Engineered vasculature induces functional maturation of pluripotent stem cell-derived islet organoids

Yesl Jun¹, Kim-Vy Nguyen-Ngoc², Somesh Sai³, R Hugh F Bender⁴, Winnie Gong², Vira Kravets⁵, Han Zhu², Christopher J Hatch⁶, Michael Schlichting⁷, Roberto Gaetani⁸, Medhavi Mallick², Stephanie J Hachey⁴, Karen L Christman⁹, Steven C George¹⁰, Christopher C W Hughes¹¹, Maike Sander¹²

Affiliations

¹ Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA; Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
² Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA.
³ Max Delbrück Center for Molecular Medicine, Berlin 13125, Germany; Institute of Chemistry and Biochemistry, Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Berlin 14195, Germany.
⁴ Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA.
⁵ Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA; Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
⁶ Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92617, USA.
⁷ Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA; Max Delbrück Center for Molecular Medicine, Berlin 13125, Germany.
⁸ Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
⁹ Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Sanford Stem Cell Institute, University of California, San Diego, La Jolla, CA 92037, USA; Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
¹⁰ Department of Biomedical Engineering, University of California, Davis, Davis, CA 95616, USA.
¹¹ Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA; Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92617, USA.
¹² Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA; Max Delbrück Center for Molecular Medicine, Berlin 13125, Germany; Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Department of Cellular & Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Charité-Universitätsmedizin, Berlin 10117, Germany. Electronic address: maike.sander@mdc-berlin.de.

PMID: 40412386
PMCID: PMC12353569 (available on 2026-05-23)
DOI: 10.1016/j.devcel.2025.04.024

Engineered vasculature induces functional maturation of pluripotent stem cell-derived islet organoids

Yesl Jun et al. Dev Cell. 2025.

. 2025 Sep 22;60(18):2455-2469.e7.

doi: 10.1016/j.devcel.2025.04.024. Epub 2025 May 23.

Authors

Affiliations

¹ Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA; Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
² Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA.
³ Max Delbrück Center for Molecular Medicine, Berlin 13125, Germany; Institute of Chemistry and Biochemistry, Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Berlin 14195, Germany.
⁴ Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA.
⁵ Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA; Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
⁶ Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92617, USA.
⁷ Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA; Max Delbrück Center for Molecular Medicine, Berlin 13125, Germany.
⁸ Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
⁹ Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Sanford Stem Cell Institute, University of California, San Diego, La Jolla, CA 92037, USA; Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
¹⁰ Department of Biomedical Engineering, University of California, Davis, Davis, CA 95616, USA.
¹¹ Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA; Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92617, USA.
¹² Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA; Max Delbrück Center for Molecular Medicine, Berlin 13125, Germany; Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Department of Cellular & Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Charité-Universitätsmedizin, Berlin 10117, Germany. Electronic address: maike.sander@mdc-berlin.de.

PMID: 40412386
PMCID: PMC12353569 (available on 2026-05-23)
DOI: 10.1016/j.devcel.2025.04.024

Abstract

Blood vessels play a critical role in pancreatic islet function, yet current methods for deriving islet organoids from human pluripotent stem cells (SC-islets) lack vasculature. We engineered three-dimensional (3D) vascularized SC-islet organoids by assembling SC-islet cells, human primary endothelial cells (ECs), and fibroblasts in a non-perfused model and a microfluidic device with perfused vessels. Vasculature improved stimulus-dependent Ca²⁺ influx into SC-β cells, a hallmark of β cell function that is blunted in non-vascularized SC-islets. Moreover, vascularization accelerated diabetes reversal post engraftment of a subtherapeutic SC-islet dose into mice. We show that vasculature leads to the formation of an islet-like basement membrane that contributes to the functional improvement of SC-β cells. Furthermore, single-cell RNA sequencing (scRNA-seq) data predicted BMP2/4-BMPR2 signaling from ECs to SC-β cells, and correspondingly, BMP4 enhanced the SC-β cell Ca²⁺ response and insulin secretion. Vascularized SC-islets will enable further studies of crosstalk between β cells and ECs and will serve as an in vitro platform for disease modeling and therapeutic testing.

Keywords: Ca(2+) imaging; diabetes; endothelial cells; engraftment; human pluripotent stem cells; islet; microfluidic device; organoid; vasculature; β cells.

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Conflict of interest statement

Declaration of interests C.C.W.H. and S.C.G. are founders and shareholders of Aracari Biosciences, Inc., which is commercializing the microfluidics technology used in this manuscript. R.H.F.B. is a shareholder of Aracari Biosciences, Inc. All work was performed with the full knowledge and approval of the UCI and UCD Conflict of Interest committees.

References

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Engineered vasculature induces functional maturation of pluripotent stem cell-derived islet organoids

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Engineered vasculature induces functional maturation of pluripotent stem cell-derived islet organoids

Authors

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Abstract

Conflict of interest statement

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