Tenille Smith - Academia.edu (original) (raw)
Papers by Tenille Smith
Stroke, 2012
Background and Purpose-Intra-arterial neural stem cell (NSC) transplantation shows promise as a m... more Background and Purpose-Intra-arterial neural stem cell (NSC) transplantation shows promise as a minimally invasive therapeutic option for stroke. We assessed the effect of timing of transplantation on cell engraftment, survival, and differentiation. Methods-Mouse NSCs transduced with a green fluorescent protein and renilla luciferase reporter gene were transplanted into animals 6 and 24 hours and 3, 7, and 14 days after hypoxia-ischemia (HI). Bioluminescent imaging was used to assess cell survival at 6 hours and 4 and 7 days after transplantation. Immunohistochemistry was used to assess NSC survival and phenotypic differentiation 1 month after transplantation. NSC receptor expression and brain gene expression were evaluated using real-time reverse transcription-quantitative polymerase chain reaction to elucidate mechanisms of cell migration. Boyden chamber assays were used to assess cell migratory potential in vitro. Results-NSC transplantation 3 days after HI resulted in significantly higher cell engraftment and survival at 7 and 30 days compared with all other groups (PϽ0.05). Early transplantation at 6 and 24 hours after HI resulted in significantly higher expression of glial fibrillary acidic protein (Pϭ0.0140), whereas late transplantation at 7 and 14 days after HI resulted in higher expression of -tubulin (PϽ0.0001). Corroborating the high cell engraftment 3 days after HI was robust expression of vascular cell adhesion molecule-1, CCL2, and CXCL12 in brain homogenates 3 days after HI.
![Research paper thumbnail of PET Imaging of Stroke-Induced Neuroinflammation in Mice Using [18F]PBR06](https://attachments.academia-assets.com/39622949/thumbnails/1.jpg)
](Molecular Imaging and Biology, 2014
Purpose: The purpose of this study is to evaluate the 18 kDa translocator protein (TSPO) radiolig... more Purpose: The purpose of this study is to evaluate the 18 kDa translocator protein (TSPO) radioligand [ 18 F]N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline ([ 18 F]PBR06) as a positron emission tomography (PET) imaging biomarker of stroke-induced neuroinflammation in a rodent model. Procedures: Stroke was induced by transient middle cerebral artery occlusion in Balb/c mice. Dynamic PET/CT imaging with displacement and preblocking using PK111195 was performed 3 days later. PET data were correlated with immunohistochemistry (IHC) for the activated microglial markers TSPO and CD68 and with autoradiography. Results: [ 18 F]PBR06 accumulation peaked within the first 5 min postinjection, then decreased gradually, remaining significantly higher in infarct compared to noninfarct regions. Displacement or preblocking with PK11195 eliminated the difference in [ 18 F]PBR06 uptake between infarct and noninfarct regions. Autoradiography and IHC correlated well spatially with uptake on PET. Conclusions: [ 18 F]PBR06 PET specifically images TSPO in microglial neuroinflammation in a mouse model of stroke and shows promise for imaging and monitoring microglial activation/ neuroinflammation in other disease models.
