Mitigating Ischemic Injury of Stem Cell-Derived Insulin-Producing Cells after Transplant
Open accessAbstract
The advent of large-scale in vitro differentiation of human stem cell-derived insulin-producing cells (SCIPC) has brought us closer to treating diabetes using stem cell technology. However, decades of experiences from islet transplantation show that ischemia-induced islet cell death after transplant severely limits the efficacy of the therapy. It is unclear to what extent human SCIPC are susceptible to ischemia. In this study, we show that more than half of SCIPC die shortly after transplantation. Nutrient deprivation and hypoxia acted synergistically to kill SCIPC in vitro. Amino acid supplementation rescued SCIPC from nutrient deprivation, likely by providing cellular energy. Generating SCIPC under physiological oxygen tension of 5% conferred hypoxia resistance without affecting their differentiation or function. A two-pronged strategy of physiological oxygen acclimatization during differentiation and amino acid supplementation during transplantation significantly improved SCIPC survival after transplant.
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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 [143]
The Results section, “Attrition of SCIPC and Mature Islet Grafts after Transplant” (page unavailable), reports better SCIPC graft survival under the highly vascularized kidney capsule than at a subcutaneous site. But it measured graft survival in non-diabetic mice, not cure efficacy, and does not establish an effect of transplant dose on cure. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTransplantation of SC-islets into mice has demonstrated that a significant portion of the cells can die shortly after transplantation due to the synergistic effects of nutrient deprivation and hypoxia.
“Similar to primary islet infusion, transplantation of SC-islets into mice has demonstrated that a significant portion of the cells can die shorty after transplantation due to the synergistic effects of nutrient deprivation and hypoxia.143”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [143]
The Results section, “Attrition of SCIPC and Mature Islet Grafts after Transplant,” reports that approximately 50% of SCIPC graft mass was lost within one week of transplantation into mice. The Results section, “Impact of Hypoxia on SCIPC and Islet Viability,” shows synergistic cell death from nutrient deprivation and hypoxia in vitro. The Discussion says these factors are likely major contributors to death after transplantation, but does not demonstrate that their synergy caused the observed loss in mice. (LLM, conf=0.83)
Experimental — accuracy not yet measuredTo improve SC-islet resistance to low oxygen conditions following transplantation, stem cells were differentiated under hypoxic conditions.
“For example, to improve SC-islet resistance to low oxygen conditions following transplantation, stem cells were differentiated under hypoxic conditions.143”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [143]
Transplanting preconditioned SC-islets in combination with supplemental amino acids drastically improved SC-islet survival within the first several weeks.
“Transplanting these preconditioned SC-islets in combination with supplemental amino acids to mitigate nutrient deprivation drastically improved SC-islet survival within the first several weeks, highlighting how cell-targeted interventions can improve graft outcomes.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [143]
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Docherty, F. M., & Sussel, L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073306 · Cited by 28 · see citing works
Safety and function of a new pre-vascularized bioartificial pancreas in an allogeneic rat model
Magisson, J., Sassi, A., Xhema, D., Kobalyan, A., Gianello, P., Mourer, B., Tran, N. H., Burcez, C.-T., Bouaoun, R., & Sigrist, S. (2020) · Journal of Tissue Engineering · doi:10.1177/2041731420924818 · Cited by 18 · see citing works
Razavi, M., Primavera, R., Kevadiya, B. D., Wang, J., Ullah, M., Buchwald, P., & Thakor, A. S. (2020) · Nano Letters · doi:10.1021/acs.nanolett.0c02576 · Cited by 22 · see citing works
