title: Post-stroke transplantation of adult subventricular zone derived neural progenitor cells--A comprehensive analysis of cell delivery routes and their underlying mechanisms.
abstract: With neuroprotective approaches having failed until recently, current focus on experimental stroke research has switched towards manipulation of post-ischemic neuroregeneration. Transplantation of subventricular zone (SVZ) derived neural progenitor cells (NPCs) is a promising strategy for promotion of neurological recovery. Yet, fundamental questions including the optimal cell delivery route still have to be addressed. Consequently, male C57BL6 mice were exposed to transient focal cerebral ischemia and allowed to survive for as long as 84 days post-stroke. At 6h post-stroke, NPCs were grafted using six different cell delivery routes, i.e., intravenous, intraarterial, ipsilateral intrastriatal, contralateral intrastriatal, ipsilateral intraventricular and ipsilateral intracortical injection. Control mice received PBS only using the aforementioned delivery routes. Intralesional numbers of GFP(+) NPCs were high only after ipsilateral intrastriatal transplantation, whereas other injection paradigms only yielded comparatively small numbers of grafted cells. However, acute neuroprotection and improved functional outcome were observed after both systemic (i.e., intraarterial and intravenous) and ipsilateral intrastriatal transplantation only. Whereas systemic cell delivery induced acute and long-term neuroprotection, reduction of brain injury after ipsilateral intrastriatal cell grafting was only temporary, in line with the loss of transplanted NPCs in the brain. Both systemic and ipsilateral intrastriatal NPC delivery reduced microglial activation and leukocyte invasion, thus reducing free radical formation within the ischemic brain. On the contrary, only systemic NPC administration stabilized the blood-brain-barrier and reduced leukocytosis in the blood. Although intraarterial NPC transplantation was as effective as intravenous cell grafting, mortality of stroke mice was high using the intraarterial delivery route. Consequently, intravenous delivery of native NPCs in our experimental model is an attractive and effective strategy for stroke therapy that deserves further proof-of-concept studies.
authors.affiliation: University of Duisburg-Essen Medical School, Department of Neurology, Essen, Germany; Istanbul Medipol University, Regenerative and Restorative Medical Research Center, Istanbul, Turkey. Electronic address: thorsten.doeppner@uk-essen.de.
authors.forename: Thorsten R
authors.initials: TR
authors.lastname: Doeppner
authors.affiliation: University of Duisburg-Essen Medical School, Department of Neurology, Essen, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Kaltwasser
authors.affiliation: University of Duisburg-Essen Medical School, Department of Neurology, Essen, Germany; National Institute of Technology Calicut, Calicut, Kerala, India.
authors.forename: Mahesh K
authors.initials: MK
authors.lastname: Teli
authors.affiliation: University of Duisburg-Essen Medical School, Department of Neurology, Essen, Germany.
authors.forename: Eduardo H
authors.initials: EH
authors.lastname: Sanchez-Mendoza
authors.affiliation: Istanbul Medipol University, Regenerative and Restorative Medical Research Center, Istanbul, Turkey.
authors.forename: Ertugrul
authors.initials: E
authors.lastname: Kilic
authors.affiliation: University of Goettingen Medical School, Department of Neurology, Goettingen, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Bähr
authors.affiliation: University of Duisburg-Essen Medical School, Department of Neurology, Essen, Germany.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Hermann
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology; D001930:Brain Injuries / Q000209:etiology / Q000601:surgery; D003342:Corpus Striatum / Q000637:transplantation; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D007839:Functional Laterality; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000150:complications / Q000601:surgery*; D020547:Lateral Ventricles / Q000166:cytology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009043:Motor Activity; D053580:Muscle Strength; D058953:Neural Stem Cells / Q000502:physiology* / Q000637:transplantation; D055495:Neurogenesis / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011597:Psychomotor Performance; D020127:Recovery of Function / Q000502:physiology*; D033581:Stem Cell Transplantation / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D000089622:Doublecortin Domain Proteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D049452:Green Fluorescent Proteins; D020780:Matrix Metalloproteinase 9
keywords: Angioneurogenesis; Cell delivery routes; Cerebral ischemia; Neural progenitor cells; Neurological recovery; Neuroprotection; Neuroregeneration; Stroke; Transplantation