Transduction of neural precursor cells with TAT-heat shock protein 70 chaperone
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Transduction of neural precursor cells with TAT-heat shock protein 70 chaperone : therapeutic potential against ischemic stroke after intrastriatal and systemic transplantation. / Doeppner, Thorsten R; Ewert, Tobias A S; Tönges, Lars; Herz, Josephine; Zechariah, Anil; ElAli, Ayman; Ludwig, Anna-Kristin; Giebel, Bernd; Nagel, Florian; Dietz, Gunnar P H; Weise, Jens; Hermann, Dirk M; Bähr, Mathias.
In: Stem cells (Dayton, Ohio), Vol. 30, No. 6, 01.06.2012, p. 1297-310.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Transduction of neural precursor cells with TAT-heat shock protein 70 chaperone
T2 - therapeutic potential against ischemic stroke after intrastriatal and systemic transplantation
AU - Doeppner, Thorsten R
AU - Ewert, Tobias A S
AU - Tönges, Lars
AU - Herz, Josephine
AU - Zechariah, Anil
AU - ElAli, Ayman
AU - Ludwig, Anna-Kristin
AU - Giebel, Bernd
AU - Nagel, Florian
AU - Dietz, Gunnar P H
AU - Weise, Jens
AU - Hermann, Dirk M
AU - Bähr, Mathias
N1 - Copyright © 2012 AlphaMed Press.
PY - 2012/6/1
Y1 - 2012/6/1
N2 - Novel therapeutic concepts against cerebral ischemia focus on cell-based therapies in order to overcome some of the side effects of thrombolytic therapy. However, cell-based therapies are hampered because of restricted understanding regarding optimal cell transplantation routes and due to low survival rates of grafted cells. We therefore transplanted adult green fluorescence protein positive neural precursor cells (NPCs) either intravenously (systemic) or intrastriatally (intracerebrally) 6 hours after stroke in mice. To enhance survival of NPCs, cells were in vitro protein-transduced with TAT-heat shock protein 70 (Hsp70) before transplantation followed by a systematic analysis of brain injury and underlying mechanisms depending on cell delivery routes. Transduction of NPCs with TAT-Hsp70 resulted in increased intracerebral numbers of grafted NPCs after intracerebral but not after systemic transplantation. Whereas systemic delivery of either native or transduced NPCs yielded sustained neuroprotection and induced neurological recovery, only TAT-Hsp70-transduced NPCs prevented secondary neuronal degeneration after intracerebral delivery that was associated with enhanced functional outcome. Furthermore, intracerebral transplantation of TAT-Hsp70-transduced NPCs enhanced postischemic neurogenesis and induced sustained high levels of brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, and vascular endothelial growth factor in vivo. Neuroprotection after intracerebral cell delivery correlated with the amount of surviving NPCs. On the contrary, systemic delivery of NPCs mediated acute neuroprotection via stabilization of the blood-brain-barrier, concomitant with reduced activation of matrix metalloprotease 9 and decreased formation of reactive oxygen species. Our findings imply two different mechanisms of action of intracerebrally and systemically transplanted NPCs, indicating that systemic NPC delivery might be more feasible for translational stroke concepts, lacking a need of in vitro manipulation of NPCs to induce long-term neuroprotection.
AB - Novel therapeutic concepts against cerebral ischemia focus on cell-based therapies in order to overcome some of the side effects of thrombolytic therapy. However, cell-based therapies are hampered because of restricted understanding regarding optimal cell transplantation routes and due to low survival rates of grafted cells. We therefore transplanted adult green fluorescence protein positive neural precursor cells (NPCs) either intravenously (systemic) or intrastriatally (intracerebrally) 6 hours after stroke in mice. To enhance survival of NPCs, cells were in vitro protein-transduced with TAT-heat shock protein 70 (Hsp70) before transplantation followed by a systematic analysis of brain injury and underlying mechanisms depending on cell delivery routes. Transduction of NPCs with TAT-Hsp70 resulted in increased intracerebral numbers of grafted NPCs after intracerebral but not after systemic transplantation. Whereas systemic delivery of either native or transduced NPCs yielded sustained neuroprotection and induced neurological recovery, only TAT-Hsp70-transduced NPCs prevented secondary neuronal degeneration after intracerebral delivery that was associated with enhanced functional outcome. Furthermore, intracerebral transplantation of TAT-Hsp70-transduced NPCs enhanced postischemic neurogenesis and induced sustained high levels of brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, and vascular endothelial growth factor in vivo. Neuroprotection after intracerebral cell delivery correlated with the amount of surviving NPCs. On the contrary, systemic delivery of NPCs mediated acute neuroprotection via stabilization of the blood-brain-barrier, concomitant with reduced activation of matrix metalloprotease 9 and decreased formation of reactive oxygen species. Our findings imply two different mechanisms of action of intracerebrally and systemically transplanted NPCs, indicating that systemic NPC delivery might be more feasible for translational stroke concepts, lacking a need of in vitro manipulation of NPCs to induce long-term neuroprotection.
KW - Animals
KW - Brain Ischemia
KW - Cell Differentiation
KW - Disease Models, Animal
KW - Gene Transfer Techniques
KW - HSP70 Heat-Shock Proteins
KW - Immunohistochemistry
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Neural Stem Cells
KW - Stem Cell Transplantation
KW - Stroke
KW - Transduction, Genetic
U2 - 10.1002/stem.1098
DO - 10.1002/stem.1098
M3 - SCORING: Journal article
C2 - 22593021
VL - 30
SP - 1297
EP - 1310
JO - STEM CELLS
JF - STEM CELLS
SN - 1066-5099
IS - 6
ER -