Human neural stem cells improve early stage stroke outcome in delayed tissue plasminogen activator-treated aged stroke brains
| Autor: | Jean-Pyo Lee, Auston Eckert, Milton H. Hamblin, Austin C. Boese |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Aging Population Inflammation Tissue plasminogen activator Article Proinflammatory cytokine Time-to-Treatment 03 medical and health sciences Mice 0302 clinical medicine Developmental Neuroscience Neural Stem Cells Neurotrophic factors Internal medicine medicine Animals Humans cardiovascular diseases education Stroke Cells Cultured education.field_of_study business.industry Brain medicine.disease Neural stem cell Transplantation Mice Inbred C57BL 030104 developmental biology Treatment Outcome Neurology Tissue Plasminogen Activator Cardiology medicine.symptom business 030217 neurology & neurosurgery medicine.drug Stem Cell Transplantation |
| Zdroj: | Exp Neurol |
| ISSN: | 1090-2430 |
| Popis: | Introduction Clinically, significant stroke injury results from ischemia-reperfusion (IR), which induces a deleterious biphasic opening of the blood-brain barrier (BBB). Tissue plasminogen activator (tPA) remains the sole pharmacological agent to treat ischemic stroke. However, major limitations of tPA treatment include a narrow effective therapeutic window of 4.5 h in most patients after initial stroke onset and off-target non-thrombolytic effects (e.g., the risk of increased IR injury). We hypothesized that ameliorating BBB damage with exogenous human neural stem cells (hNSCs) would improve stroke outcome to a greater extent than treatment with delayed tPA alone in aged stroke mice. Methods We employed middle cerebral artery occlusion to produce focal ischemia with subsequent reperfusion (MCAO/R) in aged mice and administered tPA at a delayed time point (6 h post-stroke) via tail vein. We transplanted hNSCs intracranially in the subacute phase of stroke (24 h post-stroke). We assessed the outcomes of hNSC transplantation on pathophysiological markers of stroke 48 h post-stroke (24 h post-transplant). Results Delayed tPA treatment resulted in more extensive BBB damage and inflammation relative to MCAO controls. Notably, transplantation of hNSCs ameliorated delayed tPA-induced escalated stroke damage; decreased expression of proinflammatory factors (tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6), decreased the level of matrix metalloprotease-9 (MMP-9), increased the level of brain-derived neurotrophic factor (BDNF), and reduced BBB damage. Conclusions Aged stroke mice that received delayed tPA treatment in combination with hNSC transplantation exhibited reduced stroke pathophysiology in comparison to non-transplanted stroke mice with delayed tPA. This suggests that hNSC transplantation may synergize with already existing stroke therapies to benefit a larger stroke patient population. |
| Databáze: | OpenAIRE |
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