Ryo Kiyose1, Masanori Sasaki2, Yuko Kataoka-Sasaki3, Masahito Nakazaki4, Hiroshi Nagahama5, Hirotoshi Magota1, Shinichi Oka3, Ryo Ukai3, Mitsuhiro Takemura3, Takahiro Yokoyama3, Jeffery D Kocsis6, Osamu Honmou4. 1. Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan; Tominaga Hospital, Naniwa-ku, Osaka City, Osaka, Japan. 2. Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan; Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA; Center for Neuroscience and Regeneration Research, VA Connecticut Healthcare System, West Haven, Connecticut, USA. Electronic address: msasaki@sapmed.ac.jp. 3. Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan. 4. Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan; Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA; Center for Neuroscience and Regeneration Research, VA Connecticut Healthcare System, West Haven, Connecticut, USA. 5. Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan; Division of Radioisotope Research, Biomedical Research, Education and Instrumentation Center, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan. 6. Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA; Center for Neuroscience and Regeneration Research, VA Connecticut Healthcare System, West Haven, Connecticut, USA.
Abstract
OBJECTIVE: Reperfusion therapy is a standard therapeutic strategy for acute stroke. Non-favorable outcomes are thought to partially result from impaired microcirculatory flow in ischemic tissue. Intravenous infusion of mesenchymal stem cells (MSCs) reduces stroke volume and improves behavioral function in stroke. One suggested therapeutic mechanism is the restoration of the microvasculature. The goal of this study was to determine whether infused MSCs enhance the therapeutic efficacy of reperfusion therapy following stroke in rats. METHODS: First, to establish a transient middle cerebral artery occlusion (MCAO) model displaying approximately identical neurologic function and lesion volume as seen in permanent MCAO (pMCAO) at day 7 after stroke induction, we transiently occluded the MCA for 90, 110, and 120 minutes. We found that the 110-minute occlusion met these criteria and was used as the transient MCAO (tMCAO) model. Next, 4 MCAO groups were used to compare the therapeutic efficacy of infused MSCs: (1) pMCAO+vehicle, (2) tMCAO+vehicle, (3) pMCAO+MSC, and (4) tMCAO+MSC. Our ischemic model was a unique ischemic model system in which both pMCAO and tMCAO provided similar outcomes during the study period in the groups without MSC infusion groups. Behavioral performance, ischemic volume, and regional cerebral blood flow (rCBF) using arterial spin labeling-magnetic resonance imaging and histologic evaluation of microvasculature was performed. RESULTS: The behavioral function, rCBF, and restoration of microvasculature were greater in group 4 than in group 3. Thus, infused MSCs facilitated the therapeutic efficacy of MCA reperfusion in this rat model system. CONCLUSIONS: Intravenous infusion of MSCs may enhance therapeutic efficacy of reperfusion therapy.
OBJECTIVE: Reperfusion therapy is a standard therapeutic strategy for acute stroke. Non-favorable outcomes are thought to partially result from impaired microcirculatory flow in ischemic tissue. Intravenous infusion of mesenchymal stem cells (MSCs) reduces stroke volume and improves behavioral function in stroke. One suggested therapeutic mechanism is the restoration of the microvasculature. The goal of this study was to determine whether infused MSCs enhance the therapeutic efficacy of reperfusion therapy following stroke in rats. METHODS: First, to establish a transient middle cerebral artery occlusion (MCAO) model displaying approximately identical neurologic function and lesion volume as seen in permanent MCAO (pMCAO) at day 7 after stroke induction, we transiently occluded the MCA for 90, 110, and 120 minutes. We found that the 110-minute occlusion met these criteria and was used as the transient MCAO (tMCAO) model. Next, 4 MCAO groups were used to compare the therapeutic efficacy of infused MSCs: (1) pMCAO+vehicle, (2) tMCAO+vehicle, (3) pMCAO+MSC, and (4) tMCAO+MSC. Our ischemic model was a unique ischemic model system in which both pMCAO and tMCAO provided similar outcomes during the study period in the groups without MSC infusion groups. Behavioral performance, ischemic volume, and regional cerebral blood flow (rCBF) using arterial spin labeling-magnetic resonance imaging and histologic evaluation of microvasculature was performed. RESULTS: The behavioral function, rCBF, and restoration of microvasculature were greater in group 4 than in group 3. Thus, infused MSCs facilitated the therapeutic efficacy of MCA reperfusion in this rat model system. CONCLUSIONS: Intravenous infusion of MSCs may enhance therapeutic efficacy of reperfusion therapy.
Authors: Mariana P Nucci; Fernando A Oliveira; João M Ferreira; Yolanda O Pinto; Arielly H Alves; Javier B Mamani; Leopoldo P Nucci; Nicole M E Valle; Lionel F Gamarra Journal: Cells Date: 2022-01-30 Impact factor: 6.600