Differential Function and Maturation of Human Stem Cell-Derived Islets After Transplantation
Open accessAbstract
Insulin-producing stem cell-derived islets (SC-islets) provide a virtually unlimited cell source for diabetes cell replacement therapy. While SC-islets are less functional when first differentiated in vitro compared to isolated cadaveric islets, transplantation into mice has been shown to increase their maturation. To understand the effects of transplantation on maturation and function of SC-islets, we examined the effects of cell dose, transplantation strategy, and diabetic state in immunocompromised mice. Transplantation of 2 and 5, but not 0.75 million SC-islet cells underneath the kidney capsule successfully reversed diabetes in mice with pre-existing diabetes. SQ and intramuscular injections failed to reverse diabetes at all doses and had undetectable expression of maturation markers, such as MAFA and FAM159B. Furthermore, SC-islets had similar function and maturation marker expression regardless of diabetic state. Our results illustrate that transplantation parameters are linked to SC-islet function and maturation, providing ideal mouse models for preclinical diabetes SC therapy research.
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For SC-islet transplantations in mice, site and dose influence cure efficacy, with placement underneath the kidney capsule producing much better results than subcutaneous infusions.
“For SC-islet transplantations, site and dose have been shown to influence cure efficacy in mice, with placement underneath the highly-vascularized kidney capsule producing much better results than subcutaneous infusions.143,150”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [150]
2-5 x 10^6 SC-islet cells are sufficient to reverse hyperglycemia in mice.
“While 2-5 x 106 SC-islet cells are sufficient to reverse hyperglycemia in mice,150”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [150]
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“After transplantation, the SC-islets undergo change, which includes improved beta cell maturation (Augsornworawat et al., 2020; Balboa et al., 2022; Maxwell et al., 2022), but also involves subpopulations of end-stage cells differentiating into off-target cell types (Augsornworawat et al., 2020).”
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Huang, R.-L., Yang, J., Yan, Y., Liu, X.-Q., Yin, X.-Y., Liu, C., Liu, X.-R., Aimaier, R., Ji, Q., Li, G., et al. (2025) · Engineering · doi:10.1016/j.eng.2025.06.031 · Cited by 9 · see citing works
Tankyrase inhibition promotes endocrine commitment of hPSC-derived pancreatic progenitors
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“…strategies recapitulate pancreas development using a series of growth factors and small molecules to modulate signaling pathways to guide cell fate commitment to pancreatic progenitors (PPs) and islet-like clusters that contain β -like cells at the fi nal stages of differentiation 6 – 11 .”
GFP Tagged VSELs Help Delineate Novel Stem Cells Biology in Multiple Adult Tissues
Bhartiya, D., Mohammad, S. A., Singh, P., Sharma, D., & Kaushik, A. (2022) · Stem Cell Reviews and Reports · doi:10.1007/s12015-022-10401-4 · Cited by 8
“[52] recently reported effects of transplanting sc-islets in diabetic mice.”
BackgroundNijns, 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
“It is to be noted that an impact of hyperglycemia has not been demonstrated in mouse recipients of stem cell–derived islet cells 14 .”
BackgroundBrown, M. E., Barra, J. M., Pina, M., Proia, J., Brusko, T. M., & Russ, H. A. (2025) · Science Advances · doi:10.1126/sciadv.adx9755 · Cited by 8 · see citing works
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“Gene expression pattern and function of hSC-islets were shown to resemble native human islets after transplanting into rodents [27], suggesting that the hSC-islets maturate in vivo [26,27].”
BackgroundWu, S., Chandel, S., Bryzgalova, G., Efstathopoulos, P., Blust, K., Zhao, C., Erbil, E., Falk, A., Hedhammar, M., Berggren, P., et al. (2026) · Stem Cell Reports · doi:10.1016/j.stemcr.2026.102892 · Cited by 4 · see citing works
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Modeling human prenatal adrenocortical functional zonation dynamics from pluripotent stem cells.
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Defining the chromatin and transcriptional landscape of stem cell-derived islets
Augsornworawat, P., Hogrebe, N., Ishahak, M., Marquez, E., Maestas, M. M., Schmidt, M. D., Veronese-Paniagua, D. A., Gale, S., Miller, J. R., Velazco-Cruz, L., et al. (2022) · bioRxiv · doi:10.1101/2022.02.26.482126 · Cited by 3
Self-citationRegenerative macrophages enhance stem cell–derived β cell function and engraftment
Freitas, B. F. A., Fox, S. A., Orban, P. C., Velghe, J., Mojibian, M., Dai, D., Soukhatcheva, G., Lynn, F. C., Levings, M. K., & Verchere, C. B. (2026) · Science Advances · doi:10.1126/sciadv.aed4221 · Cited by 2 · see citing works
Maestas, M. M., Bradley, K., Shunkarova, M., Mukherjee, N., Ishahak, M., Lu, J., & Millman, J. R. (2026) · Stem Cells Translational Medicine · doi:10.1093/stcltm/szag012 · Cited by 1 · see citing works
Self-citationControlling Human Stem Cell‐Derived Islet Composition Using Magnetic Sorting
Kelley, A. B., Shunkarova, M., Maestas, M. M., Gale, S. E., Mukherjee, N., Hogrebe, N. J., & Millman, J. R. (2025) · Biotechnology and Bioengineering · doi:10.1002/bit.29030 · Cited by 6 · see citing works
“Furthermore, we have demonstrated previously that both diabetic and nondiabetic mice can be used to evaluate these human SC ‐ islets (Maxwell et al. 2022).”
