Fas Ligand-Modified Scaffolds Protect Stem Cell Derived β-Cells by Modulating Immune Cell Numbers and Polarization

Li, Feiran; Crumley, Kelly; Bealer, Elizabeth J.; King, J. Stanton; Saito, Eiji; Grimany-Nuno, Orlando; Yolcu, Esma S.; Shirwan, Haval; Shea, Lonnie D.

doi:10.1021/acsami.2c12939

Cited by 4 publications

(5 citation statements)

References 70 publications

(142 reference statements)

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“…Biomaterial scaffolds are gaining increasing attractions for islet transplantation, which possess appropriate pore sizes that can accommodate islets and provide modifiable interfaces for protein immobilisation. Typical examples of modifying PD-L1 53 or FasL 54 , 55 via controllable biotin-streptavidin coupling support local immunomodulation for allogeneic islet transplantation that advances cell-based engraftment, which focuses on a single immunomodulatory protein for suppressing immune rejection. In this study, the biological properties of MMVs are well leveraged for immune modulation, and MMV-Gel is readily fabricated and used for transplants, which avoids the complications associated with graft engineering or protein modification and allows more flexibility in transplantation.…”

Section: Discussionmentioning

confidence: 99%

Immuno-protective vesicle-crosslinked hydrogel for allogenic transplantation

Wang,

Huang,

et al. 2024

Nat Commun

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The longevity of grafts remains a major challenge in allogeneic transplantation due to immune rejection. Systemic immunosuppression can impair graft function and can also cause severe adverse effects. Here, we report a local immuno-protective strategy to enhance post-transplant persistence of allografts using a mesenchymal stem cell membrane-derived vesicle (MMV)-crosslinked hydrogel (MMV-Gel). MMVs are engineered to upregulate expression of Fas ligand (FasL) and programmed death ligand 1 (PD-L1). The MMVs are retained within the hydrogel by crosslinking. The immuno-protective microenvironment of the hydrogel protects allografts by presenting FasL and PD-L1. The binding of these ligands to T effector cells, the dominant contributors to graft destruction and rejection, results in apoptosis of T effector cells and generation of regulatory T cells. We demonstrate that implantation with MMV-Gel prolongs the survival and function of grafts in mouse models of allogeneic pancreatic islet cells and skin transplantation.

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Section: Discussionmentioning

confidence: 99%

Immuno-protective vesicle-crosslinked hydrogel for allogenic transplantation

Wang,

Huang,

et al. 2024

Nat Commun

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“…We next wanted to determine if the increase in the β cell lineage by WY14643 was durable in vivo following transplantation. Thus, we treated SC-islets with WY14643 or vehicle control for 7 days in vitro prior to seeding SC-islets on a poly(lactide-co-glycolide) (PLG) microporous scaffold prior to transplantation into the epididymal fat pad of immunodeficient NOD-scid IL2Rg null (NSG) mice, as the epididymal fat pad rather than the renal subcapsular space is a translationally relevant transplant site 65,66 (Fig. 7J).…”

Section: Wy14643 Improves the Formation And Maturation Of Sc-β Cellsmentioning

confidence: 99%

“…Stem cell-derived islets (SC-islets): SC-islets were differentiated from H1 and HUES8 human pluripotent stem cells (hPSCs) using a 6-stage protocol, as reported previously 4,65,66,97 . Briefly, undifferentiated cells were dispersed into single cells, and 5 × 10 6 cells were seeded in 6-well cell culture treated plates coated with Matrigel (Corning).…”

Section: Experimental Model and Subject Detailsmentioning

confidence: 99%

Limitations in mitochondrial programming restrain the differentiation and maturation of human stem cell-derived β cells

