RESUMO
Background and Purpose- Hypertension is the most frequent comorbidity in stroke.The purpose of this study was to evaluate whether hypertension alters the response to treatment with adipose tissue-derived mesenchymal stem cells (ADMSCs) after an ischemic stroke in rats. Methods- Ischemic stroke was induced in male normotensive or hypertensive rats. Either vehicle or 1×106 ADMSC was intravenously administered at 48 hours poststroke. Functional outcome, lesion size and volume, and markers of brain repair (GFAP [glial fibrillary acidic protein], doublecortin, CD-31, α-smooth muscle actin) were evaluated. Results- Hypertensive rats had larger lesions, higher apparent diffusion coefficients (ADC) and worse functional outcomes than normotensive rats. Hypertension increased GFAP and vascular markers (CD-31 and α-smooth muscle actin). The hypertensive rats treated with ADMSC did not show any significant improvement in functional recovery, lesion size, ADC values, or histological markers compared with those which received the vehicle. Conclusions- ADMSC did not reverse the hypertension-induced increase in lesion severity or functional impairment. Gliosis, neurogenesis, or vascular markers were not affected by ADMSC in hypertensive rats. Hypertension has a negative impact on the therapeutic effect of ADMSC after an ischemic stroke.
Assuntos
Tecido Adiposo , Isquemia Encefálica , Hipertensão , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Acidente Vascular Cerebral , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Aloenxertos , Animais , Biomarcadores/sangue , Isquemia Encefálica/sangue , Isquemia Encefálica/patologia , Isquemia Encefálica/terapia , Proteína Duplacortina , Hipertensão/sangue , Hipertensão/patologia , Hipertensão/terapia , Masculino , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/terapiaRESUMO
BACKGROUND: Mesenchymal stem cell-derived extracellular vesicles (EVs) are one of the most promising therapeutics in protective and/or regenerative therapy in animal models of stroke using a dose of 100 µg. However, whether EVs dose is related to outcomes is not known. This study aimed to identify the optimal effective dose of EVs from adipose tissue-derived mesenchymal stem cells that promote functional recovery in subcortical stroke. MATERIALS AND METHODS: For this purpose, various doses of EVs were tested in an in vitro oxygen-glucose deprivation (OGD) model of oligodendrocytes and neuronal ischemia. At least 50 µg of EVs were necessary to induce proliferation and differentiation of oligodendrocyte and neurons in OGD conditions. For in vivo study, rats were subjected to subcortical stroke and various doses (50 µg, 100 µg, or 200 µg) of EVs were intravenously administered after 24 h. RESULTS: All the animals in the EV groups showed significant improvement in functional tests, with an increase in tract connectivity and brain repair-associated markers, and a decrease in cell death and in astrocyte-marker expression. Cell proliferation was increased in the groups receiving 50 µg and 100 µg doses. Only the 50-µg dose was associated with significant increases in brain-derived neurotrophic factor expression. CONCLUSION: In conclusion, 50 µg of EVs appears to be the minimal effective dose to enhance protection, brain repair, and recovery in subcortical ischemic stroke.
Assuntos
Vesículas Extracelulares/metabolismo , AVC Isquêmico/terapia , Animais , Diferenciação Celular , Proliferação de Células , Modelos Animais de Doenças , Feminino , AVC Isquêmico/patologia , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Over 50% of acute stroke patients have hyperglycemia, which is associated with a poorer prognosis and outcome. Our aim was to investigate the impact of hyperglycemia on behavioral recovery and brain repair of delivered human adipose tissue-derived mesenchymal stem cells (hAD-MSCs) in a rat model of permanent middle cerebral artery occlusion (pMCAO). METHODS: Hyperglycemia was induced in rats by the administration of nicotinamide and streptozotocin. The rats were then subjected to stroke by a pMCAO model. At 48 h post-stroke, 1 × 106 hAD-MSCs or saline were intravenously administered. We evaluated behavioral outcome, infarct size by MRI, and brain plasticity markers by immunohistochemistry (glial fibrillary acidic protein [GFAP], Iba-1, synaptophysin, doublecortin, CD-31, collagen-IV, and α-smooth muscle actin [α-SMA]). RESULTS: The hyperglycemic group exhibited more severe neurological deficits; lesion size and diffusion coefficient were larger compared with the non-hyperglycemic rats. GFAP, Iba-1, and α-SMA were increased in the hyperglycemic group. The hyperglycemic rats administered hAD-MSCs at 48 h after pMCAO had improved neurological impairment. Although T2-MRI did not show differences in lesion size between groups, the rADC values were lower in the treated group. Finally, the levels of GFAP, Iba-1, and arterial wall thickness were lower in the treated hyperglycemic group than in the nontreated hyperglycemic group at 6 weeks post-stroke. CONCLUSIONS: Our data suggest that rats with hyperglycemic ischemic stroke exhibit increased lesion size and impaired brain repair processes, which lead to impairments in behavioral recovery after pMCAO. More importantly, hAD-MSC administration induced better anatomical tissue preservation, associated with a good behavioral outcome.
Assuntos
Hiperglicemia/terapia , Transplante de Células-Tronco Mesenquimais , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral/terapia , Administração Intravenosa , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Modelos Animais de Doenças , Proteína Duplacortina , Humanos , Hiperglicemia/induzido quimicamente , Hiperglicemia/diagnóstico por imagem , Hiperglicemia/patologia , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/terapia , Imageamento por Ressonância Magnética , Células-Tronco Mesenquimais/metabolismo , Niacinamida/toxicidade , Ratos , Estreptozocina/toxicidade , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/patologiaRESUMO
Blocking axonal growth inhibitor NogoA has been of great interest for promoting axonal recovery from neurological diseases. The present study investigates the therapeutic effects of blocking NogoA, inducing functional recovery and promoting white matter repair in an experimental animal model of stroke. Adult male rats were subjected to white matter injury by subcortical ischemic stroke. Twenty-four hours after surgery, 250 ug of anti-NogoA or anti-IgG-1 were administered through the tail vein. The quantity of NogoA protein was determined by immunohistochemistry in the brain and peripheral organs. In addition, functional status, lesion size, fiber tract integrity, axonal sprouting and white matter repair markers were analyzed. Moreover, an in vitro study was performed in order to strengthen the results obtained in vivo. A lower quantity of NogoA protein was found in the brain and peripheral organs of the animals that received anti-NogoA treatment. The animals receiving anti-NogoA treatment showed significantly better results in terms of functional recovery, fiber tract integrity, axonal sprouting and white matter repair markers compared with the control group at 28 days. White matter integrity was in part restored by antibody-mediated inhibition of NogoA administration in those animals that were subjected to an axonal injury by subcortical stroke. This white matter restoration triggered functional recovery.