Self-citationLoss-of-function of ALDH3B2 transdifferentiates human pancreatic duct cells into beta-like cells
Li, J., Bode, K., Lee, Y.-C., Morrow, N., Ma, A., He, M.-L., Wei, S.-Y., Pereira, J. A. D. S., Stewart, T., Lee-Papastavros, A., et al. (2026) · Science Translational Medicine · doi:10.1126/scitranslmed.ady2234 · Cited by 1
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“This new differentiation strategy could also be combined with other advances in transplantation to develop novel cell therapy products 44 – 47 .”
Self-citationEndocrine-enriched stem cell-derived islets improve long-term safety in vivoPreprint
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“Notably, secretion levels in all three groups remained above the threshold required to maintain normoglycemia (>100 pM) 12 following the destruction of endogenous -cells.”
The comparative cell physiology of stem cell-derived and primary human β cells
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Bandral, M., Alvarez-Castanon, J., & Lorberbaum, D. S. (2026) · Current Protocols · doi:10.1002/cpz1.70467
“Importantly, this research has also demonstrated that between 2 × 10 6 and 5 × 10 6 SC-islet cells suffice to reverse diabetes in mice, 750,000 SC-islet cells are insufficient (Maxwell et al., 2022).”
Chen, D., Wang, H., Tang, Y., Li, J., Tian, X., Pang, Y., Bao, S., Lang, L., Wang, Z., Wang, H., et al. (2026) · Bioactive Materials · doi:10.1016/j.bioactmat.2026.07.057
“Cellular therapies, such as using cadaveric islets or stem-cell-derived β cells, can restore glucose-responsive insulin secretion and have shown considerable promise in both preclinical investigations and clinical settings [3 – 5].”
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Groot, K. D., Suenens, K. G., Stangé, G. M., Ling, Z., Paep, D. L. D., Segers, E., KROON, E. J., Keymeulen, B., Jacobs‐Tulleneers‐Thevissen, D., & PIPELEERS, D. G. (2026) · Stem Cells Translational Medicine · doi:10.1093/stcltm/szag068
“1,31 We have previously used normoglycemic mice to assess, and demonstrate the formation of a functional beta cell mass in hu-SC-PE implants in a subcutaneous device.”
Lu, J., Ishahak, M., Maestas, M. M., & Millman, J. R. (2026) · BMC Methods · doi:10.1186/s44330-026-00075-6
“Furthermore, reliably locating and assessing transplanted islets in the subcutaneous space is very difficult due to graft dispersion and limited visual contrast with surrounding tissue [13].”
Self-citationLu, J., Ishahak, M., Maestas, M. M., & Millman, J. (2026) · bioRxiv · doi:10.64898/2026.01.06.697969
“Among these, the renal subcapsular space (kidney capsule), intramuscular region, and subcutaneous cavity have gained particular interest (13).”
Self-citationLü, J., Kim, H., Zhu, J., Martin, C., Zhang, J., Polavarapu, V., Lacko, L. A., Ariyachet, C., Dattoli, A. A., Liu, T., et al. (2025) · Stem Cell Reports · doi:10.1016/j.stemcr.2025.102708
“Transplantation of the sc-islets into animal models led to functional maturation and regulated insulin secretion (Augsornworawat et al., 2020; Maxwell et al., 2022).”
The role of fetal pancreatic islet cell transplantation in the treatment of type 2 diabetes mellitus
Kaibagarova, I., Saparbaev, S., Aringazina, R., Zhumabaev, M., & Nurgaliyeva, Z. (2024) · Journal of Diabetes and Metabolic Disorders · doi:10.1007/s40200-024-01448-w
Ratiu, J. J., Southard, S., & Rust, W. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.10.20.563345
- Authors
- Maxwell, K. G., Kim, M. H., Gale, S. E., & Millman, J. R.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Millman, Jeffrey R
- Venue
- Stem Cells Translational Medicine
- Publisher
- Oxford University Press (OUP)
- Published
- 2022-03-01
- Volume
- 11
- Issue
- 3
- Pages
- 322-331
- ISSN
- 2157-6564 (ISSN-L)
- 2157-6580
- PMC
- PMC8968674
- OpenAlex
- W4205104389
- Cited by
- 54
- References
- 55
- Citations by year
- 2026: 15 · 2025: 12 · 2024: 14 · 2023: 12 · 2022: 1
- FWCI
- 6.34
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Stem Cells Translational Medicine (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by-nc)
- Funders
- Washington University
- Mid-America Transplant Services
- Foundation for Barnes-Jewish Hospital
- National Institutes of Health (R01DK114233)
- JDRF Career Development Award (5-CDA-2017-391-A-N)
- Washington University Diabetes Research Center (P30DK020579)
- 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
- stem cell-derived islets, islet transplantation, islet maturation, transplantation route, subcutaneous injection, intramuscular injection, kidney capsule transplantation, cell dose, MafA, islet function
- MeSH terms
- Animals, Cell Differentiation, Diabetes Mellitus, Humans, Insulin, Islets of Langerhans, Stem Cells, Islets of Langerhans Transplantation, Mice
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