An international team led by scientists from the University of California, San Diego, in an article, published May 9, 2018 in Science Translational Medicine, describes a successful grafting induced pluripotent stem cell (iPSC)-derived neural precursor cells into pigs with spinal cord injury without immunosuppression.
The main obstacle in using allogenic (derived from donors) neural stem cells to repair damaged tissues, for example, in spinal cord injury, is a permanent rejection of the transplant. To prevent the “graft versus host” reaction, complex therapy is used that suppresses the recipient’s immune response.
An international team of scientists from the United States and the Czech Republic successfully transplanted genetically identical neural precursor cells (NPCs), obtained from autologous iPSCs, into the spinal cords of adult pigs without suppressing the immune response. The transplanted cells survived for a long time, differentiated and did not form tumors.
The researchers also demonstrated that these same cells showed similar long-term survival in adult pigs with injured spinal cord in allogeneic transplantation after a short course of immunosuppressors.
“The promise of iPSCs is huge, but so too have been the challenges. In this study, we’ve demonstrated an alternate approach”, – said senior author Martin Marsala, MD, professor in the Department of Anesthesiology at UC San Diego School of Medicine.
“We took skin cells from an adult pig, an animal species with strong similarities to humans in spinal cord and central nervous system anatomy and function, reprogrammed them back to stem cells, then induced them to become neural precursor cells (NPCs), destined to become nerve cells. Because they are syngeneic — genetically identical with the cell-graft recipient pig — they are immunologically compatible. They grow and differentiate with no immunosuppression required”.
Co-author Samuel Pfaff, PhD, professor at Salk Institute for Biological Studies, also noted “Using RNA sequencing and innovative bioinformatic methods to deconvolute the RNA’s species-of-origin, the research team demonstrated that pig iPSC-derived neural precursors safely acquire the genetic characteristics of mature CNS tissue even after transplantation into rat brains.”
During the study, scientists transplanted the NPCs into the intact spinal cord of syngeneous pigs without immunosuppression. They found that the NPCs survived and differentiated into neurons, and maintained glial cells for the entire observation period. Transplanted neurons were observed even seven months after transplantation.
Then the scientists transplanted allogeneic neural progenitor cells into pigs with chronic spinal cord injury who received four-week regimen of immunosuppression drugs. NPCs, as in the previous stage of research, showed long-term survival and successful differentiation.
“Our current experiments are focusing on generation and testing of clinical grade human iPSCs, which is the ultimate source of cells to be used in future clinical trials for treatment of spinal cord and central nervous system injuries in a syngeneic or allogeneic setting”, – said Marsala.
“Because long-term post-grafting periods (one to two years) are required to achieve a full grafted cells-induced treatment effect, the elimination of immunosuppressive treatment will substantially increase our chances in achieving more robust functional improvement in spinal trauma patients receiving iPSC-derived NPCs”.
“In our current clinical cell-replacement trials, immunosuppression is required to achieve the survival of allogeneic cell grafts. The elimination of immunosuppression requirement by using syngeneic cell grafts would represent a major step forward”, – said co-author Joseph Ciacci, MD, a neurosurgeon and professor of surgery at UC San Diego School of Medicine.