RetractedChendke, G. S., Faleo, G., Juang, C., Parent, A. V., Bernards, D. A., Hebrok, M., Tang, Q., & Desai, T. A. (2019) · Advanced Biosystems · doi:10.1002/adbi.201900086 · Cited by 19 · see citing works
Self-citationLIN28B Impairs the Transition of hESC-Derived β Cells from the Juvenile to Adult State
Zhou, X., Nair, G. G., Russ, H. A., Belair, C. D., Li, M., Shveygert, M., Hebrok, M., & Blelloch, R. H. (2019) · Stem Cell Reports · doi:10.1016/j.stemcr.2019.11.009 · Cited by 18 · see citing works
Self-citationUse of Induced Pluripotent Stem Cells to Build Isogenic Systems and Investigate Type 1 Diabetes
Armitage, L. H., Stimpson, S. E., Santostefano, K. E., Sui, L., Ogundare, S. O., Newby, B. N., Castro-Gutiérrez, R., Huber, M. K., Taylor, J. P., Sharma, P., et al. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.737276 · Cited by 19 · see citing works
Self-citationStem cell-based multi-tissue platforms to model human autoimmune diabetes
Leavens, K. F., Alvarez‐Dominguez, J. R., Vo, L. T., Russ, H. A., & Parent, A. V. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101610 · Cited by 18 · see citing works
Self-citationShilleh, A. H., Beard, S., & Russ, H. (2023) · Stem Cell Reports · doi:10.1016/j.stemcr.2023.05.010 · Cited by 14 · see citing works
Self-citationGeneration of Human Stem Cell-Derived Pancreatic Organoids (POs) for Regenerative Medicine
Navarro‐Tableros, V., Gomez, Y., Brizzi, M. F., & Camussi, G. (2019) · Advances in experimental medicine and biology · doi:10.1007/5584_2019_340 · Cited by 17 · see citing works
New advances in insulin products
Rajpoot, K., Tekade, M., Sharma, M. C., Molugulu, N., & Tekade, R. K. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-814455-8.00014-1 · Cited by 15 · see citing works
Shilleh, A. H., & Russ, H. A. (2023) · Cells · doi:10.3390/cells12050698 · Cited by 15 · see citing works
Self-citationRecent progress in modeling and treating diabetes using stem cell-derived islets
Maestas, M. M., Bui, M. H., & Millman, J. R. (2024) · Stem Cells Translational Medicine · doi:10.1093/stcltm/szae059 · Cited by 14 · see citing works
Regeneration of Insulin-Producing Islets From Dental Pulp Stem Cells Using a 3D Culture System
Mendoza, H. Y., Yokoyama, T., Tanaka, T., Ii, H., & Yaegaki, K. (2018) · Regenerative Medicine · doi:10.2217/rme-2018-0074 · Cited by 14 · see citing works
Chendke, G. S., Kharbikar, B. N., Ashe, S., Faleo, G., Sneddon, J. B., Tang, Q., Hebrok, M., & Desai, T. A. (2023) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10520 · Cited by 11 · see citing works
Self-citationImproving cellular fitness of human stem cell-derived islets under hypoxia
Wang, X., Brielle, S., Kenty, J. H.-R., Korover, N., Bavli, D., Pop, R., & Melton, D. A. (2025) · Nature Communications · doi:10.1038/s41467-025-59924-7 · Cited by 13 · see citing works
Non-invasive quantification of stem cell-derived islet graft size and composition
Lithovius, V., Lahdenpohja, S., Ibrahim, H., Saarimäki‐Vire, J., Uusitalo, L., Montaser, H., Mikkola, K., Yim, C., Keller, T., Rajander, J., et al. (2024) · Diabetologia · doi:10.1007/s00125-024-06194-5 · Cited by 10 · see citing works
Moeun, B. N., Lemaire, F., Smink, A. M., Orimi, H. E., Leask, R. L., de Vos, P., & Hoesli, C. A. (2025) · Journal of Tissue Engineering · doi:10.1177/20417314241284826 · Cited by 10 · see citing works
Wartchow, K. M., Rodrigues, L., Lissner, L. J., Federhen, B. C., Selistre, N. G., Moreira, A., Gonçalves, C., & Sesterheim, P. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.117587 · Cited by 10 · see citing works
Glucose metabolism and regulation in establishing human stem cell-derived β cell maturation
Lin, H., Liu, X., Chen, L., Guo, Y., Xu, T., & Liu, H. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115892 · Cited by 9 · see citing works
Yitayew, M. Y., Luginina, M., & Tabrizian, M. (2024) · Advanced NanoBiomed Research · doi:10.1002/anbr.202300097 · Cited by 9 · see citing works
Oxygen dynamics and delivery strategies to enhance beta cell replacement therapy
Shang, K., Suzuki, T., Kato, H., Toyoda, T., Tai, Y., & Komatsu, H. (2025) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00984.2024 · Cited by 13 · see citing works
Hypoimmune stem cells and islets: hype or a true breakthrough in diabetes treatment?
