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Precision Medicine in Surgery: Regeneration Strategies Come of Age for Treatment of Immunologic and Surgical Diseases.
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Mingyang Ma1, *Preeti Chhabra
1, *Gordon Laurie
2, Kenneth L. Brayman
11Surgery, University of Virginia, Charlottesville, VA; 2Cell Biology, University of Virginia, Charlottesville, VA
Background: Immunologic and inflammatory diseases, including autoimmune and organ-specific injuries, often resist treatment due to persistent inflammation and limited regeneration. Combining immunomodulation and regeneration offers therapeutic potential for conditions like Crohn’s disease, heart failure, pulmonary fibrosis, chronic kidney disease, multisystem organ failure, and neurological injuries. Lacritin, a regenerative glycoprotein recently identified in human plasma using ultra-sensitive proteomics was found to be diminished in diabetic patients, raising the question as to whether this family of peptides is a promising candidate for immunomodulatory and regenerative therapy. Using islet transplant and T1D models, we analyzed lacritin N-104’s effects on regeneration and immune modulation, with PEG-N-80/C-25 and C-95 serving as controls.
Methods: Human and mouse islets were treated with PEG-N-104 or control peptides to assess viability, glucose-stimulated insulin secretion (GSIS), and ?-cell proliferation via CyTOF. Pretreated islets were transplanted into syngeneic or xenogeneic diabetic mice, with daily blood glucose monitoring. In autoimmune NOD mice, PEG-N-104 was administered from weeks 9–16, followed by evaluation of blood glucose, insulitis scores, imaging mass cytometry (IMC), and single-cell RNA sequencing (scRNAseq) of pancreatic lymph nodes.
Results: Plasma analysis revealed a 70% reduction in active lacritin monomer in human T1D patients, with levels declining further with age (n=49). In vitro, PEG-N-104 enhanced GSIS in islets and improved islet viability over 15 days (n=6). CyTOF analysis revealed enhanced ?-cell proliferation, with a lesser effect on ?- and ?-cells and minimal impact on other cell types (n=4). In minimal mass syngeneic and xenogeneic models, N-104-pretreated islets rapidly achieved and maintained normoglycemia in diabetic recipients. In NOD mice, PEG-N-104 injection prevented T1D onset for at least 23 weeks post-treatment (n= 20, P<0.001), and reduced islet insulitis scores. IMC demonstrated preservation of islet cell composition and modulated immune cell activity, reducing key inflammatory markers. scRNAseq analysis confirmed suppression of progenitor and cytotoxic T cells and memory B cells, reflecting PEG-N-104’s immunomodulatory effects.
Conclusion: Lacritin proteoform N-104 is a promising dual-action therapy for T1D, enhancing ?-cell regeneration and modulating immune responses. Our findings demonstrate PEG-N-104’s potential to improve islet proliferation and reduce inflammation, underscoring its suitability as a therapeutic candidate for autoimmune and inflammatory conditions as well as transplantation. By targeting both cellular regeneration and immune regulation, a novel approach for managing inflammation and cell regeneration is identified. This family of novel peptides holds potential for treating other inflammatory and degenerative conditions in pre and post surgical care.
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