Intracerebral xenotransplantation: recent findings and perspectives for local immunosuppression

Jiang

Stem Cells and Development

et al. 2013

Immunological response hampers the investigation of human embryonic stem cells (hESCs) or their derivates for tissue regeneration in vivo. Immunosuppression is often used after surgery, but exhibits side effects of significant weight loss and allows only short-term observation. The purpose of this study was to investigate whether neonatal desensitization supports relative long-term survival of hESC-derived mesenchymal stem cells (hESCMSCs) and promotes cartilage regeneration. hESC-MSCs were injected on the day of birth in rats. Six weeks after neonatal injection, a full-thickness cylindrical cartilage defect was created and transplanted with a hESC-MSCseeded collagen bilayer scaffold (group d + s + c) or a collagen bilayer scaffold (group d + s). Rats without neonatal injection were transplanted with the hESC-MSC-seeded collagen bilayer scaffold to serve as controls (group s + c). Cartilage regeneration was evaluated by histological analysis, immunohistochemical staining, and biomechanical test. The role of hESC-MSCs in cartilage regeneration was analyzed by CD4 immunostaining, cell death detection, and visualization of human cells in regenerated tissues. hESC-MSCs expressed CD105, CD73, CD90, CD29, and CD44, but not CD45 and CD34, and possessed trilineage differentiation potential. Group d + s + c exhibited greater International Cartilage Repair Society (ICRS) scores than group d + s or group s + c. Abundant collagen type II and improved mechanical properties were detected in group d + s + c. There were less CD4 + inflammatory cell infiltration and cell death at week 1, and hESC-MSCs were found to survive as long as 8 weeks after transplantation in group d + s + c. Our study suggests that neonatal desensitization before transplantation may be an efficient way to develop a powerful tool for preclinical study of human cell-based therapies in animal models.

mentioning

confidence: 99%

Neonatal Desensitization Supports Long-Term Survival and Functional Integration of Human Embryonic Stem Cell-Derived Mesenchymal Stem Cells in Rat Joint Cartilage Without Immunosuppression

Jiang

Stem Cells and Development

et al. 2013

Expert Review of Clinical Immunology

“…Although less emphasis has been directed to the transplantation of pig neuronal cells in monkeys with a Parkinson-like state, encouraging results have been reported [74]. Similar encouraging results have been reported following pig corneal transplantation in monkeys [75,76].…”

Section: Pig-to-primate Cell Transplantationmentioning

confidence: 76%

Recent advances in understanding xenotransplantation: implications for the clinic

Cooper

Bottino

2015

Summary The results of organ and cell allotransplantation continue to improve, but the field remains limited by a lack of deceased donor organs. Xenotransplantation, e.g., between pig and human, offers unlimited organs and cells for clinical transplantation. The immune barriers include a strong innate immune response in addition to the adaptive T cell response. The innate response has largely been overcome by the transplantation of organs from pigs with genetic modifications that protect their tissues from this response. T cell-mediated rejection can be controlled by immunosuppressive agents that inhibit costimulation. Coagulation dysfunction between the pig and primate remains problematic but is being overcome by the transplantation of organs from pigs that express human coagulation-regulatory proteins. The remaining barriers will be resolved by the introduction of novel genetically-engineered pigs. Limited clinical trials of pig islet and corneal transplantation are already underway.

Clinical Transplantation

“…These successes have been related to improvements in the immunosuppressive agents available, e.g., agents that block T cell costimulation, but also to advances in the genetic engineering of the source pigs. There have also been encouraging reports on pig dopamine-producing neuronal cell transplantation in monkeys in which a Parkinson-like state has been induced, with significant functional improvement in several monkeys for periods of months or even a year (6). …”

Section: How Far Has Xenotransplantation Research Progressed Today?mentioning

confidence: 99%

The case for xenotransplantation

Cooper

2015

The availability of organs and cells from deceased humans for transplantation is not meeting the demand. Xenotransplantation, specifically the transplantation of organs and cells from genetically-engineered pigs, could resolve this problem. Diabetic monkeys have remained normoglycemic and insulin-independent after pig islet transplantation for >1 year, and a pig heterotopic (non-life-supporting) heart transplant recently reached the one-year milestone in a baboon. With these encouraging results, why is it that, with some notable exceptions, research into xenotransplantation has received relatively little support by industry, government funding agencies, and medical charitable foundations? Industry appears reluctant to support research that will take more than 2–3 years to come to clinical trial, and the funding agencies appear to have been “distracted” by the current appeal of stem cell technology and regenerative medicine. It has only been the willingness of living donors to provide organs that has significantly increased the number of transplants being performed worldwide. These altruistic donations are not without risk of morbidity and even mortality to the donor. Although with the best of intentions, we are therefore traversing the Hippocratic Oath of doctors to “do no harm”. This should be a stimulus to fund exploration of alternative approaches, including xenotransplantation.