Effects of Neural Stem Cell and Olfactory Ensheathing Cell Co-transplants on Tissue Remodelling After Transient Focal Cerebral Ischemia in the Adult Rat
- 387 Downloads
Effective transplant-mediated repair of ischemic brain lesions entails extensive tissue remodeling, especially in the ischemic core. Neural stem cells (NSCs) are promising reparative candidates for stroke induced lesions, however, their survival and integration with the host-tissue post-transplantation is poor. In this study, we address this challenge by testing whether co-grafting of NSCs with olfactory ensheathing cells (OECs), a special type of glia with proven neuroprotective, immunomodulatory, and angiogenic effects, can promote graft survival and host tissue remodelling. Transient focal cerebral ischemia was induced in adult rats by a 60-min middle cerebral artery occlusion (MCAo) followed by reperfusion. Ischemic lesions were verified by neurological testing and magnetic resonance imaging. Transplantation into the globus pallidus of NSCs alone or in combination with OECs was performed at two weeks post-MCAo, followed by histological analyses at three weeks post-transplantation. We found evidence of extensive vascular remodelling in the ischemic core as well as evidence of NSC motility away from the graft and into the infarct border in severely lesioned animals co-grafted with OECs. These findings support a possible role of OECs as part of an in situ tissue engineering paradigm for transplant mediated repair of ischemic brain lesions.
KeywordsStroke Tissue engineering Vascular remodeling CNS regeneration
ILA, AKH, AS, and IS would like to acknowledge funding by the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology—Samarbeidsorganet HMN-NTNU. Additionally, IS and AS acknowledge funding by the Norwegian Financial Mechanism 2009–2014 and the Czech Ministry of Education, Youth and Sports under Project Contract No. MSMT-28477/2014, Project 7F14057. The authors would like to thank Dr. Marius Widerøe for technical assistance with setting up the MR scanning parameters. Many thanks to Professors Berit Strand and Michel Modo for useful discussions.
Compliance with Ethical Standards
Conflict of interest
The authors have no conflict of interest to declare.
- 9.Smith EJ, Stroemer RP, Gorenkova N, Nakajima M, Crum WR, Tang E, Stevanato L, Sinden JD, Modo M (2012) Implantation site and lesion topology determine efficacy of a human neural stem cell line in a rat model of chronic stroke. Stem cells (Dayton, Ohio) 30:785–796Google Scholar
- 19.Sandvig I, Thuen M, Hoang L, Olsen O, Sardella TC, Brekken C, Tvedt KE, Barnett SC, Haraldseth O, Berry M, Sandvig A (2012) In vivo MRI of olfactory ensheathing cell grafts and regenerating axons in transplant mediated repair of the adult rat optic nerve. NMR Biomed 25:620–631CrossRefPubMedGoogle Scholar
- 22.Tabakow P, Raisman G, Fortuna W, Czyz M, Huber J, Li D, Szewczyk P, Okurowski S, Miedzybrodzki R, Czapiga B, Salomon B, Halon A, Li Y, Lipiec J, Kulczyk A, Jarmundowicz W (2014) Functional regeneration of supraspinal connections in a patient with transected spinal cord following transplantation of bulbar olfactory ensheathing cells with peripheral nerve bridging. Cell Transplant 23:1631–1655CrossRefPubMedGoogle Scholar
- 26.Haberg A, Qu H, Haraldseth O, Unsgard G, Sonnewald U (1998) In vivo injection of [1-13C]glucose and [1,2-13C]acetate combined with ex vivo 13C nuclear magnetic resonance spectroscopy: a novel approach to the study of middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab 18:1223–1232CrossRefPubMedGoogle Scholar
- 31.Liu SJ, Zou Y, Belegu V, Lv LY, Lin N, Wang TY, McDonald JW, Zhou X, Xia QJ, Wang TH (2014) Co-grafting of neural stem cells with olfactory en sheathing cells promotes neuronal restoration in traumatic brain injury with an anti-inflammatory mechanism. J Neuroinflammation 11:66CrossRefPubMedPubMedCentralGoogle Scholar
- 45.Jackson JS, Golding JP, Chapon C, Jones WA, Bhakoo KK (2010) Homing of stem cells to sites of inflammatory brain injury after intracerebral and intravenous administration: a longitudinal imaging study. Stem Cell Res Ther 1:17Google Scholar
- 46.Guzman R, Uchida N, Bliss TM, He D, Christopherson KK, Stellwagen D, Capela A, Greve J, Malenka RC, Moseley ME, Palmer TD, Steinberg GK (2007) Long-term monitoring of transplanted human neural stem cells in developmental and pathological contexts with MRI. Proc Natl Acad Sci USA 104:10211–10216CrossRefPubMedPubMedCentralGoogle Scholar
- 50.Doeppner TR, Kaltwasser B, Teli MK, Sanchez-Mendoza EH, Kilic E, Bahr M, Hermann DM (2015) Post-stroke transplantation of adult subventricular zone derived neural progenitor cells—a comprehensive analysis of cell delivery routes and their underlying mechanisms. Exp Neurol 273:45–56CrossRefPubMedGoogle Scholar
- 52.Fluri F, Schuhmann MK, Kleinschnitz C (2015) Animal models of ischemic stroke and their application in clinical research. Drug Des Dev Ther 9:3445–3454Google Scholar
- 55.Sandvig I, Karstensen K, Rokstad AM, Aachmann FL, Formo K, Sandvig A, Skjak-Braek G, Strand BL (2014) RGD-peptide modified alginate by a chemoenzymatic strategy for tissue engineering applications. J Biomed Mater Res Part A 103:896–906Google Scholar