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Article History

Received: 2 September 2025

Accepted: 24 February 2026

First Online: 7 May 2026

Acknowledgements

: We are grateful for the generosity of the organ donors and their families who made this work possible. We are thankful for services provided by the Southern California Islet Cell Resource Center (SC-IRC), Histocompatibility (HLA) and Immunogenetics Laboratory, Analytical Flow Cytometry, Light Microscopy Digital Imaging, Integrative Genomics, Biostatistics and High Performance Research Computing Center (HPRCC) at the City of Hope. Some figure panels were created with BioRender.com. Data shown in Fig. j,k were acquired from the database ( ) of the Human Pancreas Analysis Program (HPAP; RRID:SCR_016202) [ ]. HPAP is part of the Human Islet Research Network (HIRN; RRID:SCR_014393) consortium (UC4-DK112217, U01-DK123594, UC4-DK112232 and U01-DK123716). Figure j,k also contained data from the Pancreas Knowledgebase Program (PanKbase; ), an initiative supported by NIDDK U24DK138515, U24DK138512 and supplemental funds from the NIH Office of Data Science Strategies. PanKbase is also a part of the HIRN, and includes data derived from human pancreatic islets and/or other resources provided by the NIDDK-funded Integrated Islet Distribution Program (IIDP; RRID:SCR _014387) at City of Hope, NIH grant no. U24DK098085.

: Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, HTK (hku@coh.org). The bulk mRNA-seq dataset is deposited to the Gene Expression Omnibus (GEO; ) with accession number GSE309294. The PanKbase Seurat object for publicly available scRNA-seq datasets [ , , ] is archived at and code to reproduce the associated figures is available at .

: Microsoft Copilot was used for language enhancement. Claude (Anthropic) was used to develop R code for analysis of publicly available scRNA-seq and to assist with interpretation. All AI-generated content was carefully reviewed and edited by the authors, who take full responsibility for the final manuscript.

: Open access funding provided by SCELC, Statewide California Electronic Library Consortium. Research reported in this publication was supported, in part, by the National Institutes of Health grants to HTK (R01DK099734 and R01DK134652) and the City of Hope Research Facilities (P30CA33572). Support from the H.N. & Frances C. Berger Foundation Fellowship (NE), the Dr. Norman and Melinda Payson Graduate Student Fellowship (NE), a postdoctoral fellowship from the California Institute for Regenerative Medicine (EDU4-12772, HNZ), the Wanek Family Project for Type 1 Diabetes (HTK), an anonymous donor S.S. (HTK) and The Margie & Robert E. Petersen Foundation (HR) is also gratefully acknowledged. This manuscript was written with use of resources and/or funding provided by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-supported Human Islet Research Network (HIRN; Research Resource Identifier [RRID]: SCR_014393) ( ), including U24DK104162 to DO and JSK. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

: HTK is an inventor of a patent, no. 9,783,784, titled ‘Methods for establishing and improving the survival of a population of pancreatic progenitor or stem cells’. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.

: NE, HR and HTK designed the study. The methodology was developed by NE, DA-L, DO, RCV, EM, JSK, HR and HTK. The data acquisition, validation and interpretation was carried out by NE, DA-L, DO, HNZ, JCQ, JAO, CD, JM and KJ. Resources were provided by HR and HTK. The original draft was prepared by NE and HTK. All authors provided substantial contributions to the conception or design of the work, or the acquisition, analysis or interpretation of the data, drafted or reviewed the article critically for intellectual content, and final approval of the version to be published. Funding for the project was acquired by HTK, HR, NE and HNZ. HTK is the guarantor of this work.