Reprogrammed neuronal stem cells survive long-term in spinal cord injury model

Written by Sharon Salt, Editor

An international team led by scientists at the University of California San Diego School of Medicine (UCSD; CA, USA) has revealed recent research that utilizes neuronal cells programmed from genetically identical pigs to eliminate the need for immunosuppression measures.
Using neural stem cells derived from genetically different donors in order to replace damaged or destroyed tissue has been extremely challenging, given the persistent rejection of the introduced cells. This usually necessitates the use of complex drugs and techniques to suppress the host’s immune system.

In a new study published in Science Translational Medicine, the team describes successfully grafting induced pluripotent stem cell (iPSC)-derived neural precursors cells (NPCs) back into the spinal cords of genetically identical adult pigs with no immunosuppression efforts. The grafted cells were reported to survive long-term, displayed differentiated functionality and did not result in tumor formation.

The researchers also demonstrated that the same cells displayed 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,” commented Martin Marsala (UCSD), senior author of the study.

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In the study, researchers removed skin cells from an adult pig and reprogrammed them back to stem cells. These cells were then induced to become NPCs, which are destined to become nerve cells. According to the researchers, because these cells are syngeneic – that is, genetically identical with the cell-graft recipient pig – they are immunologically compatible; they grow and differentiate with no immunosuppression required.

“Using RNA sequencing and innovative bioinformatics 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,” explained co-author Samuel Pfaff (Salk Institute for Biological Studies, CA, USA).

The researchers grafted NPCs into spinal cords of syngeneic non-injured pigs with no immunosuppression and reported that at all observed time points, the NPCs survived and differentiated into neurons and supporting glial cells. At 7 months post-transplantation, the grafted neurons were still detected as functioning.

They then went on to graft NPCs into allogeneic – that is, genetically dissimilar pigs – with chronic spinal cord injuries, followed by a transient 4-week regimen of immunosuppression drugs. They observed similar results with long-term cell survival and maturation.

“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 CNS injuries in a syngeneic or allogeneic setting,” remarked Marsala.

“Because long-term post-grafting periods (1–2 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.”

Joseph Ciacci (UCSD), co-author of the study, concluded: “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.”

Sources: Strnadel J, Carromeu C, Bardy C et al. Survival of syngeneic and allogeneic iPSC-derived neural precursors after spinal grafting in minipigs. Sci. Transl. Med. 10(440), eaam6651 (2018) (Epub ahead of print);