Transplantation of Human Pancreatic Endoderm Cells Reverses Diabetes Post Transplantation in a Prevascularized Subcutaneous Site
Open accessAbstract
Beta-cell replacement therapy is an effective means to restore glucose homeostasis in select humans with autoimmune diabetes. The scarcity of "healthy" human donor pancreata restricts the broader application of this effective curative therapy. "β-Like" cells derived from human embryonic stem cells (hESC), with the capacity to secrete insulin in a glucose-regulated manner, have been developed in vitro, with limitless capacity for expansion. Here we report long-term diabetes correction in mice transplanted with hESC-derived pancreatic endoderm cells (PECs) in a prevascularized subcutaneous site. This advancement mitigates chronic foreign-body response, utilizes a device- and growth factor-free approach, facilitates in vivo differentiation of PECs into glucose-responsive insulin-producing cells, and reliably restores glycemic control. Basal and stimulated human C-peptide secretion was detected throughout the study, which was abolished upon graft removal. Recipient mice demonstrated physiological clearance of glucose in response to metabolic challenge and safely retrieved grafts contained viable glucose regulatory cells.
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Implanting a device into the subcutaneous space one month prior to cell transplantation pre-vascularized the graft site and avoided the several week lag time for vascularization.
“For example, implanting a device into the subcutaneous space one month prior to cell transplantation pre-vascularized the graft site and avoided the several week lag time that it takes for vascularization to occur.145,151”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [151]
The Introduction describes temporarily implanting an angiocatheter to create a vascularized subcutaneous site before infusing the cell graft, and Experimental Procedures confirms that vascular catheters were used to prepare the site. Our copy does not specify implantation one month before transplantation or state that this avoided a several-week vascularization lag. (LLM, conf=0.84)
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Self-citationNijns, J. R., Mesmaeker, I. D., Suenens, K., Stangé, G., Groot, K. D., de Lima, M. M., Kraus, M., Keymeulen, B., Waelput, W., Thevissen, D. J.-T., et al. (2023) · Cell Transplantation · doi:10.1177/09636897231167323 · Cited by 6 · see citing works
Rickels, M. (2019) · Diabetes · doi:10.2337/dbi18-0054 · Cited by 6 · see citing works
A Gelatin Hydrogel Nonwoven Fabric Enhances Subcutaneous Islet Engraftment in Rats
Saito, R., Inagaki, A., Nakamura, Y., Imura, T., Kanai, N., Mitsugashira, H., Kumata, Y. E., Katano, T., Suzuki, S., Tokodai, K., et al. (2023) · Cells · doi:10.3390/cells13010051 · Cited by 6 · see citing works
Dadheech, N., Cuesta‐Gomez, N., Jasra, I. T., Verhoeff, K. K., Marfil‐Garza, B. A., Mouhammed, O., & Shapiro, A. M. J. (2022) · Journal of Immunology and Regenerative Medicine · doi:10.1016/j.regen.2022.100064 · Cited by 6 · see citing works
Self-citationVascular and immune interactions in islets transplantation and 3D islet models
Migliorini, A., & Nostro, M. C. (2024) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2024.102237 · Cited by 5 · see citing works
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Membrane bioreactors for bio-artificial pancreas
Jellali, R., Essaouiba, A., Leclerc, É., & Legallais, C. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-814225-7.00004-8 · Cited by 5 · see citing works
