Xenograft of microencapsulated Sertoli cells restores glucose homeostasis in db/db mice with spontaneous diabetes mellitus

Luca, Giovanni; Arato, Iva; Mancuso, Francesca; Calvitti, Mario; Falabella, G.; Murdolo, Giuseppe; Basta, Giuseppe; Cameron, Don F.; Hansen, Barbara C.; Fallarino, Francesca; Baroni, Tiziano; Aglietti, Maria Chiara; Tortoioli, Cristina; Bodo, Maria; Calafiore, Riccardo

doi:10.1111/xen.12274

Cited by 17 publications

(19 citation statements)

References 28 publications

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“…In association with these results, a significant upregulated expression of the adipose tissue uncoupling protein 1 (UCP‐1) was demonstrated along with a consistent increase in regulatory B cells and anti‐inflammatory macrophages, while pro‐inflammatory macrophages decreased. iNOS and pro‐inflammatory molecules diminished in the treated animals while levels of anti‐inflammatory cytokine IL‐10 and circulating adiponectin increased (Luca et al ., ,b). After transplantation, the anti‐hyperglycemic effects were associated with a downregulated expression of GLUT‐2 and an upregulated expression of GLUT‐4 in the liver and skeletal muscle, respectively (Luca et al ., ,b).…”

Section: Current Applications Of Sertoli Cells To Transplantation: Prmentioning

confidence: 99%

“…iNOS and pro‐inflammatory molecules diminished in the treated animals while levels of anti‐inflammatory cytokine IL‐10 and circulating adiponectin increased (Luca et al ., ,b). After transplantation, the anti‐hyperglycemic effects were associated with a downregulated expression of GLUT‐2 and an upregulated expression of GLUT‐4 in the liver and skeletal muscle, respectively (Luca et al ., ,b). Additionally, Luca and colleagues also demonstrated that the i.p.…”

Section: Current Applications Of Sertoli Cells To Transplantation: Prmentioning

confidence: 99%

“…Moreover, as demonstrated for the first time by Luca et al ., MC‐SC injected i.p into R6/2 mice (an animal model of HD) increased the mouse lifespan and improved motor function. In part, this was associated with a reduction in striatal inflammation (Luca et al ., ,b).…”

Section: Current Applications Of Sertoli Cells To Transplantation: Prmentioning

confidence: 99%

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Sertoli cells for cell transplantation: pre‐clinical studies and future perspectives

et al. 2018

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Sertoli cells are located in the testes where they control several key functions in spermatogenesis. Over the past 30 years, Sertoli cells have been upgraded from a simple scaffold-like structural system to a dynamic functional system of intercellular support that delivers potent immunomodulatory and trophic factors. Since the discovery of new Sertoli cell secretory products, these cells have been utilized in experimental cell transplantation and co-transplantation protocols aimed at treating both chronic inflammatory and degenerative disorders. For these reasons, this work reviews the application of both naked and microencapsulated Sertoli cells used in cell transplantation studies of several chronic or autoimmune diseases such as diabetes mellitus, Laron dwarfism, and Duchenne muscular dystrophy and in studies aimed at the prevention of skin allograft rejection.

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Section: Current Applications Of Sertoli Cells To Transplantation: Prmentioning

confidence: 99%

Section: Current Applications Of Sertoli Cells To Transplantation: Prmentioning

confidence: 99%

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Sertoli cells for cell transplantation: pre‐clinical studies and future perspectives

et al. 2018

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“…Transplantation of pancreatic β‐cells, thermogenic, fetal and genetically modified adipocytes, and other minor cell populations showed therapeutic promise for treatment of many degenerative disorders including diabetes and obesity. However, systemic and immune effects in vivo limit possibilities to dissect mechanisms for interaction between xenograft and host organism.…”

Section: Discussionmentioning

confidence: 99%

“…Xenotransplantation of organs, specific cell populations, and genetically engineered cells continue to be investigated to address shortage of donor organs and for the treatment of genetic, autoimmune, and degenerative diseases . The survival and longevity of xenografts depend on interaction with the host immune system as well as an ability to integrate into the host's metabolism and energy pathways.…”

Section: Introductionmentioning

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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Alginate Microcapsules for Drug Delivery

Gonzalez‐Pujana

Orive

Pedraz

et al. 2017

Springer Series in Biomaterials Science and Engineering

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Xenograft of microencapsulated Sertoli cells restores glucose homeostasis in db/db mice with spontaneous diabetes mellitus

Abstract: Preliminarily, xenograft of MC-SC holds promises for an effective cell therapy approach for treatment of experimental T2D.

Cited by 17 publications

References 28 publications

Sertoli cells for cell transplantation: pre‐clinical studies and future perspectives

Sertoli cells for cell transplantation: pre‐clinical studies and future perspectives

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

Alginate Microcapsules for Drug Delivery

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