Alginate-microencapsulation of human stem cell–derived β cells with CXCL12 prolongs their survival and function in immunocompetent mice without systemic immunosuppression
Open accessAbstract
Pancreatic β-cell replacement by islet transplantation for the treatment of type 1 diabetes (T1D) is currently limited by donor tissue scarcity and the requirement for lifelong immunosuppression. The advent of in vitro differentiation protocols for generating functional β-like cells from human pluripotent stem cells, also referred to as SC-β cells, could eliminate these obstacles. To avoid the need for immunosuppression, alginate-microencapsulation is widely investigated as a safe path to β-cell replacement. Nonetheless, inflammatory foreign body responses leading to pericapsular fibrotic overgrowth often causes microencapsulated islet-cell death and graft failure. Here we used a novel approach to evade the pericapsular fibrotic response to alginate-microencapsulated SC-β cells; an immunomodulatory chemokine, CXCL12, was incorporated into clinical grade sodium alginate to microencapsulate SC-β cells. CXCL12 enhanced glucose-stimulated insulin secretion activity of SC-β cells and induced expression of genes associated with β-cell function in vitro. SC-β cells co-encapsulated with CXCL12 showed enhanced insulin secretion in diabetic mice and accelerated the normalization of hyperglycemia. Additionally, SC-β cells co-encapsulated with CXCL12 evaded the pericapsular fibrotic response, resulting in long-term functional competence and glycemic correction (>150 days) without systemic immunosuppression in immunocompetent C57BL/6 mice. These findings lay the groundwork for further preclinical translation of this approach into large animal models of T1D.
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Alginate microcapsules fabricated to release the immunomodulatory chemokine CXCL12 improved encapsulated SC-islet survival and reduced the fibrotic response in mice.
“For example, alginate microcapsules fabricated to release the immunomodulatory chemokine CXCL12 improved encapsulated SC-islet survival and reduced the fibrotic response in mice.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [108]
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“Of note, recently it has been shown that co-culturing of mouse or porcine cells together with CXCL12 leads to immunoprotection and long-term function with no further need of systemic host immunosuppression (Alagpulinsa et al., 2019).”
BackgroundSaha, A., Samadder, A., & Nandi, S. (2022) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026623666221201150933 · Cited by 23 · see citing works
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Building Biomimetic Potency Tests for Islet Transplantation
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Applying Immunomodulation to Promote Longevity of Immunoisolated Pancreatic Islet Grafts
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“Notably, CXCL12 improved functional survival of human stem cell-derived b cells in a mouse model and reduced FBR in an NHP model.(115,116) However, further research demonstrating efficacy in larger animal models and subsequent clinical trials are needed.”
The Feasibility and Applicability of Stem Cell Therapy for the Cure of Type 1 Diabetes
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“An encapsulation device is also useful for T1D patients to prevent autoimmune reactions against transplanted SC-islet [29].”
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Integration of Islet/Beta-Cell Transplants with Host Tissue Using Biomaterial Platforms
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Advancements and Challenges in Immune Protection Strategies for Islet Transplantation
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Importance of multiple endocrine cell types in islet organoids for type 1 diabetes treatment
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Recent 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
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Adrian, E., Treľová, D., Filová, E., Kumorek, M., Lobaz, V., Poręba, R., Janoušková, O., Pop‐Georgievski, O., Lacı́k, I., & Kubies, D. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111666 · Cited by 14 · see citing works
“Locally administered CXCL12 can induce local immune isolation and prolong allo- or xenograft function without systemic immunosuppression; because of this function, CXCL12 has been recently considered a prospective immunomodulatory agent to support or even replace immunosuppression therapy in, for example, islet transp…”
BackgroundImmunomodulation as a Novel Strategy for Prevention and Treatment of Bordetella spp. Infections
Gestal, M. C., Johnson, H. M., & Harvill, E. T. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02869 · Cited by 14 · see citing works
Natural Biopolymers as Additional Tools for Cell Microencapsulation Applied to Cellular Therapy
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“This is a proof of concept demonstrating the possibility of transplanting pancreatic β cells to treat patients with diabetes mellitus [25].”