Cell Transplantation, 2000
Intra-arterial (IA) neural stem cell (NSC) therapy has the potential to improve long-term outcome... more Intra-arterial (IA) neural stem cell (NSC) therapy has the potential to improve long-term outcomes after stroke. Here we evaluate if pre-treatment of NSCs with brain derived neurotrophic factor (BDNF) prior to transplantation improves cell engraftment and functional recovery following hypoxic-ischemia (HI). Human embryonic-derived NSCs with or without BDNF pre-treatment (1 hour, 100ng/mL) were transplanted 3 days after HI. Functional recovery was assessed using the horizontal ladder test. Cell engraftment was evaluated using bioluminescence imaging (BLI) and histological counts of SC121(+) cells. Fluoro-JadeC (FJC) and NeuN stains were used to evaluate neuroprotection. The effect of BDNF on NSCs was analyzed using a migration assay, immunocytochemistry, Luminex proteomic assay, and RT-qPCR. BLI analysis demonstrated significantly higher photon flux in the BDNF-treated NSC group compared to untreated NSC (p=0.049) and control groups (p=0.0021) at 1 week after transplantation. Immunohistochemistry confirmed increased transplanted cell survival in the cortex (p=0.0126) and hippocampus (p=0.0098) of animals injected with BDNF-treated NSCs compared to untreated NSCs. Behavioral testing revealed that the BDNF-treated NSC group demonstrated increased sensorimotor recovery compared to the untreated NSC and control groups (p<0.001) over the 1-month period (p<0.001) following transplantation. A significant improvement in performance was found in the BDNF-treated NSC group compared to the control group at 14, 21, and 28, (p<0.05) days after transplantion. The cortex and hippocampus of the BDNF-treated NSC group had significantly more SC121(+) NSCs (p=0.0125, p=0.0098), fewer FJC(+) neurons (p=0.0370, p=0.0285) and a higher percentage of NeuN (+)=expression (p=0.0354) in the cortex as compared to the untreated NSC group. BDNF treatment of NSCs resulted in significantly greater migration to SDF-1, secretion of M-CSF, VEGF, and expression of CXCR4, VCAM-1, Thrombospondins 1 and 2, and BDNF.
Translational Stroke Research, 2011
Stroke is the third leading cause of death and the leading cause of adult disability in North Ame... more Stroke is the third leading cause of death and the leading cause of adult disability in North America. Emphasis has been placed on developing treatments that reduce the devastating long-term impacts of this disease, and preclinical research on stem cell therapy has demonstrated promising results. However, questions about the optimal cell delivery method and timing of cell transplantation are not fully answered. Recent findings suggest that intravascular stem cell delivery is a safe and efficacious alternative to stereotactic cell injections. It also offers advantages should repeat treatments prove beneficial. Recent reports further suggest that intra-arterial injection results in a wider distribution of cells throughout the stroked hemisphere with a significantly greater cell engraftment compared to intravenous injection. In this review, we describe the benefits and potential risks associated with intravascular stem cell delivery and compare intra-arterial to intravenous cell transplantation methods. We discuss the importance of cell biodistribution and timing of transplantation in driving cell survival. We examine current proposed mechanisms involved in cell migration and functional recovery and discuss future directions for intravascular stem cell therapy research.
Stroke, 2012
Background and Purpose-Intra-arterial neural stem cell (NSC) transplantation shows promise as a m... more Background and Purpose-Intra-arterial neural stem cell (NSC) transplantation shows promise as a minimally invasive therapeutic option for stroke. We assessed the effect of timing of transplantation on cell engraftment, survival, and differentiation. Methods-Mouse NSCs transduced with a green fluorescent protein and renilla luciferase reporter gene were transplanted into animals 6 and 24 hours and 3, 7, and 14 days after hypoxia-ischemia (HI). Bioluminescent imaging was used to assess cell survival at 6 hours and 4 and 7 days after transplantation. Immunohistochemistry was used to assess NSC survival and phenotypic differentiation 1 month after transplantation. NSC receptor expression and brain gene expression were evaluated using real-time reverse transcription-quantitative polymerase chain reaction to elucidate mechanisms of cell migration. Boyden chamber assays were used to assess cell migratory potential in vitro. Results-NSC transplantation 3 days after HI resulted in significantly higher cell engraftment and survival at 7 and 30 days compared with all other groups (PϽ0.05). Early transplantation at 6 and 24 hours after HI resulted in significantly higher expression of glial fibrillary acidic protein (Pϭ0.0140), whereas late transplantation at 7 and 14 days after HI resulted in higher expression of -tubulin (PϽ0.0001). Corroborating the high cell engraftment 3 days after HI was robust expression of vascular cell adhesion molecule-1, CCL2, and CXCL12 in brain homogenates 3 days after HI.