Subcutaneous angiogenesis induced by transdermal delivery of gel-in-oil nanogel dispersion
Zhang, Y., Fardous, J., Inoue, Y., Doi, R., Obata, A., Sakai, Y., Aishima, S., & Ijima, H. (2023) · Biomaterials Advances · doi:10.1016/j.bioadv.2023.213628 · Cited by 4 · see citing works
Gilglioni, E. H., Bansal, M., St‐Pierre‐Wijckmans, W., Talamantes, S., Kasarinaite, A., Hay, D. C., & Gurzov, E. N. (2025) · Obesity Reviews · doi:10.1111/obr.13899 · Cited by 4 · see citing works
Hydrogel-Composited Laminate for Islet Immune-Isolation to Treat Type 1 Diabetes
Wang, Y., Wang, K., Wang, X., Luo, Y., & Chen, H. (2024) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.3c12359 · Cited by 3 · see citing works
In Vivo Differentiation of Stem Cell-derived Human Pancreatic Progenitors to Treat Type 1 Diabetes
Maloy, M. H., Ferrer, M. A., & Parashurama, N. (2020) · Stem Cell Reviews and Reports · doi:10.1007/s12015-020-10018-5 · Cited by 3 · see citing works
Korbutt, G. S., & Pepper, A. R. (2021) · Transplantation · doi:10.1097/tp.0000000000003746 · Cited by 2 · see citing works
Self-citationMartinez-Garcia, F. D. (2022) · doi:10.33612/diss.242182725 · Cited by 3 · see citing works
Navigating challenges in human pluripotent stem cell-derived islet therapy for type 1 diabetes
Usama, M., Deng, Y., Chen, Y., Milland, T., Malleshaiah, M. K., & Aghazadeh, Y. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1625439 · Cited by 3 · see citing works
Pancreas and islet preservation
Papas, K. K., & León, H. D. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-814833-4.00042-3 · Cited by 2 · see citing works
Verhoeff, K. K., Marfil‐Garza, B. A., Cuesta‐Gomez, N., Jasra, I. T., Dadheech, N., & Shapiro, A. M. J. (2022) · Advances in experimental medicine and biology · doi:10.1007/5584_2022_711 · Cited by 1 · see citing works
Self-citationSaber, N., & Kieffer, T. J. (2023) · Springer eBooks · doi:10.1007/978-3-031-41943-0_4 · Cited by 1 · see citing works
Verhoeff, K. K., & Shapiro, A. M. J. (2024) · Springer eBooks · doi:10.1007/978-981-99-7119-0_18 · Cited by 1 · see citing works
Self-citationIslet Identity in Transplantation Procedures: The Intersection of Cellular Maturity and Function
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Human embryonic stem cells (hESC) as a source of insulin-producing cells
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Jacob, A., Southard, S. M., & Rust, W. (2020) · Current Transplantation Reports · doi:10.1007/s40472-020-00281-3
Transplantation: Pancreatic and Islet Cells
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Self-citationImmunoprotective Encapsulation of Micro-Organs
Assis, A., Sapozhnikov, L., Camargo, S., & Mitrani, E. (2019) · OBM Transplantation · doi:10.21926/obm.transplant.1903078
A preview of selected articles
Atkinson, S. P. (2020) · Stem Cells · doi:10.1002/stem.3172
Generation of pancreatic islets from stem cells
Soria-Juan, B., López‐Beas, J., Soria, B., & Hmadcha, A. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-818422-6.00036-8
Shevchenko, Y. L., & Григорьевич, Г. В. (2023) · Archives of Clinical and Medical Case Reports · doi:10.26502/acmcr.96550583
Verhoeff, K. K., & Shapiro, A. M. J. (2023) · Springer eBooks · doi:10.1007/978-981-99-0846-2_18-1
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Iworima, D. G., Baker, R. K., Ellis, C. E., Sherwood, C., Zhan, L., Rezania, A., Piret, J. M., & Kieffer, T. J. (2024) · Figshare · doi:10.6084/m9.figshare.26659423
