Transplantation of microencapsulated genetically modified xenogeneic cells augments angiogenesis and improves heart function

Abstract

Cell-based gene therapy offers an alternative strategy for therapeutic angiogenesis for the management of myocardial infarction (MI). However, immune rejection poses a significant obstacle to the implantation of genetically engineered allogeneic or xenogeneic cells. In the present study, an ex vivo gene therapy approach utilizing cell microencapsulation was employed to deliver vascular endothelial growth factor (VEGF) to ischemic myocardium. Chinese hamster ovary (CHO) cells were genetically modified to secrete VEGF and enveloped into semipermeable microcapsules. In vitro assay indicated that the microencapsulated engineered CHO cells could secrete VEGF as high as 3852 pg ml À1 per 48 h at day 8 after encapsulation. Then the microencapsulated CHO cells were implanted into the injured myocardium in a rat MI model, while engineered CHO cells, blank microcapsules and serum-free culture media were implanted as controls. The humoral immunity to xenogeneic CHO cells were evaluated and we found that the titer of anti-CHO antibodies was significantly lower in the microencapsulated CHO transplantation group than the group receiving unencapsulated CHO cells at two weeks after implantation. However, 1 week later, there was almost no difference between these groups. Histology and western blotting confirmed that the microencapsulated CHO cells maintained their original structure and VEGF secretion three weeks after implantation. The capillary density in the treatment region was also significantly higher in the microencapsulated CHO cell group than control groups, which was consistent with gross heart functional improvement. These data suggest that microencapsulated xenogeneic cell-based gene therapy might be a novel approach for therapeutic angiogenesis in ischemic heart disease.

Use of Encapsulated Stem Cells to Overcome the Bottleneck of Cell Availability for Cell Therapy Approaches

“…The immune response to the encapsulated CHO cells was low. The VEGFexpressing CHO cells significantly increased angiogenesis resulting in improvement of heart function [23]. Other approaches using encapsulated, genetically modified cells are the expression of b-glucuronidase in epithelial cells treating mucopolysaccharidosis type VII [24], the expression of erythropoietin in myoblast cells [25,26] or the expression of IL-6 in CHO cells, inhibiting tumor progression [27].…”

Emerging technologies in the delivery of erythropoietin for therapeutics

“…These facts improve permeability of the membrane and thus cell viability. 205 Finally, they can be implanted with minimal-invasive surgery into the peritoneal cavity, 206 subcutaneous tissue, 207 myocardium, 208 or elsewhere. Our research group has recently studied the proof of principle of cell encapsulation technology by implanting Epo-secreting C 2 C 12 myoblasts immobilized in microcapsules in the peritoneum and subcutaneous tissue of syngeneic and allogeneic mice (Fig.…”

Superior Cell Delivery Features of Genipin Crosslinked Polymeric Microcapsules: Preparation, In Vitro Characterization and Pro-Angiogenic Applications Using Human Adipose Stem Cells

“…This system involves trapping cells in a semi-permeable polymer membrane, to allow free bi-directional exchange of oxygen, nutrients, and waste between entrapped cells and their environment, while excluding the influx of immune cells [17,18]. Theoretically, cells can be implanted without immune-suppression since the capsule membrane physically protects them.…”