Immunological Challenges Facing Translation of Alginate Encapsulated Porcine Islet Xenotransplantation to Human Clinical Trials

Krishnan, Rahul; Ko, David; Foster, Clarence E.; Liu, Wendy; Smink, Alexandra M.; Haan, Bart de; Vos, Paul de; Lakey, Jonathan R. T.

doi:10.1007/978-1-4939-6364-5_24

Cited by 38 publications

(26 citation statements)

References 113 publications

(102 reference statements)

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“…In our study, paracrine mediators from encapsulated KO adipocytes acted autonomously upon induction of Ucp1 expression in canine adipocytes. Encapsulation in APP should protect KO cells from immune rejection . Therefore, development of encapsulated engineered xenografts of KO adipocytes can present a cost‐effective solution for long‐lasting treatment of obesity in many species.…”

Section: Discussionmentioning

confidence: 99%

Aldehyde dehydrogenase 1 a1 regulates energy metabolism in adipocytes from different species

Yang

Adin

Shen

et al. 2017

Xenotransplantation

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Background Survival and longevity of xenotransplants depend on immune function and ability to integrate energy metabolism between cells from different species. However, mechanisms for inter-species crosstalk in energy metabolism are not well understood. White adipose tissue stores energy and is capable of mobilization and dissipation of energy as heat (thermogenesis) by adipocytes expressing uncoupling protein 1 (Ucp1). Both pathways are under the control of vitamin A metabolizing enzymes. Deficient retinoic acid production in aldehyde dehydrogenase 1 family fember A1 (Aldh1a1) knock out adipocytes (KO) inhibits adipogenesis and increase thermogenesis. Here we test the role Aldh1a1 in regulation of lipid metabolism in xenocultures. Methods Murine wide type (WT) and KO preadipocytes were encapsulated into a poly-L-lysine polymer that allows exchange of humoral factors <32kD via nanopores. Encapsulated murine adipocytes were co-incubated with primary differentiated canine adipocytes. Then, expression of adipogenic and thermogenic genes in differentiated canine adipocytes were detected by real-time polymerase chain reaction (PCR). The regulatory factors in WT and KO cells were identified by comparison of secretome using proteomics and in transcriptome by gene microarray. Results Co-culture of encapsulated mouse KO vs. WT adipocytes increased expression of peroxisome proliferator-activated receptor gamma (Pparg), but reduced expression of its target genes fatty acid binding protein 4 (Fabp4), and adipose triglyceride lipase (Atgl) in canine adipocytes, suggesting inhibition of PPARγ activation. Co-culture with KO adipocytes also induced expression of Ucp1 in canine adipocytes compared to expression with WT adipocytes. Cumulatively, murine KO compared to WT adipocytes decreased lipid accumulation in canine adipocytes. Comparative proteomics revealed significantly higher levels of vitamin A carriers, retinol binding protein 4 (RBP4) and lipokalin 2 (LCN2) in KO vs WT adipocytes. Conclusion Our data demonstrate the functional exchange of regulatory factors between adipocytes from different species for regulation of energy balance. RBP4 and LCN2 appear to be involved in the transport of retinoids for regulation of lipid accumulation and thermogenesis in xenocultures. While the rarity of thermogenic adipocytes in humans and dogs precludes their use for autologous transplantation, our study demonstrates that xenotransplantation of engineered cells could be a potential solution for reduction of obesity in dogs and a strategy for translation to patients.

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Section: Discussionmentioning

confidence: 99%

Aldehyde dehydrogenase 1 a1 regulates energy metabolism in adipocytes from different species

Yang

Adin

Shen

et al. 2017

Xenotransplantation

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“…Diabetic rats receiving unencapsulated islets within the intraperitoneal cavity maintained normoglycemia for up to 1 week, while encapsulated islets maintained normoglycemia for 2–3 weeks without immunosuppression. Since this study, islet microencapsulation has considerable attention as a therapeutic strategy for preventing immune destruction of islet allo- and xenografts (55,56). In contrast to unencapsulated islets, encapsulated islets are mainly delivered to extrahepatic transplantation sites such as the omentum, intraperitoneal cavity, and subcutaneous space (57,58).…”

Section: Biosynthetic Materials For Islet Deliverymentioning

confidence: 99%

Bio-synthetic materials for immunomodulation of islet transplants

Foster

Garcı́a

2017

Advanced Drug Delivery Reviews

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Clinical islet transplantation is an effective therapy in restoring physiological glycemic control in type 1 diabetics. However, allogeneic islets derived from cadaveric sources elicit immune responses that result in acute and chronic islet destruction. To prevent immune destruction of islets, transplant recipients require lifelong delivery of immunosuppressive drugs, which are associated with debilitating side effects. Biomaterial-based strategies to eliminate the need for immunosuppressive drugs are an emerging therapy for improving islet transplantation. In this context, two main approaches have been used: 1) encapsulation of islets to prevent infiltration and contact of immune cells, and 2) local release of immunomodulatory molecules from biomaterial systems that suppress local immunity. Synthetic biomaterials provide excellent control over material properties, molecule presentation, and therapeutic release, and thus, are an emerging platform for immunomodulation to facilitate islet transplantation. This review highlights various synthetic biomaterial-based strategies for preventing immune rejection of islet allografts.

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“…Various alternative cell sources are being explored (Orive et al, 2018), such as pig islets (Krishnan et al, 2017;Markmann et al, 2016;Salama and Korbutt, 2017) and stem cellderived insulin-producing cell clusters (D'Amour et al, 2006;Millman and Pagliuca, 2017;Tomei et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Conformal Coating of Stem Cell-Derived Islets for β Cell Replacement in Type 1 Diabetes

et al. 2020

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The scarcity of donors and need for immunosuppression limit pancreatic islet transplantation to a few patients with labile type 1 diabetes. Transplantation of encapsulated stem cell-derived islets (SC islets) might extend the applicability of islet transplantation to a larger cohort of patients. Transplantation of conformal-coated islets into a confined well-vascularized site allows long-term diabetes reversal in fully MHC-mismatched diabetic mice without immunosuppression. Here, we demonstrated that human SC islets reaggregated from cryopreserved cells display glucose-stimulated insulin secretion in vitro. Importantly, we showed that conformally coated SC islets displayed comparable in vitro function with unencapsulated SC islets, with conformal coating permitting physiological insulin secretion. Transplantation of SC islets into the gonadal fat pad of diabetic NOD-scid mice revealed that both unencapsulated and conformal-coated SC islets could reverse diabetes and maintain human-level euglycemia for more than 80 days. Overall, these results provide support for further evaluation of safety and efficacy of conformal-coated SC islets in larger species.

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Immunological Challenges Facing Translation of Alginate Encapsulated Porcine Islet Xenotransplantation to Human Clinical Trials

Cited by 38 publications

References 113 publications

Aldehyde dehydrogenase 1 a1 regulates energy metabolism in adipocytes from different species

Aldehyde dehydrogenase 1 a1 regulates energy metabolism in adipocytes from different species

Bio-synthetic materials for immunomodulation of islet transplants

Conformal Coating of Stem Cell-Derived Islets for β Cell Replacement in Type 1 Diabetes

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