Iworima, D. G., Baker, R. K., Ellis, C. E., Sherwood, C., Zhan, L., Rezania, A., Piret, J. M., & Kieffer, T. J. (2024) · Figshare · doi:10.6084/m9.figshare.26659420
Iworima, D. G., Baker, R. K., Ellis, C. E., Sherwood, C., Zhan, L., Rezania, A., Piret, J. M., & Kieffer, T. J. (2024) · Figshare · doi:10.6084/m9.figshare.26659426
Iworima, D. G., Baker, R. K., Ellis, C. E., Sherwood, C., Zhan, L., Rezania, A., Piret, J. M., & Kieffer, T. J. (2024) · Figshare · doi:10.6084/m9.figshare.26659435
Iworima, D. G., Baker, R. K., Ellis, C. E., Sherwood, C., Zhan, L., Rezania, A., Piret, J. M., & Kieffer, T. J. (2024) · Figshare · doi:10.6084/m9.figshare.26659432
Iworima, D. G., Baker, R. K., Ellis, C. E., Sherwood, C., Zhan, L., Rezania, A., Piret, J. M., & Kieffer, T. J. (2024) · Figshare · doi:10.6084/m9.figshare.26659414
Iworima, D. G., Baker, R. K., Ellis, C. E., Sherwood, C., Zhan, L., Rezania, A., Piret, J. M., & Kieffer, T. J. (2024) · Figshare · doi:10.6084/m9.figshare.26659429
Transplantation: Pancreatic and Islet Cells
Gamble, A., Bruni, A., & Shapiro, A. M. J. (2019) · Elsevier eBooks · doi:10.1016/b978-0-443-13825-6.00396-4
Self-citationBalboni, E., Campa‐Carranza, J. N., Bo, T., Rome, G. E., Seaborne, H., Venugopalan, A., Ouni, R., Paez‐Mayorga, J., Chua, C. Y. X., & Grattoni, A. (2026) · Biomedical Microdevices · doi:10.1007/s10544-026-00826-w · Cited by 1 · see citing works
Kuppan, P., Castro, C., Paramor, J., Waduthanthri, K. D., Cuesta‐Gomez, N., Bose, A. K., Ma, I., Rosko, M., Pepper, A. R., & Korbutt, G. S. (2026) · Diabetes · doi:10.2337/db26-0149
Self-citationMicroscale strategies in engineering the pancreas: Toward clinical translation.
Billaud, M., Campbell, B. E., Zhu, X., Ling, S.-D., Movasat, H., Li, C., Prezelj, D., Vdovenko, D., Shakiba, N., Hoesli, C. A., et al. (2026) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2026.115919
Stem Cell–Derived Islet Therapy for Type 1 Diabetes
Barsby, T., Balboa, D., & Otonkoski, T. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-11985-9.00025-1
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
Self-citation
- Authors
- Pepper, A. R., Pawlick, R., Bruni, A., Wink, J., Rafiei, Y., O’Gorman, D., Yan-Do, R., Gala-Lopez, B., Kin, T., MacDonald, P. E., & Shapiro, A. M. J.
- Affiliations
- University of Alberta (CA)
- Corresponding author
- Shapiro, A.M. James
- Venue
- Stem Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-06
- Volume
- 8
- Issue
- 6
- Pages
- 1689-1700
- ISSN
- 2213-6711 (ISSN-L)
- PMC
- PMC5470173
- OpenAlex
- W2621794998
- Cited by
- 96
- References
- 34
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 16 · 2023: 10 · 2022: 10 · 2021: 13 · 2020: 10 · 2019: 11 · 2018: 14 · 2017: 2
- FWCI
- 10.37
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Stem Cell Reports (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Canadian Institutes of Health Research
- Alberta Innovates - Health Solutions
- University of Alberta
- Canada Research Chairs
- 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
- human embryonic stem cells, beta cell replacement therapy, type 1 diabetes, glucose-dependent insulin secretion, C-peptide, graft survival, foreign body reaction, in vivo differentiation, glycemic control
- MeSH terms
- Human Embryonic Stem Cells, Animals, Blood Glucose, C-Peptide, Calcium, Cell Differentiation, Diabetes Mellitus, Experimental, Endoderm, Humans, Injections, Subcutaneous, Oxygen Consumption, Pancreas, Transplantation, Heterologous, Neovascularization, Physiologic, Insulin-Secreting Cells, Mice
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