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Regenerative potential of combined administration of iPS cell-derived neural progenitor cells and neuroprotective compounds in a rat model of focal traumatic brain injury

Subject Area Molecular and Cellular Neurology and Neuropathology
Clinical Neurology; Neurosurgery and Neuroradiology
Orthopaedics, Traumatology, Reconstructive Surgery
Term from 2014 to 2018
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 261920491
 
Final Report Year 2020

Final Report Abstract

Traumatic brain injury (TBI) is one of the leading causes of mortality among young adults in the developed world. TBI is not only a health problem but also a major economic burden for both patients and societies with an overall cost amounting to $400 billion each year globally. Brain damage following injury results both from a direct tissue destruction imposed by the external force as well as by indirect mechanisms which include inflammation, edema, disruption of the blood-brain barrier, oxidative stress, excitotoxicity, metabolic dysfunctions, and axonal damage terminating in cellular degeneration and long-term sensorimotor and cognitive dysfunction. Despite advances in acute care, diagnostic procedures, rehabilitation strategies, and extensive preclinical research in this area, there is still no effective treatment for TBI. Because the brain has limited capacity for self-repair, therapeutic approaches based on transplantation of various types of stem cells have been developed for replacement of dysfunctional and dead cells in the injured brain as well as for promoting endogenous regeneration. Among different stem cell types that have been tested for this purpose, neural stem cells (NSCs) derived from endogenous sources or pluripotent stem cells (PSCs) represent a promising source of cells for regeneration of injured brain. In addition to cell-based approaches, neuroprotective agents have also been developed for the management of neuroinflammation, cell degeneration and neurobehavioral deficits associated with TBI. One of the promising neuroprotective compounds is P7C3-S243, an aminopropyl carbazole that was shown to have a pro-neurogenic and neuroprotective activity in mice and rats. In this project, we tested the hypothesis that combined use of P7C3-S243 and human iPSC-derived NSCs results in a synergistic and enhanced therapeutic effect in the rat model of TBI. Our data show that P7C3-S243 is not toxic to hiPSC-NSCs in vitro and that stimulates their proliferation in vivo after transplantation in the vicinity of the injured area after TBI as determined by scoring Ki-67 and BrdU-positive cells. These analyses also revealed that the proliferation rate of endogenous NSCs in the subventricular zone (SVZ) was also increased in P7C3-S243-treated animals compared to untreated controls, which corroborates the finding of other groups. The assessment of the neuromotor recovery after TBI was performed by Rotarod and composite neuroscore tests. These analyses showed that P7C3-S243 improves composite neuroscore deficits after treatment of rats for 14 and 21 days after cerebral injury but does not have a significant effect on neuromotor recovery in rats with TBI in a Rotarod test under the applied experimental conditions. This data show that combined administration of hiPSC-NSCs and P7C3-S243 to rats with TBI might have better therapeutic efficacy than administration of hiPSC-NSCs alone, most likely due to enhanced endogenous and exogenous neurogenesis in drug-treated animals. However, further analyses with higher numbers of animals, different cell and drug doses, longer treatment durations and broader palette of neurobehavioral tests will be required in order to substantiate this conclusion.

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