American Diabetes Association
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Protective Renalase-deficiency in beta cells shapes immune metabolism and function in autoimmune diabetes

posted on 2023-05-22, 20:19 authored by Kevin Bode, Tara MacDonald, Taylor Stewart, Bryhan Mendez, Erica P. Cai, Noelle Morrow, Yu-Chi Lee, Peng Yi, Stephan Kissler

Type 1 diabetes (T1D) is caused by the immune-mediated loss of pancreatic beta cells that produce insulin. The latest advances in stem cell (SC)-beta cell differentiation methods have made a cell replacement therapy for T1D feasible. However, recurring autoimmunity would rapidly destroy transplanted SC-beta cells. A promising strategy to overcome immune rejection is to genetically engineer SC-beta cells. We previously identified Renalase (Rnls) as a novel target for beta cell protection. Here we show that Rnls deletion endows beta cells with the capacity to modulate the metabolism and function of immune cells within the local graft microenvironment. We used flow cytometry and single-cell RNA sequencing to characterize beta cell graft-infiltrating immune cells in a mouse model for T1D. Loss of Rnls within transplanted beta cells affected both the composition and the transcriptional profile of infiltrating immune cells in favor of an anti-inflammatory profile with decreased antigen presenting capacity. We propose that changes in beta cell metabolism mediate local immune regulation and that this feature could be exploited for therapeutic goals.  


We thank the Joslin Flow Cytometry core (funded in part by NIDDK grant P30DK036836) and the Joslin Bioinformatics core for support of this project. In particular, we would like to acknowledge the expert help of Drs. Jonathan Dreyfuss and Hui Pan with scRNAseq analyses. We also thank Jenna Collier for advice on T cell scRNAseq methods. K.B. and T.M. were support in part by postdoctoral fellowships from the Mary K. Iacocca Foundation. This project was also supported by NIDDK grant R01DK120445 awarded to P.Y. and S.K.


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