Single-Cell Transcriptome Profiling Reveals β Cell Maturation in Stem Cell-Derived Islets after Transplantation
Open accessAbstract
Human pluripotent stem cells differentiated to insulin-secreting β cells (SC-β cells) in islet organoids could provide an unlimited cell source for diabetes cell replacement therapy. However, current SC-β cells generated in vitro are transcriptionally and functionally immature compared to native adult β cells. Here, we use single-cell transcriptomic profiling to catalog changes that occur in transplanted SC-β cells. We find that transplanted SC-β cells exhibit drastic transcriptional changes and mature to more closely resemble adult β cells. Insulin and IAPP protein secretions increase upon transplantation, along with expression of maturation genes lacking with differentiation in vitro, including INS, MAFA, CHGB, and G6PC2. Other differentiated cell types, such as SC-α and SC-enterochromaffin (SC-EC) cells, also exhibit large transcriptional changes. This study provides a comprehensive resource for understanding human islet cell maturation and provides important insights into maturation of SC-β cells and other SC-islet cell types to enable future differentiation strategy improvements.
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Transcriptional changes after transplantation appeared to occur temporally, as some genes (e.g., G6PC2) increased in expression shortly after transplantation, while others (e.g., MAFA) took several months to upregulate.
“These transcriptional changes appeared to occur temporally, as some genes (e.g., G6PC2) increased in expression shortly after transplantation, while others (e.g., MAFA) took several months to upregulate.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [51]
The Results section (‘SC-β Cells Mature within Transplanted Grafts’; page unavailable) reports that both G6PC2 and MAFA increase after transplantation and with pseudotime. The Discussion says some maturation genes are expressed before MAFA in pseudotime, but does not identify G6PC2 as one of them. Pseudotime does not establish that G6PC2 rose shortly after transplantation or that MAFA took several months to rise. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThis differentiation methodology takes approximately a month or more to complete, and functional maturation can continue for months once the cells are transplanted in vivo.
“This differentiation methodology takes approximately a month or more to complete, and functional maturation can continue for months once the cells are transplanted in vivo.43,51”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [51]
The Results (Retrieval and Identification of SC-Islet Cell Populations after Transplantation; page unavailable) report improved glucose regulation after four weeks, further reversal of diabetes at six months, and increasing glucose-stimulated human C-peptide secretion. This supports functional maturation over months after transplantation. The Methods (Stem cell-derived β Cell differentiation; page unavailable) describe a six-stage protocol and transplantation on days 13–16 of stage 6, but do not establish that the full differentiation takes a month or more. (LLM, conf=0.86)
Experimental — accuracy not yet measuredKnown markers of β cell maturation, such as INS, MAFA, IAPP, MNX1, and G6PC2, became more highly expressed in a greater proportion of SC-islet cells after transplantation.
“Specifically, known markers of β cell maturation, such as INS, MAFA, IAPP, MNX1, and G6PC2, became more highly expressed in a greater proportion of SC-islet cells after transplantation.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [51]
In Results, “SC-β Cells Mature within Transplanted Grafts” (page unavailable), the paper reports higher expression in a greater fraction of grafted SC-β cells for INS, MAFA, MNX1, and G6PC2. It also reports increased IAPP transcript after transplantation, but does not explicitly say IAPP was expressed in a greater fraction of cells. The finding is specific to SC-β cells, rather than SC-islet cells generally. (LLM, conf=0.83)
Experimental — accuracy not yet measuredSC-EC cells persisted after transplantation and exhibited increased expression of key gene markers of their identity, such as TPH1.
“Interestingly, SC-EC cells also persisted after transplantation and exhibited increased expression of key gene markers of their identity, such as TPH1.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [51]
The Results section, “Transcriptional Changes of EC Cells within Transplanted Grafts” (page unavailable), says SC-EC cells continue to exist after transplantation and lists several EC-cell genes that are upregulated. It says TPH1 protein is expressed after transplantation, but does not say TPH1 gene expression increased. (LLM, conf=0.86)
Experimental — accuracy not yet measuredComparison of scRNA-seq and snATAC-seq data from transplanted SC-islets and primary islets has indicated that SC-islets become more similar to human islets over time in vivo in terms of both their transcriptional and chromatin accessibility profiles, though some important differences still remain.
“Overall, comparison of scRNA-seq and snATAC-seq data from transplanted SC-islets and primary islets has indicated that SC-islets become more similar to human islets overtime in vivo in terms of both their transcriptional and chromatin accessibility profiles, though some important differences still remain.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [51]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
Hepatic, 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 [51]
The Results section, “Retrieval and Identification of SC-Islet Cell Populations after Transplantation” (page unavailable), reports exocrine cells among the cell types found in SC-islet samples. The passages from our copy do not identify hepatic or mesenchyme cells as off-targets; searches for “hepatic” and “mesenchyme” found no supporting passage. (LLM, conf=0.86)
Experimental — accuracy not yet measuredRecent 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 [51]
scRNA-seq analysis of transplanted SC-islets revealed that improved function corresponded with transcriptional maturation.
“scRNA-seq analysis of transplanted SC-islets revealed that improved function corresponded with transcriptional maturation.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [51]
SC-EC cells have been subsequently identified in SC-islets generated from various differentiation protocols and stem cell lines by multiple groups.
“These cells have been subsequently identified in SC-islets generated from various differentiation protocols and stem cell lines by multiple groups.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [51]
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- Authors
- Augsornworawat, P., Maxwell, K. G., Velazco-Cruz, L., & Millman, J. R.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Millman, Jeffrey R.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2020-08
- Volume
- 32
- Issue
- 8
- Pages
- 108067
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC7491368
- OpenAlex
- W3080955168
- Cited by
- 200
- References
- 51
- Citations by year
- 2026: 27 · 2025: 36 · 2024: 42 · 2023: 36 · 2022: 31 · 2021: 26 · 2020: 2
- FWCI
- 21.70
- Type
- journal article
- Language
- en
- Update notices
- erratum (2021-03-09)
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Foundation for Barnes-Jewish Hospital (UL1TR000448, P30CA91842, T32DK108742)
- Juvenile Diabetes Research Foundation International (5-CDA-2017-391-A-N)
- University of Washington
- National Institutes of Health (P30CA91842, T32DK108742, UL1TR000448, 5R01DK114233)
- Juvenile Diabetes Research Foundation United States of America
- Topics
- Health Sciences › Medicine › Surgery › 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
- beta cell maturation, stem cell-derived islets, islet organoids, human pluripotent stem cells, transplantation, single-cell transcriptomics, insulin secretion, amylin, MafA, G6PC2, alpha cells, enterochromaffin cells, islet differentiation
- MeSH terms
- Animals, B-Lymphocytes, Humans, Islets of Langerhans, Islets of Langerhans Transplantation, Gene Expression Profiling, Pluripotent Stem Cells, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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