Molecular Imaging and Biology, 2014
Purpose: The purpose of this study is to evaluate the 18 kDa translocator protein (TSPO) radiolig... more Purpose: The purpose of this study is to evaluate the 18 kDa translocator protein (TSPO) radioligand [ 18 F]N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline ([ 18 F]PBR06) as a positron emission tomography (PET) imaging biomarker of stroke-induced neuroinflammation in a rodent model. Procedures: Stroke was induced by transient middle cerebral artery occlusion in Balb/c mice. Dynamic PET/CT imaging with displacement and preblocking using PK111195 was performed 3 days later. PET data were correlated with immunohistochemistry (IHC) for the activated microglial markers TSPO and CD68 and with autoradiography. Results: [ 18 F]PBR06 accumulation peaked within the first 5 min postinjection, then decreased gradually, remaining significantly higher in infarct compared to noninfarct regions. Displacement or preblocking with PK11195 eliminated the difference in [ 18 F]PBR06 uptake between infarct and noninfarct regions. Autoradiography and IHC correlated well spatially with uptake on PET. Conclusions: [ 18 F]PBR06 PET specifically images TSPO in microglial neuroinflammation in a mouse model of stroke and shows promise for imaging and monitoring microglial activation/ neuroinflammation in other disease models.
Cell Transplantation, 2000
Intra-arterial (IA) neural stem cell (NSC) therapy has the potential to improve long-term outcome... more Intra-arterial (IA) neural stem cell (NSC) therapy has the potential to improve long-term outcomes after stroke. Here we evaluate if pre-treatment of NSCs with brain derived neurotrophic factor (BDNF) prior to transplantation improves cell engraftment and functional recovery following hypoxic-ischemia (HI). Human embryonic-derived NSCs with or without BDNF pre-treatment (1 hour, 100ng/mL) were transplanted 3 days after HI. Functional recovery was assessed using the horizontal ladder test. Cell engraftment was evaluated using bioluminescence imaging (BLI) and histological counts of SC121(+) cells. Fluoro-JadeC (FJC) and NeuN stains were used to evaluate neuroprotection. The effect of BDNF on NSCs was analyzed using a migration assay, immunocytochemistry, Luminex proteomic assay, and RT-qPCR. BLI analysis demonstrated significantly higher photon flux in the BDNF-treated NSC group compared to untreated NSC (p=0.049) and control groups (p=0.0021) at 1 week after transplantation. Immunohistochemistry confirmed increased transplanted cell survival in the cortex (p=0.0126) and hippocampus (p=0.0098) of animals injected with BDNF-treated NSCs compared to untreated NSCs. Behavioral testing revealed that the BDNF-treated NSC group demonstrated increased sensorimotor recovery compared to the untreated NSC and control groups (p<0.001) over the 1-month period (p<0.001) following transplantation. A significant improvement in performance was found in the BDNF-treated NSC group compared to the control group at 14, 21, and 28, (p<0.05) days after transplantion. The cortex and hippocampus of the BDNF-treated NSC group had significantly more SC121(+) NSCs (p=0.0125, p=0.0098), fewer FJC(+) neurons (p=0.0370, p=0.0285) and a higher percentage of NeuN (+)=expression (p=0.0354) in the cortex as compared to the untreated NSC group. BDNF treatment of NSCs resulted in significantly greater migration to SDF-1, secretion of M-CSF, VEGF, and expression of CXCR4, VCAM-1, Thrombospondins 1 and 2, and BDNF.
Translational Stroke Research, 2011
Stroke is the third leading cause of death and the leading cause of adult disability in North Ame... more Stroke is the third leading cause of death and the leading cause of adult disability in North America. Emphasis has been placed on developing treatments that reduce the devastating long-term impacts of this disease, and preclinical research on stem cell therapy has demonstrated promising results. However, questions about the optimal cell delivery method and timing of cell transplantation are not fully answered. Recent findings suggest that intravascular stem cell delivery is a safe and efficacious alternative to stereotactic cell injections. It also offers advantages should repeat treatments prove beneficial. Recent reports further suggest that intra-arterial injection results in a wider distribution of cells throughout the stroked hemisphere with a significantly greater cell engraftment compared to intravenous injection. In this review, we describe the benefits and potential risks associated with intravascular stem cell delivery and compare intra-arterial to intravenous cell transplantation methods. We discuss the importance of cell biodistribution and timing of transplantation in driving cell survival. We examine current proposed mechanisms involved in cell migration and functional recovery and discuss future directions for intravascular stem cell therapy research.