Lietzke,

Bealer,

Crumley

et al. 2024

Preprint

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Pluripotent stem cell (SC)-derived islets offer hope as a renewable source for β cell replacement for type 1 diabetes (T1D), yet functional and metabolic immaturity may limit their long-term therapeutic potential. Here, we show that limitations in mitochondrial transcriptional programming impede the formation and maturation of SC-derived β (SC-β) cells. Utilizing transcriptomic profiling, assessments of chromatin accessibility, mitochondrial phenotyping, and lipidomics analyses, we observed that SC-β cells exhibit reduced oxidative and mitochondrial fatty acid metabolism compared to primary human islets that are related to limitations in key mitochondrial transcriptional networks. Surprisingly, we found that reductions in glucose-stimulated mitochondrial respiration in SC-islets were not associated with alterations in mitochondrial mass, structure, or genome integrity. In contrast, SC-islets show limited expression of targets of PPARα and PPARγ, which regulate mitochondrial programming, yet whose functions in β cell differentiation are unknown. Importantly, treatment with WY14643, a potent PPARα agonist, induced expression of mitochondrial targets, improved insulin secretion, and increased the formation and maturation of SC-β cells both in vitro and following transplantation. Thus, mitochondrial programming promotes the differentiation and maturation of SC-β cells and may be a promising target to improve β cell replacement efforts for T1D.

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“…These attempts reported, in preclinical setting promising result in protecting beta cells from recipient immune attack. Additional experimental are on-going to observe long term function of this devices and their efficacy in protecting the graft based on local immunomodulatory compounds with pancreatic islet or stem cell derived beta-cells form immune recognition (340). Alternatively, advanced macro-engineering devices are preimplanted to foster vascular integration.…”

Section: Tissue Engineering and Encapsulationmentioning

confidence: 99%

Allo Beta Cell transplantation: specific features, unanswered questions, and immunological challenge

Caldara,

Tomajer,

Monti

et al. 2023

Front. Immunol.

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Type 1 diabetes (T1D) presents a persistent medical challenge, demanding innovative strategies for sustained glycemic control and enhanced patient well-being. Beta cells are specialized cells in the pancreas that produce insulin, a hormone that regulates blood sugar levels. When beta cells are damaged or destroyed, insulin production decreases, which leads to T1D. Allo Beta Cell Transplantation has emerged as a promising therapeutic avenue, with the goal of reinstating glucose regulation and insulin production in T1D patients. However, the path to success in this approach is fraught with complex immunological hurdles that demand rigorous exploration and resolution for enduring therapeutic efficacy. This exploration focuses on the distinct immunological characteristics inherent to Allo Beta Cell Transplantation. An understanding of these unique challenges is pivotal for the development of effective therapeutic interventions. The critical role of glucose regulation and insulin in immune activation is emphasized, with an emphasis on the intricate interplay between beta cells and immune cells. The transplantation site, particularly the liver, is examined in depth, highlighting its relevance in the context of complex immunological issues. Scrutiny extends to recipient and donor matching, including the utilization of multiple islet donors, while also considering the potential risk of autoimmune recurrence. Moreover, unanswered questions and persistent gaps in knowledge within the field are identified. These include the absence of robust evidence supporting immunosuppression treatments, the need for reliable methods to assess rejection and treatment protocols, the lack of validated biomarkers for monitoring beta cell loss, and the imperative need for improved beta cell imaging techniques. In addition, attention is drawn to emerging directions and transformative strategies in the field. This encompasses alternative immunosuppressive regimens and calcineurin-free immunoprotocols, as well as a reevaluation of induction therapy and recipient preconditioning methods. Innovative approaches targeting autoimmune recurrence, such as CAR Tregs and TCR Tregs, are explored, along with the potential of stem stealth cells, tissue engineering, and encapsulation to overcome the risk of graft rejection. In summary, this review provides a comprehensive overview of the inherent immunological obstacles associated with Allo Beta Cell Transplantation. It offers valuable insights into emerging strategies and directions that hold great promise for advancing the field and ultimately improving outcomes for individuals living with diabetes.

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Fas Ligand-Modified Scaffolds Protect Stem Cell Derived β-Cells by Modulating Immune Cell Numbers and Polarization

Cited by 4 publications

References 70 publications

Immuno-protective vesicle-crosslinked hydrogel for allogenic transplantation

Immuno-protective vesicle-crosslinked hydrogel for allogenic transplantation

Limitations in mitochondrial programming restrain the differentiation and maturation of human stem cell-derived β cells

Allo Beta Cell transplantation: specific features, unanswered questions, and immunological challenge

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