BackgroundLathuilière, A., Vernet, R., Charrier, E., Urwyler, M., Rohr, O. V., Belkouch, M., Saingier, V., Bouvarel, T., Guillarme, D., Engel, A., et al. (2022) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2022.07.017 · Cited by 13 · see citing works
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“In addition, it is known that the cell deposition can be mitigated by modifying the alginate (Liu et al., 2019, Yang et al., 2019) and other chemicals (Doloff et al., 2017, Farah et al., 2019, Alagpulinsa et al., 2019, Kikawa et al., 2014).”
BackgroundMu-u-min, R., Diané, A., Allouch, A., & Al-Siddiqi, H. (2025) · Biomedicines · doi:10.3390/biomedicines13020383 · Cited by 13 · see citing works
“The cells were able to regulate hyperglycemia and maintain functionality for over 150 days without immunosuppression [47].”
Mooranian, A., Jones, M., Ionescu, C. M., Walker, D., Wagle, S. R., Kovačević, B., Chester, J., Foster, T., Johnston, E., Kuthubutheen, J., et al. (2021) · Journal of Functional Biomaterials · doi:10.3390/jfb12040068 · Cited by 12 · see citing works
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“…modified alginate biomaterials (triazole-thi-omorpholine dioxide alginate and CXCL12-containing sodium alginate) have significantly improved biocompatibility and long-term performance of hPSC-derived β cell islet transplants in immunocompetent mice without any immunosuppression [153, 154].”
Jeong, J., Park, K., Kim, J. H., Noh, K.-L., Hur, S., Kim, Y.-H., Hong, M., Chung, J., Park, J. H., Lee, J., et al. (2023) · Biomaterials Research · doi:10.1186/s40824-023-00419-1 · Cited by 10 · see citing works
“…functional human β-cells can be generated in vitro from human pluripotent stem cells (hPSCs) and these hPSC-derived β-cells function in a manner similar to primary human β-cells, demonstrating enhanced glucose-stimulated insulin secretion in diabetic mice along with reduced hyperglycemia [6–8].”
BackgroundIslet Transplantation: Microencapsulation, Nanoencapsulation, and Hypoimmune Engineering
Lee, K., Vargas, A. A., Bottino, R., & Wang, Y. (2025) · Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.70016 · Cited by 11 · see citing works
“CXCL12, a chemokine with immunoregulatory and anti-inflammatory properties, is known to reduce immune cell infiltration and mitigate the pericapsular fibrotic response (Alagpulinsa et al. 2019; Chen et al. 2015).”
Mochizuki, Y., Kogawa, R., Takegami, R., Nakamura, K., Wakabayashi, A., Ito, T., & Yoshioka, Y. (2020) · Biomedicines · doi:10.3390/biomedicines8090318 · Cited by 10 · see citing works
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PEGDA microencapsulated allogeneic islets reverse canine diabetes without immunosuppression
Harrington, S., Karanu, F., Ramachandran, K., Williams, S. J., & Stehno‐Bittel, L. (2022) · PLoS ONE · doi:10.1371/journal.pone.0267814 · Cited by 9 · see citing works
“Localized immune protection by gel encapsulation holds the promise of transplantation of allogeneic cells without systemic immunosuppression [2].”
BackgroundOrimi, H. E., Champion, K. S., Gauvin, L., Brassard, J. A., Strand, B. L., Leask, R. L., & Hoesli, C. A. (2025) · Biotechnology and Bioengineering · doi:10.1002/bit.70095 · Cited by 8 · see citing works
“…M.S. Chang 1964), in 3D bioprinting applications (Eswaramoorthy et al. 2021; Jia et al. 2014; Narayanan et al. 2016), as well as to retain or protect grafted cells in transplantation applications (Alagpulinsa et al. 2019; Swioklo et al. 2017; Trouche et al. 2010; Yu et al. 2010; Ziv et al. 2014).”
