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Cell Therapy in Models of Moderate and Severe Hemorrhagic Strokes
Stroke is the second leading cause of death in the world and the third leading cause of disability. The disease represents the first cause of death and incapacity in Brazil, which generates great economic and social impact. Stroke is a multicausal disease and can be classified as hemorrhagic or ischemic, with hemorrhagic stroke being the second most common type, accounting for 10% to 20% of cases.
Objetivos - Metodologia - Resultados - Discussão dos Resultados/Objectives - Methodology - Results - Discussion of Results/Objetivos - Metodología - Resultados - Discusión de los resultados
The objective of this study was to evaluate the therapeutic potential of human Wharton’s jelly-derived mesenchymal stem cells (MSCs) in models of moderate and severe intracerebral hemorrhage (ICH) in rats.
Male Wistar rats were anesthetized and positioned in the stereotaxic apparatus. An incision was made in the midline of the scalp, bregma was located and the point with the following stereotactic coordinates was found: 3 mm anteroposterior and 0.2 mm medial-lateral. A craniotomy was made around this point, the cerebral parenchyma was exposed, 6 mm of the dorsal-ventral axis coordinate was subtracted and 0.10U or 0.25U of collagenase (models of moderate and severe ICH, respectively) was injected in the striatum. The animals were randomized to receive an intravenous injection of 3 million MSCs or vehicle 24 h after the injury. A group of false-operated animals (sham) received an intrastriatal injection of saline. In order to evaluate the functional alterations due to ICH, two behavioral tests were performed: elevated body swing test (EBST) and Rotarod test, before surgery and for a period of 21 days after injury. To evaluate lesion volume, the animals were anesthetized and perfused transcardially with saline and 4% paraformaldehyde on the 22nd day. Magnetic resonance imaging (MRI) of animal heads was acquired on a 7T scanner. 3D gradient echo images were performed and data was processed using OsiriX software. The biodistribution of MSCs was evaluated in a separate cohort of animals by labeling the cells with 99mTechnetium (99mTc) before injection into ICH, sham, and naive animals. After 24 hours, the remaining radioactivity in each organ was measured in a gamma counter. The results of the behavioral tests showed no significant differences between the saline and MSCs groups after moderate ICH. There was no differences between the sham group and the MSCs or saline groups at almost all time points, indicating that the moderate injury did not cause significant functional impairments. However, compared to the saline group, the MSCs group exhibited a decreased residual hematoma volume assessed by MRI.The biodistribution analysis demonstrated that the organs containing larger quantities of 99mTc-labeled MSCs after 24 h were the kidneys, lungs, spleen and liver, with no difference among ICH, sham and naive groups. Nevertheless, by analyzing the cerebral distribution of MSCs, we noticed that there was an almost two-fold increase in the quantity of MSCs in the ipsilateral hemisphere in relation to the contralateral hemisphere, only in the ICH group. Finally, in the severe model of ICH, we observed significant differences between the saline and MSCs groups at 20 days in the Rotarod and EBST tests, with the MSCs group exhibiting a better functional outcome.
Considerações Finais/Final considerations/Consideraciones finales
Both the reduction of lesion volume in the model of moderate ICH and the functional improvements in the severe-grade ICH model provide a good perspective for the development of novel therapies using MSCs, considering that, as of yet, there are no specific treatment for ICH.
Palavras-chave/Key words/Palabras clave
hemorrhagic stroke, mesenchymal stem cell, collagenase, magnetic resonance imaging
TANIRA GIARA MELLO, William Simões Rangel Junior, Raphael Santos Almeida, Marcos Assis Nascimento, Teresa Puig Pijuan, Bianca Gutfilen, Sergio Augusto Lopes Souza, Paulo Henrique Rosado-de-Castro, Rosália Mendez-Otero, Pedro Moreno Pimentel-Coelho