Shalaby, K. E., & Abdelalim, E. M. (2025) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-025-00786-8 · Cited by 10 · see citing works
Jiang, H., & Jiang, F. (2023) · World Journal of Stem Cells · doi:10.4252/wjsc.v15.i4.182 · Cited by 8 · see citing works
Lan, K., Wang, C., Yen, Y.-P., Yang, R., Liu, S., & Chan, D. (2018) · Artificial Cells Nanomedicine and Biotechnology · doi:10.1080/21691401.2018.1492421 · Cited by 8 · see citing works
Progranulin enhances the engraftment of transplanted human iPS cell-derived cerebral neurons
Yamagami, K., Samata, B., Doi, D., Tsuchimochi, R., Kikuchi, T., Amimoto, N., Ikeda, M., Yoshimoto, K., & Takahashi, J. B. (2024) · Stem Cells Translational Medicine · doi:10.1093/stcltm/szae066 · Cited by 9 · see citing works
β Cell replacement: improving on the design.
Castro-Gutiérrez, R., Michels, A. W., & Russ, H. A. (2018) · PubMed · doi:10.1097/med.0000000000000418 · Cited by 6 · see citing works
Self-citationPrimavera, R., Wang, J., Buchwald, P., Ganguly, A., Patel, S., Bettencourt, L., Chetty, S. S., Yarani, R., Regmi, S., Levitte, S., et al. (2025) · Nano Letters · doi:10.1021/acs.nanolett.4c03613 · Cited by 6 · see citing works
Regulatory T cells aid stem-cell therapy for Parkinson’s disease
Tang, Q. (2023) · Nature · doi:10.1038/d41586-023-02177-5 · Cited by 6 · see citing works
Self-citationJacobson, E. F., Chen, Z., Stoukides, D. M., Nair, G. G., Hebrok, M., & Tzanakakis, E. S. (2020) · Biotechnology and Bioengineering · doi:10.1002/bit.27629 · Cited by 6 · see citing works
Self-citationEngineering precision therapies: lessons and motivations from the clinic
Xie, M., Viviani, M., & Fussenegger, M. (2020) · Synthetic Biology · doi:10.1093/synbio/ysaa024 · Cited by 6 · see citing works
Morton, J. J., Ramos, S. A., Alzofon, N., Keysar, S. B., Armitage, L. H., Baker, A. S., Barra, J. M., Chimed, T.-S., Le, P. N., Nieto, C., et al. (2025) · Cancer Research Communications · doi:10.1158/2767-9764.crc-25-0357 · Cited by 4 · see citing works
Self-citationStem cell–derived islets take a leap toward patients
Pullen, L. C. (2022) · American Journal of Transplantation · doi:10.1111/ajt.16647 · Cited by 4 · see citing works
Wang, Z., Xu, M., Hu, R., Chen, X., Wang, X., Shi, G., Lu, S., Yang, Y., Su, Y., Gong, M., et al. (2026) · Cell stem cell · doi:10.1016/j.stem.2026.03.004 · Cited by 3 · see citing works
Advancing diabetes treatment: from human beta cell technology to bioartificial pancreas development
Sá, J., Sá, S. C., Leménager, H., Costa, R., Onteniente, B., Soares, R. A., Ribeiro, V. P., & de Oliveira, A. L. F. (2025) · Frontiers in Biomaterials Science · doi:10.3389/fbiom.2025.1524518 · Cited by 3 · see citing works
Hogrebe, N. J., Schmidt, M. D., Augsornworawat, P., Gale, S. E., Shunkarova, M., & Millman, J. R. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.10.21.618465 · Cited by 2 · see citing works
Castro-Gutiérrez, R., Arora, A., Vaeth, K. F., Taliaferro, J. M., & Russ, H. A. (2025) · Cells · doi:10.3390/cells14030184 · Cited by 1 · see citing works
Self-citationDivergent cell-type specific hypoxia responses in human stem cell-derived and primary islets
