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ABSTRACT: A consortium of translational stem cell and stroke experts from multiple academic institutes and biotechnology companies, under the guidance of the government (FDA/NIH), is missing. Here, we build a case for the establishment of this consortium if cell therapy for stroke is to advance from the laboratory to the clinic.
Cell Transplantation 09/2009; 18(7):691-3. · 5.13 Impact Factor
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Weibo Cai,
Raphael Guzman,
Andrew R Hsu,
Hui Wang,
Kai Chen,
Guohua Sun,
Atul Gera,
Raymond Choi, Tonya Bliss,
Lina He,
Zi-Bo Li,
Anne-Lise D Maag,
Nobutaka Hori,
Heng Zhao,
Michael Moseley,
Gary K Steinberg,
Xiaoyuan Chen
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ABSTRACT: Vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) play important roles during neurovascular repair after stroke. In this study, we imaged VEGFR expression with positron emission tomography (PET) to noninvasively analyze poststroke angiogenesis.
Female Sprague-Dawley rats after distal middle cerebral artery occlusion surgery were subjected to weekly MRI, (18)F-FDG PET, and (64)Cu-DOTA-VEGF(121) PET scans. Several control experiments were performed to confirm the VEGFR specificity of (64)Cu-DOTA-VEGF(121) uptake in the stroke border zone. VEGFR, BrdU, lectin staining, and (125)I-VEGF(165) autoradiography on stroke brain tissue slices were performed to validate the in vivo findings.
T2-weighed MRI correlated with the "cold spot" on (18)F-FDG PET for rats undergoing distal middle cerebral artery occlusion surgery. The (64)Cu-DOTA-VEGF(121) uptake in the stroke border zone peaked at approximately 10 days after surgery, indicating neovascularization as confirmed by histology (VEGFR-2, BrdU, and lectin staining). VEGFR specificity of (64)Cu-DOTA-VEGF(121) uptake was confirmed by significantly lower uptake of (64)Cu-DOTA-VEGF(mutant) in vivo and intense (125)I-VEGF(165) uptake ex vivo in the stroke border zone. No appreciable uptake of (64)Cu-DOTA-VEGF(121) was observed in the brain of sham-operated rats.
For the first time to our knowledge, we successfully evaluated the VEGFR expression kinetics noninvasively in a rat stroke model. In vivo imaging of VEGFR expression could become a significant clinical tool to plan and monitor therapies aimed at improving poststroke angiogenesis.
Stroke 11/2008; 40(1):270-7. · 5.73 Impact Factor
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Jason Liauw,
Stanley Hoang,
Michael Choi,
Cagla Eroglu,
Matthew Choi,
Guo-hua Sun,
Matthew Percy,
Benjamin Wildman-Tobriner, Tonya Bliss,
Raphael G Guzman,
Ben A Barres,
Gary K Steinberg
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ABSTRACT: Thrombospondins 1 and 2 (TSP-1/2) belong to a family of extracellular glycoproteins with angiostatic and synaptogenic properties. Although TSP-1/2 have been postulated to drive the resolution of postischemic angiogenesis, their role in synaptic and functional recovery is unknown. We investigated whether TSP-1/2 are necessary for synaptic and motor recovery after stroke. Focal ischemia was induced in 8- to 12-week-old wild-type (WT) and TSP-1/2 knockout (KO) mice by unilateral occlusion of the distal middle cerebral artery and the common carotid artery (CCA). Thrombospondins 1 and 2 increased after stroke, with both TSP-1 and TSP-2 colocalizing mostly to astrocytes. Wild-type and TSP-1/2 KO mice were compared in angiogenesis, synaptic density, axonal sprouting, infarct size, and functional recovery at different time points after stroke. Using the tongue protrusion test of motor function, we observed that TSP-1/2 KO mice exhibited significant deficit in their ability to recover function (P<0.05) compared with WT mice. No differences were found in infarct size and blood vessel density between the two groups after stroke. However, TSP-1/2 KO mice exhibited significant synaptic density and axonal sprouting deficits. Deficiency of TSP-1/2 leads to impaired recovery after stroke mainly due to the role of these proteins in synapse formation and axonal outgrowth.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 08/2008; 28(10):1722-32. · 5.46 Impact Factor
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ABSTRACT: Endogenous neural stem cells normally reside in their niche, the subventricular zone, in the uninjured rodent brain. Upon stroke, these cells become more proliferative and migrate away from the subventricular zone into the surrounding parenchyma. It is not known whether this stroke-induced behavior is due to changes in the niche or introduction of attractive cues in the infarct zone, or both. A related question is how transplanted neural stem cells respond to subsequent insults, including whether exogenous stem cells have the plasticity to respond to subsequent injuries after engraftment. We addressed this issue by transplanting neural progenitor cells (NPCs) into the uninjured brain and then subjecting the animal to stroke. We were able to follow the transplanted NPCs in vivo by labeling them with superparamagnetic iron oxide particles and imaging them via high-resolution magnetic resonance imaging (MRI) during engraftment and subsequent to stroke. We find that transplanted NPCs that are latent can be activated in response to stroke and exhibit directional migration into the parenchyma, similar to endogenous neural NPCs, without a niche environment.
Journal of Neuroscience Research 04/2008; 86(4):873-82. · 2.74 Impact Factor
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ABSTRACT: No treatment currently exists to restore lost neurological function after stroke. A growing number of studies highlight the potential of stem cell transplantation as a novel therapeutic approach for stroke. In this review we summarize these studies, discuss potential mechanisms of action of the transplanted cells, and emphasize the need to determine parameters that are critical for transplantation success.
Stroke 03/2007; 38(2 Suppl):817-26. · 5.73 Impact Factor
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ABSTRACT: Glucocorticoids (GCs), the adrenal steroids released during stress, can compromise the ability of hippocampal neurons to survive necrotic neurological insults. This GC-induced endangerment has energetic facets, in that it can be attenuated with energy supplementation. In the present report, we studied the effects of GCs on the metabolic response of specific hippocampal cell fields to necrotic insults. We used silicon microphysiometry, which allows indirect measurement of metabolism in real time in tissue explants. Aglycemia caused a significant decline in metabolism in dentate gyrus explants, but not in CA1 or CA3 explants. When coupled with our prior report of cyanide disrupting metabolism only in CA1 explants, and the glutamatergic excitotoxin kainic acid disrupting metabolism only in CA3 explants, this demonstrates that microphysiometry can detect the selective regional vulnerability that characterizes the hippocampal response to these necrotic insults. We then examined the effects of GCs on the response to these insults, monitoring explants taken from rats that were adrenalectomized, intact, or treated with corticosterone (the GC of rats) that produced circulating levels equivalent to those of major stressors. Increased exposure to GCs worsened the decline in metabolism in dentate gyrus explants induced by hypoglycemia, and in CA1 explants induced by cyanide (after eliminating the effects of glial release of lactate for the support of neuronal metabolism). Thus, GCs worsen the metabolic consequences of necrotic insults in hippocampal explants.
Brain Research.
