrine fates and populations expressing mesenchymal markers during SC-islet differentiation. It does not report hepatic off-target cells, so this source supports only part of the list. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn subsequent stages, high expression of PDX1 in combination with expression of NKX6-1 and PTF1A was predictive of endocrine induction potential.
“In subsequent stages, high expression of PDX1 in combination with expression of NKX6-1 and PTF1A was predictive of endocrine induction potential.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [47]
Current differentiation methodologies still produce off-target cell types, notably cells that resemble a type of intestinal endocrine called the enterochromaffin cell.
“Furthermore, the current differentiation methodologies still produce off-target cell types, notably cells that resemble a type of intestinal endocrine called the enterochromaffin cell.47”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [47]
After sequencing 40,444 cells during the second half of SC-islet differentiation, the first study reported a mostly homogeneous population of PDX1+ progenitors at the end of stage 3.
“After sequencing 40,444 cells during the second half of SC-islet differentiation, the first study reported a mostly homogeneous population of PDX1+ progenitors at end of stage 3.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [47]
Both scRNA-seq roadmaps detected significant cell diversification following the pancreatic progenitor stages.
“Interestingly, both scRNA-seq roadmaps detected significant cell diversification following the pancreatic progenitor stages.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [47]
Despite distinguishable differences in gene expression between SC-EC and SC-β cells, the two populations appear to have a relatively similar overall transcriptional profile.
“Despite distinguishable differences in gene expression between SC-EC and SC-β cells, the two populations appear to have a relatively similar overall transcriptional profile.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [47]
Recent advances in single-cell sequencing technologies have allowed for unprecedented characterization of these cells to further elucidate ways to refine SC-β cell differentiation strategies.
“and recent advances in single-cell sequencing technologies have allowed for unprecedented characterization of these cells to further elucidate ways to refine SC-β cell differentiation strategies.43,47,50,51”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [47]
Despite the use of different pluripotent stem cell lines and protocols, two scRNA-seq roadmaps observed well-known markers of pancreatic progenitors (e.g., PDX1, NKX6-1) during the middle stages of differentiation and islet-specific endocrine identity markers in their final cell populations.
“Despite the use of different pluripotent stem cell lines and protocols, both roadmaps observed well-known markers of pancreatic progenitors (e.g., PDX1, NKX6-1) during the middle stages of differentiation as well as islet-specific endocrine identity markers in their final cell populations (e.g., INS for β cells, GCG for α cells, SST for δ cells).”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [47]
The non-endocrine cell populations of ductal-like, acinar-like, and mesenchymal-like cells were derived from populations that retained expression of cell cycle-associated genes.
“Notably, the non-endocrine cell populations of ductal-like, acinar-like, and mesenchymal-like cells were derived from populations that retained expression of cell cycle-associated genes.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [47]
SC-β cells and off-target SC-EC cells appear to emerge from a common NEUROG3+ progenitor population.
“SC-β cells and off-target SC-EC cells appear to emerge from a common NEUROG3+ progenitor population.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [47]
SC-EC cells are one of the most common off-targets in SC-islet differentiation.
“In the context of SC-islet differentiation, SC-EC cells are one of the most common off-targets.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [47]
SC-EC cells may be detrimental to SC-β cell potency, but no safety issues have been reported to date.
“Fortunately, while they may be detrimental to SC-β cell potency,47 no safety issues have been reported to date.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [47]
SC-EC cells comprise a significant percentage of the final cell population in SC-islets but do not secrete insulin.
“Because SC-EC cells comprise a significant percentage of the final cell population in SC-islets but do not secrete insulin, differentiation efficiency and SC-islet insulin secretion on a per cell basis could be greatly improved by diverting these SC-EC cells toward a SC-β cell lineage during either the cell specification or maturation stages.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [47]
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- Authors
- Veres, A., Faust, A. L., Bushnell, H. L., Engquist, E. N., Kenty, J. H.-R., Harb, G., Poh, Y.-C., Sintov, E., Gürtler, M., Pagliuca, F. W., Peterson, Q. P., & Melton, D. A.
- Affiliations
- Harvard University (US)
- Semma Therapeutics (United States) (US)
- Mayo Clinic (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Melton, Douglas A.
- ORCID
- Venue
- Nature
- Published
- 2019-05-08
- Volume
- 569
- Issue
- 7756
- Pages
- 368-373
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6903417
- OpenAlex
- W2944658035
- Cited by
- 552
- References
- 9
- Citations by year
- 2026: 72 · 2025: 68 · 2024: 81 · 2023: 81 · 2022: 75 · 2021: 86 · 2020: 61 · 2019: 27
- FWCI
- 58.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of General Medical Sciences (T32GM007226)
- National Institute of Diabetes and Digestive and Kidney Diseases (UC4DK104159, UC4DK104165)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- beta cell differentiation, human stem cells, pancreatic endocrine cells, gene expression profiling, enterochromaffin cells, pancreatic exocrine cells, beta-cell identity, beta cell maturation, magnetic cell separation, gene expression dynamics, type 1 diabetes, regenerative medicine
- MeSH terms
- RNA-Seq, Animals, Cell Differentiation, Cell Separation, Humans, Insulin, Male, Stem Cells, Biomarkers, Cell Lineage, Integrin alpha1, Insulin-Secreting Cells, Mice, Single-Cell Analysis
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