Regeneratives Potenzial der kombinierten Applikation von aus induziert-pluripotenten Stammzellen generierten neuralen Progenitorzellen und neuroprotektiven Substanzen beim Schädel-Hirn Trauma - Untersuchung zur Transplantation im Ratten-Tiermodell
Klinische Neurologie; Neurochirurgie und Neuroradiologie
Orthopädie, Unfallchirurgie, rekonstruktive Chirurgie
Zusammenfassung der Projektergebnisse
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.
Projektbezogene Publikationen (Auswahl)
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(2020) Acquisition of chromosome 1q duplication in parental and genome-edited human-induced pluripotent stem cell-derived neural stem cells results in their higher proliferation rate in vitro and in vivo. Cell proliferation 53 (10) e12892
Mehrjardi, Narges Zare; Molcanyi, Marek; Hatay, Firuze Fulya; Timmer, Marco; Shahbazi, Ebrahim; Ackermann, Justus P.; Herms, Stefan; Heilmann-Heimbach, Stefanie; Wunderlich, Thomas F.; Prochnow, Nora; Haghikia, Aiden; Lampert, Angelika; Hescheler, Jürgen;
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Conversion of Human Fibroblasts to Stably Self-Renewing Neural Stem Cells with a Single Zinc-Finger Transcription Factor. Stem Cell Rep. 2016;6:539-551
Shahbazi E, Moradi S, Nemati S, Satarian L, Basiri M, Gourabi H, Zare Mehrjardi N, Günther P, Lampert A, Händler K, Hatay FF, Schmidt D, Molcanyi M, Hescheler J, Schultze JL, Šarić T, Baharvand H
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Characterisation of the Immune Response after Implantation of hiPSC-Derived Neural Stem/Progenitor Cells into the Brain of RNU Rat. 1st Cologne Neuroscience Day, March 17th, 2017, Cologne, Germany
Hatay FF, Mehrjardi NZ, Timmer M, Hescheler J, Saric T, Molcanyi M
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Genetic manipulation of neural progenitor cells derived from human induced pluripotent stem cells by using zinc finger nucleases. Canadian Stem Cell Network travel award to Narges Zare Mehrjardi. 2017 Till and McCulloch Meeting, November 6-8, 2017, Mont-Tremblant, Québec, Canada
Mehrjardi NZ, Satarian L, Neef K, Baharvand H, Hescheler J, Šarić T
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Recurrent duplication of Chr1q in clonally selected human induced pluripotent stem cell-derived neural progenotor cells prior to and after targeted genome editing. 1st Cologne Neuroscience Day, March 17th, 2017, Cologne, Germany
Mehrjardi NZ, Molcanyi M, Timmer M, Satarian L, Haghikia A, Prochnow N, Shahbazi E, Ackermann PJ, Herms S, Heilmann S, Neef K, Wunderlich TF, Hescheler J, Baharvand H, Šarić T
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Recapitulation of Human Neural Microenvironment Signatures in iPSC-Derived NPC 3D Differentiation. Stem Cell Rep. 2018;11:552-564
Simão D, Silva MM, Terrasso AP, Arez F, Sousa MFQ, Mehrjardi NZ, Šarić T, Gomes-Alves P, Raimundo N, Alves PM, Brito C
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Recurring chromosome 1q duplication in parental and zinc-finger nuclease-edited human iPSC-derived neural stem cells results in their higher proliferation rate in vitro and in vivo. 6th Annual Conference of the German Stem Cell Network (GSCN), September 19th-21st, 2018, Heidelberg, Germany
Narges ZM, Molcanyi M, Hatay FF, Timmer M, Shahbazi E, Herms S, Heilmann S, Lampert A, Ackermann JP, Wunderlich T, Baharvand H, Hescheler J, Neugebauer E, Šarić T
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Acid Sensitive Ion channels are expressed in human induced pluripotent stem cell-derived cardiomyocytes. Stem Cells Dev 2019;28:920-932
Zhang XH, Šarić T, Mehrjardi NZ, Hamad S, Morad M