Bradley, K., Moore, C., Ishahak, M., Maestas, M. M., Veronese-Paniagua, D., & Millman, J. R. (2026) · Scientific Reports · doi:10.1038/s41598-026-52074-w · Cited by 1 · 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
WOLANIN, M., STACHYRA, B., STAWIKOWSKI, C., ZIELONKA, B., Osińska, A., WOLANIN, I., MADEJ, K., Dengler, B., KOWALCZYK, I., & KRAWIEC, P. (2023) · Journal of Education Health and Sport · doi:10.12775/jehs.2023.32.01.004 · Cited by 1 · see citing works
Widener, A. E., Manson, C. T., Barra, J. M., Spencer, C. P., Grodman, A. D., Ladd, A. M., Russ, H. A., & Phelps, E. A. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.11.11.687837 · Cited by 2 · see citing works
Self-citationPractical ways to achieve targets in diabetes care conference
Biba, U., Teng, R. W., Kurian, M. J., & Close, K. L. (2019) · Journal of Diabetes · doi:10.1111/1753-0407.12971
Lee, R. A., Gambhir, D., Nguyen, V. Q., Huang, X., Zhang, Y., Shariati, K., Yiv, N., Schugar, R. C., Annes, J. P., Roth, B. L., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.05.01.591950
Self-citationLess is more: Reducing zinc to boost stem cell-derived islet function and survival
Ibrahim, H., Balboa, D., & Otonkoski, T. (2026) · Cell stem cell · doi:10.1016/j.stem.2026.03.010
Lin, P., Hu, X., Tan, X.-Z., Wang, G., Jiang, M., Zhang, R.-T., Li, J., Liang, C., Huo, F.-J., Li, P., et al. (2026) · Biomaterials · doi:10.1016/j.biomaterials.2026.124414
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
Simaeys, D. V., & Berggren, P. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-026-02934-8
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
- Authors
- Faleo, G., Russ, H. A., Wisel, S., Parent, A. V., Nguyen, V., Nair, G. G., Freise, J. E., Villanueva, K. E., Szot, G. L., Hebrok, M., & Tang, Q.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Tang, Qizhi
- ORCID
- Venue
- Stem Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 9
- Issue
- 3
- Pages
- 807-819
- ISSN
- 2213-6711 (ISSN-L)
- PMC
- PMC5599226
- OpenAlex
- W2744100033
- Cited by
- 65
- References
- 65
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 6 · 2023: 7 · 2022: 6 · 2021: 9 · 2020: 7 · 2019: 5 · 2018: 7
- FWCI
- 5.32
- 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)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- Foundation for Diabetes Research
- American Diabetes Association (1-15-BS-179)
- Larry Hillblom Foundation Fellowship
- UCSF Program for Breakthrough Biomedical Research
- JDRF (3-2012-266)
- Eli and Edy the Broad Regeneration Medicine and Stem Cell Fellowship (T32AI125222)
- NIH (DK105831, DK108666, P30DK063720)
- 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 transplantation, ischemic injury, hypoxia, nutrient deprivation, amino acid supplementation, oxygen partial pressure, cell survival, diabetes treatment, islet cell death
- MeSH terms
- Amino Acids, Animals, Humans, Ischemia, Mice, Inbred C57BL, Oxygen, Stem Cells, Tissue Survival, Cell Hypoxia, Islets of Langerhans Transplantation, Cell Death, Pyruvic Acid, Cytoprotection, Stem Cell Transplantation, Insulin-Secreting Cells, TOR Serine-Threonine Kinases
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