Susanna Sampaolesi, Francesco Nicotra, Laura Russo
Glycans have been selected by nature for both structural and ‘recognition’ purposes. Taking inspiration from nature, nanomedicine exploits glycans not only as structural constituents of nanoparticles and nanostructured biomaterials but also as selective interactors of such glyco-nanotools. Surface glycosylation of nanoparticles finds application in targeting specific cells, whereas recent findings give evidence that the glycan content of cell microenvironment is able to induce the cell fate. This review will highlight the role of glycans in nanomedicine, schematizing the different uses and roles in drug-delivery systems and in biomaterials for regenerative medicine.
PURPOSE OF REVIEW:
Xenotransplantation of porcine islets is a realistic option to restore β-cell function in type 1 diabetic patients. Among other factors, such as islet donor age (fetal, neonatal and adult) and genotype (wild type and genetically modified), choice of the transplantation site, and immune protection of the islets, efficient strategies for islet isolation, culture and engraftment are critical for the success of islet xenotransplantation.
Neonatal porcine islets (NPIs) are immature at isolation and need to be matured in vitro or in vivo before they become fully functional. Recent developments include a scalable protocol for isolation of clinically relevant batches of NPIs and a stepwise differentiation protocol for directed maturation of NPIs. In addition, different sources of mesenchymal stem cells were shown to support survival and functional maturation of NPIs in vitro and in various transplantation models in vivo.
A plethora of different culture media and supplements have been tested; however, a unique best culture system for NPIs is still missing. New insights, for example from single-cell analyses of islets or from stem cell differentiation toward β cells may help to optimize culture of porcine islets for xenotransplantation in an evidence-based manner.
PURPOSE OF REVIEW:
Porcine islets represent a potentially attractive beta-cell source for xenotransplantation into patients with type 1 diabetes, who are not eligible to islet allo-transplantation due to a lack of suitable human donor organs. Recent progress in genetic engineering/gene editing of donor pigs provides new opportunities to overcome rejection of xeno-islets, to improve their engraftment and insulin secretion capacity, and to reduce the risk for transmission of porcine endogenous retroviruses. This review summarizes the current issues and progress in islet xenotransplantation with special emphasis on genetically modified/gene edited donor pigs.
Attempts to overcome acute rejection of xeno-islets, especially after intraportal transplantation into the liver, include the genetic elimination of specific carbohydrate antigens such as αGal, Neu5Gc, and Sd(a) for which humans and-in part-non-human primates have natural antibodies that bind to these targets leading to activation of complement and coagulation. A complementary approach is the expression of one or more human complement regulatory proteins (hCD46, hCD55, hCD59). Transgenic attempts to overcome cellular rejection of islet xenotransplants include the expression of proteins that inhibit co-stimulation of T cells. Expression of glucagon-like peptide-1 and M3 muscarinic receptors has been shown to increase the insulin secretion of virally transduced porcine islets in vitro and it will be interesting to see the effects of these modifications in transgenic pigs and islet products derived from them. Genome-wide inactivation of porcine endogenous retrovirus (PERV) integrants by mutating their pol genes using CRISPR/Cas9 is a recent approach to reduce the risk for PERV transmission by xeno-islets. Genetic engineering/gene editing of xeno-islet donor pigs facilitated major progress towards clinical islet xenotransplantation. The required set of genetic modifications will depend on the source of islets (fetal/neonatal vs. adult), the mode of delivery (encapsulated vs. free), and the transplantation site.
Gene editing; Islet transplantation; Pig; Xenotransplantation
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