A major hurdle to using neural stem cells derived from genetically different donors to replace damaged or destroyed tissues, such as in a spinal cord injury, has been the persistent rejection of the introduced material (cells), necessitating the use of complex drugs and techniques to suppress the host’s immune response.
In a new paper, publishing May 9 in Science Translational Medicine, an international team led by scientists at University of California San Diego School of Medicine describe successfully grafting induced pluripotent stem cell (iPSC)-derived neural precursor cells back into the spinal cords of genetically identical adult pigs with no immunosuppression efforts. The grafted cells survived long-term, displayed differentiated functionality and caused no tumors.
The researchers also demonstrated that the same cells showed similar long-term survival in adult pigs with different genetic backgrounds after only short course use of immunosuppressive treatment once injected into injured spinal cord.
“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 and a member of the Sanford Consortium for Regenerative Medicine.
Survival of syngeneic and allogeneic iPSC-derived neural precursors after spinal grafting in minipigs
May 9 in Science Translational Medicine
Abstract: The use of autologous (or syngeneic) cells derived from induced pluripotent stem cells (iPSCs) holds great promise for future clinical use in a wide range of diseases and injuries. It is expected that cell replacement therapies using autologous cells would forego the need for immunosuppression, otherwise required in allogeneic transplantations. However, recent studies have shown the unexpected immune rejection of undifferentiated autologous mouse iPSCs after transplantation. Whether similar immunogenic properties are maintained in iPSC-derived lineage-committed cells (such as neural precursors) is relatively unknown. We demonstrate that syngeneic porcine iPSC-derived neural precursor cell (NPC) transplantation to the spinal cord in the absence of immunosuppression is associated with long-term survival and neuronal and glial differentiation. No tumor formation was noted. Similar cell engraftment and differentiation were shown in spinally injured transiently immunosuppressed swine leukocyte antigen (SLA)-mismatched allogeneic pigs. These data demonstrate that iPSC-NPCs can be grafted into syngeneic recipients in the absence of immunosuppression and that temporary immunosuppression is sufficient to induce long-term immune tolerance after NPC engraftment into spinally injured allogeneic recipients. Collectively, our results show that iPSC-NPCs represent an alternative source of transplantable NPCs for the treatment of a variety of disorders affecting the spinal cord, including trauma, ischemia, or amyotrophic lateral sclerosis.
Authors: Strnadel J1,2, Carromeu C3, Bardy C4,5, Navarro M1, Platoshyn O1, Glud AN1, Marsala S1, Kafka J1, Miyanohara A1,6, Kato T Jr7, Tadokoro T1, Hefferan MP1, Kamizato K1, Yoshizumi T1, Juhas S8, Juhasova J8, Ho CS9, Kheradmand T9, Chen P1, Bohaciakova D1,10, Hruska-Plochan M1,11, Todd AJ12, Driscoll SP13, Glenn TD13, Pfaff SL13, Klima J8, Ciacci J14, Curtis E14, Gage FH4, Bui J15, Yamada K16, Muotri AR3, Marsala M17,18.