Safley, S. A., Barber, G. F., Holdcraft, R. W., Gazda, L. S., Duncanson, S., Poznansky, M. C., Sambanis, A., & Weber, C. J. (2020) · Xenotransplantation · doi:10.1111/xen.12577 · Cited by 8 · see citing works
Self-citationImmunocompatibility in transplantation: adapting to a changing therapeutic landscape
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Advances in alginate encapsulation of pancreatic islets for immunoprotection in type 1 diabetes
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“Similarly, alginate microencapsulation of human stem cell-derived β cells (SC-β cells) along with chemokine, CXCL12 refrained fibrotic reactions in immunocompetent C57BL/6 mice (Alagpulinsa et al. 2019; Ashimova et al. 2019).”
BackgroundCurrent Perspective and Advancements of Alginate-Based Transplantation Technologies
Rodriguez, S., Tuli, R., Wheeler, A., Nguyen, A., Luong, J. C., Mohammadi, R., Alexander, M., & Lakey, J. R. T. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.87120 · Cited by 7 · see citing works
Cell therapy research for Diabetes: Pancreatic β cell differentiation from pluripotent stem cells
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Modulating immune response for the prevention and treatment of type 1 diabetes
Vohidova, D., Desai, P., Lozano, A. M., & Omid Veiseh, A. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1715863 · Cited by 5 · see citing works
Augmenting engraftment of beta cell replacement therapies for T1DM
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Nanoencapsulated Human Pancreatic Islets for β-Cell Replacement in Type 1 Diabetes
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Cell Therapies and Gene Therapy for Diabetes: Current Progress
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Secreted cytokines provide local immune tolerance for human stem cell-derived isletsPreprint
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“Our previous study demonstrated that compared with unmodified alginate, incorporation of CXCL12 into the alginate to microencapsulate SC-islets provides long-term immuno-isolation and function in diabetic mice without the use of immunosuppressive agents [16].”
InfluentialSelf-citationWaris, S., Begam, H. H., Kumar, M. P., Abdulrasool, Z., Avudaiappan, M., Butler, A. E., & Nandakumar, M. (2026) · Cells · doi:10.3390/cells15020191 · Cited by 4 · see citing works
“…encapsulated into alginate beads implanted into the intraperitoneal space of mice treated with streptozotocin, achieving short-term success up to 174 days without any immunosuppression [43]; the implants induced glycemic correction as demonstrated by C-peptide levels and glucose responsiveness.”
Tran, H., Rodprasert, W., Padeta, I., Oontawee, S., Purbantoro, S. D., Thongsit, A., Siriarchavatana, P., Srisuwatanasagul, S., Egusa, H., Osathanon, T., et al. (2025) · PLoS ONE · doi:10.1371/journal.pone.0318204 · Cited by 2 · see citing works
- Authors
- Alagpulinsa, D. A., Cao, J. J. L., Driscoll, R. K., Sîrbulescu, R. F., Penson, M. F. E., Sremac, M., Engquist, E. N., Brauns, T. A., Markmann, J. F., Melton, D. A., & Poznansky, M. C.
- Affiliations
- Harvard University (US)
- Brigham Young University (US)
- Corresponding author
- Poznansky, Mark C.
- ORCID
- Venue
- American Journal of Transplantation
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 19
- Issue
- 7
- Pages
- 1930-1940
- ISSN
- 1600-6135 (ISSN-L)
- OpenAlex
- W2913947571
- Cited by
- 130
- References
- 33
- Citations by year
- 2026: 12 · 2025: 12 · 2024: 15 · 2023: 17 · 2022: 19 · 2021: 29 · 2020: 17 · 2019: 9
- FWCI
- 17.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- American Journal of Transplantation (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- alginate microencapsulation, stem cell-derived beta cells, CXCL12, type 1 diabetes, islet transplantation, foreign body reaction, glucose-stimulated insulin secretion, immunomodulation, immunocompetent mice, beta cell replacement
- MeSH terms
- Alginates, Animals, Blood Glucose, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 1, Female, Graft Survival, Humans, Insulin, Mice, Inbred C57BL, Stem Cells, Islets of Langerhans Transplantation, Insulin-Secreting Cells, Mice, Chemokine CXCL12
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