Functional, metabolic and transcriptional maturation of human pancreatic islets derived from stem cells
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Abstract
Transplantation of pancreatic islet cells derived from human pluripotent stem cells is a promising treatment for diabetes. Despite progress in the generation of stem-cell-derived islets (SC-islets), no detailed characterization of their functional properties has been conducted. Here, we generated functionally mature SC-islets using an optimized protocol and benchmarked them comprehensively against primary adult islets. Biphasic glucose-stimulated insulin secretion developed during in vitro maturation, associated with cytoarchitectural reorganization and the increasing presence of alpha cells. Electrophysiology, signaling and exocytosis of SC-islets were similar to those of adult islets. Glucose-responsive insulin secretion was achieved despite differences in glycolytic and mitochondrial glucose metabolism. Single-cell transcriptomics of SC-islets in vitro and throughout 6 months of engraftment in mice revealed a continuous maturation trajectory culminating in a transcriptional landscape closely resembling that of primary islets. Our thorough evaluation of SC-islet maturation highlights their advanced degree of functionality and supports their use in further efforts to understand and combat diabetes.
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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 [43]
In Results (‘SC-islets present organotypic cytoarchitecture and function’), Balboa et al. report SC-EC cells in islets made with their optimized protocol. In Results (‘SC-islets transcriptionally mature in vitro and in vivo’), they compare those cells with SC-EC cells identified by Veres et al., supporting identification by more than one group using different protocols. Methods lists several stem cell lines used in the study, but the passages do not establish that SC-EC cells were identified in islets from each line. (LLM, conf=0.82)
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 [43]
The Results section, “SC-islets transcriptionally mature in vitro and in vivo” (page unavailable), reports that IAPP rose upon engraftment and MAFA rose six months after engraftment; it also reports an increasing proportion of cells in more mature β-cell categories. But INS and G6PC2 increased early in vitro, not specifically after transplantation. The cited passages do not report post-transplant upregulation of MNX1 or an increased proportion of cells expressing each listed marker. (LLM, conf=0.89)
Experimental — accuracy not yet measuredTransplantation of SC-islets into mice improves their insulin secretion and glucose responsiveness, suggesting that SC-islet immaturity can be resolved.
“Transplantation of SC-islets into mice improves their insulin secretion and glucose responsiveness, suggesting that SC-islet immaturity can be resolved.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [43]
The Results section, “SC-islets control the glycemia of mice in vivo” (page unavailable), reports glucose-regulated insulin secretion after engraftment, with higher C-peptide levels and faster glucose clearance for grafts matured longer in vitro. The Discussion (page unavailable) reports continued maturation after engraftment, but does not establish that transplantation itself improved insulin secretion or fully resolved SC-islet immaturity. (LLM, conf=0.84)
Experimental — accuracy not yet measuredTranscriptional 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 [43]
The Results section reports that MAFA was sharply upregulated at six months postengraftment, supporting the claim that it took months. It says G6PC2 increased early in in vitro culture, not shortly after transplantation, although it also reports further upregulation following engraftment without specifying when that occurred. (LLM, conf=0.88)
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 [43]
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
These SC-β cells have been shown to improve glycemic control in diabetic mice.
“These cells have been shown to improve glycemic control in diabetic mice, highlighting their potential utility in vivo.36,37,39–44”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [43]
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 [43]
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 [43]
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.
“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 [43]
Despite transcriptional improvements, SC-islets nonetheless had significantly reduced activity of metabolic pathways compared to primary islets.
“Despite transcriptional improvements, SC-islets nonetheless had significantly reduced activity of metabolic pathways compared to primary islets.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [43]
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- Authors
- Balboa, D., Barsby, T., Lithovius, V., Saarimäki-Vire, J., Omar-Hmeadi, M., Dyachok, O., Montaser, H., Lund, P.-E., Yang, M., Ibrahim, H., Näätänen, A., Chandra, V., Vihinen, H., Jokitalo, E., Kvist, J., Ustinov, J., Nieminen, A. I., Kuuluvainen, E., Hietakangas, V., Katajisto, P., Lau, J., Carlsson, P.-O., Barg, S., Tengholm, A., & Otonkoski, T.
- Affiliations
- University of Helsinki (FI)
- Uppsala University (SE)
- Institute for Molecular Medicine Finland (FI)
- Corresponding author
- Otonkoski, Timo
- ORCID
- Balboa, Diego
- Barsby, Tom
- Lithovius, Väinö
- Saarimäki-Vire, Jonna
- Omar-Hmeadi, Muhmmad
- Dyachok, Oleg
- Montaser, Hossam
- Lund, Per-Eric
- Yang, Mingyu
- Ibrahim, Hazem
- Chandra, Vikash
- Vihinen, Helena
- Jokitalo, Eija
- Kvist, Jouni
- Nieminen, Anni I.
- Kuuluvainen, Emilia
- Hietakangas, Ville
- Katajisto, Pekka
- Lau, Joey
- Carlsson, Per-Ola
- Barg, Sebastian
- Tengholm, Anders
- Otonkoski, Timo
- Venue
- Nature Biotechnology
- Published
- 2022-03-03
- Volume
- 40
- Issue
- 7
- Pages
- 1042-1055
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC9287162
- OpenAlex
- W4214950345
- Cited by
- 433
- References
- 106
- Citations by year
- 2026: 95 · 2025: 96 · 2024: 113 · 2023: 88 · 2022: 35 · 2021: 4 · 2020: 1
- FWCI
- 81.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Biotechnology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
- Työväentutkimus Vuosikirja (submittedVersion)
- Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by)
- Funders
- Leona M. and Harry B. Helmsley Charitable Trust (115797)
- European Federation of Pharmaceutical Industries and Associations (115797)
- University of Alberta
- Academy of Finland (297466, 312437)
- Novo Nordisk
- Vetenskapsrådet
- Barndiabetesfonden
- Sigrid Juséliuksen Säätiö
- Stiftelsen Familjen Ernfors Fond
- Novo Nordisk Fonden (NNF20OC0063654, NNF15OC0016260, NNF20OC0064000, NNF19OC0057286, NNF18OC0034450, NNF14OC0010001, NNF17OC0027344)
- Innovative Medicines Initiative (115797], 945268)
- Diabetes Wellness Suomi Säätiö
- Biocenter Finland
- Helsinki Institute of Life Science, Helsingin Yliopisto
- 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
- islet maturation, diabetes mellitus, glucose-stimulated insulin secretion, alpha cells, exocytosis, glycolytic metabolism, single-cell transcriptomics, islet engraftment, islet transplantation, pluripotent stem cells
- MeSH terms
- Animals, Glucose, Humans, Insulin, Islets of Langerhans, Islets of Langerhans Transplantation, Pluripotent Stem Cells, Mice
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