Transplantation of TAT-Bcl-xL-transduced neural precursor cells: long-term neuroprotection after stroke.
Neural precursor cells (NPC) are an interesting tool in experimental stroke research, but their therapeutic potential is limited due to poor long-term survival. We therefore in vitro transduced subventricular zone-(SVZ)-derived NPC with the anti-apoptotic fusion protein TAT-Bcl-x(L) and analyzed NPC survival, differentiation, and post-stroke functional deficits after experimental ischemia in mice. Survival of TAT-Bcl-x(L)-transduced NPC, which were injected at day 7 post-stroke into the ischemic striatum, was significantly increased at 4 weeks after stroke. Increased survival of NPC was associated with reduced infarct injury and decreased post-stroke functional deficits. Animals grafted with TAT-Bcl-x(L)-transduced NPC showed an increased number of immature cells expressing the neuronal marker doublecortin. Since mature neuronal differentiation of NPC was not observed, reduced post-stroke injury cannot be attributed to enhanced neuronal regeneration, but rather to indirect by-stander effects of grafted NPC. In line with this, NPC-mediated neuroprotection of cortical neurons in vitro was associated with increased secretion of growth factors. Thus, in vitro transduction of cultivated NPC with TAT-Bcl-x(L) results in enhanced resistance of transplanted NPC followed by long-term neuroprotection and ameliorated functional deficits after transient focal cerebral ischemia in mice.
Doeppner
Thorsten R
TR
Department of Neurology, University of Goettingen Medical School, 37075 Goettingen, Germany. thorsten.doeppner@medizin.uni-goettingen.de
El Aanbouri
Mimount
M
Dietz
Gunnar P H
GP
Weise
Jens
J
Schwarting
Sönke
S
Bähr
Mathias
M
D000818:Animals; D002545:Brain Ischemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D002470:Cell Survival / Q000235:genetics; D019610:Cytoprotection / Q000235:genetics; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D020127:Recovery of Function / Q000235:genetics; D033581:Stem Cell Transplantation / Q000379:methods*; D020521:Stroke / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D013995:Time; D014161:Transduction, Genetic / Q000379:methods*; D051020:bcl-X Protein / Q000235:genetics* / Q000627:therapeutic use; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000627:therapeutic use
C494811:BCL2L1 protein, human; D051020:bcl-X Protein; D054322:tat Gene Products, Human Immunodeficiency Virus