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Review
. 2025 Jul 1;74(7):1068-1077.
doi: 10.2337/db25-0037.

Advances in Cell Replacement Therapies for Diabetes

Bernhard J Hering  1 , Michael R Rickels  2 , Melena D Bellin  3 , Jeffrey R Millman  4 , Alice A Tomei  5 , Andrés J García  6 , Haval Shirwan  7 , Cherie L Stabler  8 , Minglin Ma  9 , Peng Yi  10 , Xunrong Luo  11 , Qizhi Tang  12 , Sabarinathan Ramachandran  1 , Jose Oberholzer  13 , Camillo Ricordi  5 , Timothy J Kieffer  14 , A M James Shapiro  15
Affiliations
Review

Advances in Cell Replacement Therapies for Diabetes

Bernhard J Hering et al. Diabetes. .

Abstract

Islet cell replacement therapies have evolved as a viable treatment option for type 1 diabetes complicated by problematic hypoglycemia and glycemic lability. Refinements of islet manufacturing, islet transplantation procedures, peritransplant recipient management, and immunosuppressive protocols allowed most recipients to achieve favorable outcomes. Subsequent phase 3 trials of transplantation of deceased donor islets documented the effectiveness of transplanted islets in restoring near-normoglycemia, glycemic stability, and protection from severe hypoglycemia, with an acceptable safety profile for the enrolled high-risk population. Health authorities in several countries have approved deceased donor islet transplantation for treating patients with type 1 diabetes and recurrent severe hypoglycemia. These achievements amplified academic and industry efforts to generate pluripotent stem cell-derived β-cells through directed differentiation for β-cell replacement. Preliminary results of ongoing clinical trials suggest that the transplantation of stem cell-derived β-cells can consistently restore insulin independence in immunosuppressed recipients with type 1 diabetes, thus signaling the profound progress made in generating an unlimited and a uniform supply of cells for transplant. Avoiding the risks of chronic immunosuppression represents the next frontier. Several strategies have entered or are approaching clinical investigation, including immune-isolating islets, engineering immune-privileged islet implantation sites, rendering islets immune evasive, and inducing immune tolerance in transplanted islets. Capitalizing on high-dimensional, multiomic technologies for deep profiling of graft-directed immunity and the fate of the graft will provide new insights that promise to translate into sustaining functional graft survival long-term. Leveraging these parallel progression paths will facilitate the wider clinical adoption of cell replacement therapies in diabetes care.

Article highlights: Transplantation of deceased donor-derived primary human islets has restored near-normoglycemia and protection from severe hypoglycemia in immunosuppressed recipients with type 1 diabetes. Transplantation of embryonic stem cell-derived β-cells has restored insulin independence in immunosuppressed recipients with type 1 diabetes. Clinical trials are underway and planned to evaluate the safety and efficacy of transplantation of mature stem cell-derived β-cells with transient, local, minimal, and/or no-maintenance immunosuppression in recipients with type 1 diabetes. The high-dimensional, multiomic monitoring of immunity to transplanted islets and of the fate of the islet graft will faciliate the identification of determinants of sustained islet graft function and of patients most likely to benefit from cell replacement therapies.

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Conflict of interest statement

Duality of Interest. B.J.H. holds equity in and serves as a paid executive officer and director of Diabetes Free, Inc., a company that may commercially benefit from the results of research in islet transplantation. This interest has been reviewed and managed by the University of Minnesota in accordance with its conflict of interest policies. M.R.R. received research support from Dompé farmaceutici and from Tandem Diabetes Care and serves on the Type 1 Diabetes Clinical Development Program Steering Committee for Vertex Pharmaceuticals and the independent data and safety monitoring board for Sernova. M.D.B. received research support from ViaCyte and serves on the independent data and monitoring committee for Vertex Pharmaceuticals. J.R.M. is an inventor on patents and patent applications related to SC-islets. J.R.M. was recently employed at and has stock in Sana Biotechnology. A.A.T. is an inventor of the conformal coating intellectual property, which has been licensed to Sernova. A.A.T. has received payment from Sernova related to IP and stands to gain royalties from commercialization of the IP. Additionally, A.A.T. is an equity holder in Sernova. A.J.G. and H.S. are scientific cofounders of iTolerance, Inc., pursuing microgel presenting FasL technology as an immunomodulatory strategy for β-cell transplantation. M.M. is a cofounder of Persista Bio, a company formed to commercialize oxygenated islet encapsulation technologies. S.R. received research support from Diabetes Free, Inc. J.O. is the founder and president of CellTrans Inc. and was the principal investigator of the pivotal phase 1, 2 and 3 trials at the University of Illinois that led to the U.S. Food and Drug Administration approval of Lantidra. His conflicts of interest have been reviewed and managed by the University of Illinois according to its conflict of interest policies. J.O. has been a consultant to Vertex Pharmaceuticals. C.R is a cofounder and equity holder of AION Healthspan and Lipogems International and consultant of Vertex Pharmaceuticals, Novo Nordisk, Seraxis, and iTolerance, Inc. C.R. has received funding support from Humacyte (SA00002358) and Vertex Pharmaceuticals (VX-880 and VX-264 clinical trials). T.J.K. received research support from ViaCyte, served as chief scientific officer (CSO) at ViaCyte, and at the time of writing serves as CSO at Fractyl Health, developing gene therapy for diabetes and obesity. A.M.J.S. previously served as a consultant for ViaCyte and has ongoing consultancies with Vertex Pharmaceuticals, Betalin Therapeutics, and Aspect Biosystems. No other potential conflicts of interest relevant to this article were reported.

Figures

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Graphical abstract
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References

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