Six‐Month Ischemic Mice Show Sensorimotor and Cognitive Deficits Associated with Brain Atrophy and Axonal Disorganization

Zanier, Elisa R.; Pischiutta, Francesca; Villa, Pia; Paladini, Alessandra; Montinaro, Mery; Micotti, Edoardo; Orrù, Alessandro; Cervo, Luigi; Simoni, Maria Grazia De

doi:10.1111/cns.12128

Cited by 17 publications

(20 citation statements)

References 42 publications

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“…Data are expressed as percentage of the baseline value. Two consecutive passive rotations without walking, but accompanying the rod, were considered as a fall 90 .…”

Section: Methodsmentioning

confidence: 99%

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Intravenous infusion of human bone marrow mesenchymal stromal cells promotes functional recovery and neuroplasticity after ischemic stroke in mice

Sammali

Alia

Vegliante

et al. 2017

Sci Rep

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Transplantation of human bone marrow mesenchymal stromal cells (hBM-MSC) promotes functional recovery after stroke in animal models, but the mechanisms underlying these effects remain incompletely understood. We tested the efficacy of Good Manufacturing Practices (GMP) compliant hBM-MSC, injected intravenously 3.5 hours after injury in mice subjected to transient middle cerebral artery occlusion (tMCAo). We addressed whether hBM-MSC are efficacious and if this efficacy is associated with cortical circuit reorganization using neuroanatomical analysis of GABAergic neurons (parvalbumin; PV-positive cells) and perineuronal nets (PNN), a specialized extracellular matrix structure which acts as an inhibitor of neural plasticity. tMCAo mice receiving hBM-MSC, showed early and lasting improvement of sensorimotor and cognitive functions compared to control tMCAo mice. Furthermore, 5 weeks post-tMCAo, hBM-MSC induced a significant rescue of ipsilateral cortical neurons; an increased proportion of PV-positive neurons in the perilesional cortex, suggesting GABAergic interneurons preservation; and a lower percentage of PV-positive cells surrounded by PNN, indicating an enhanced plastic potential of the perilesional cortex. These results show that hBM-MSC improve functional recovery and stimulate neuroprotection after stroke. Moreover, the downregulation of “plasticity brakes” such as PNN suggests that hBM-MSC treatment stimulates plasticity and formation of new connections in the perilesional cortex.

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“…Data are expressed as percentage of the baseline value. Two consecutive passive rotations without walking, but accompanying the rod, were considered as a fall 90 .…”

Section: Methodsmentioning

confidence: 99%

“…Post-stroke atrophy was calculated on 40 µm coronal brain cryosections stained with cresyl violet as previously described 90 .…”

Section: Methodsmentioning

confidence: 99%

Intravenous infusion of human bone marrow mesenchymal stromal cells promotes functional recovery and neuroplasticity after ischemic stroke in mice

Sammali

Alia

Vegliante

et al. 2017

Sci Rep

Self Cite

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“…Sensorimotor deficits were evaluated by neuroscore and beam walk tests [9,21,23] before injury (day 0) and at 7, 21, and 35 days post-TBI. For neuroscore, animals were scored from 4 (normal) to 0 (severely impaired) for 1) forelimb function, 2) hind limb function, and 3) resistance to lateral pulsion, as previously described [9,24].…”

Section: Sensorimotor Deficitsmentioning

confidence: 99%

“…The beam walk test measures the number of foot faults of a trained mouse walking twice on an elevated, narrow wooden beam (5 mm wide and 100 cm long). The best score is 0 [9,23]. …”

Section: Sensorimotor Deficitsmentioning

confidence: 99%

Bone Marrow Mesenchymal Stromal Cells Drive Protective M2 Microglia Polarization After Brain Trauma

et al. 2014

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Microglia/macrophages (M) are major contributors to postinjury inflammation, but they may also promote brain repair in response to specific environmental signals that drive classic (M1) or alternative (M2) polarization. We investigated the activation and functional changes of M in mice with traumatic brain injuries and receiving intracerebroventricular human bone marrow mesenchymal stromal cells (MSCs) or saline infusion. MSCs upregulated Ym1 and Arginase-1 mRNA (p<0.001), two M2 markers of protective M polarization, at 3 and 7 d postinjury, and increased the number of Ym1 + cells at 7 d postinjury (p<0.05). MSCs reduced the presence of the lysosomal activity marker CD68 on the membrane surface of CD11b-positive M (p<0.05), indicating reduced phagocytosis. MSC-mediated induction of the M2 phenotype in M was associated with early and persistent recovery of neurological functions evaluated up to 35 days postinjury (p<0.01) and reparative changes of the lesioned microenvironment. In vitro, MSCs directly counteracted the proinflammatory response of primary murine microglia stimulated by tumor necrosis factor-α+interleukin 17 or by tumor necrosis factor-α + interferon-γ and induced M2 proregenerative traits, as indicated by the downregulation of inducible nitric oxide synthase and upregulation of Ym1 and CD206 mRNA (p < 0.01). In conclusion, we found evidence that MSCs can drive the M transcriptional environment and induce the acquisition of an early, persistent M2-beneficial phenotype both in vivo and in vitro. Increased Ym1 expression together with reduced in vivo phagocytosis suggests M selection by MSCs towards the M2a subpopulation, which is involved in growth stimulation and tissue repair.

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“…This event may further favor T-cell recruitment to lesion site. In a clinically relevant model of brain ischemia (Zanier et al, 2013) we analyzed the opening of the BBB by 2-PM and quantified it on the basis of the extravasated fluorescent signal associated with fluorescent dextran, injected before to ischemia to label blood vessels. We focused on the brain microvasculature, and individually analyzed small vessels, exploiting the high resolution achievable with 2-PM.…”

Section: Route Of Infiltration and Imaging T-cells Infiltrating In Thmentioning

confidence: 99%

A close look at brain dynamics: Cells and vessels seen by in vivo two-photon microscopy

Fumagalli

Ortolano

Simoni

2014

Progress in Neurobiology

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Six‐Month Ischemic Mice Show Sensorimotor and Cognitive Deficits Associated with Brain Atrophy and Axonal Disorganization

Cited by 17 publications

References 42 publications

Intravenous infusion of human bone marrow mesenchymal stromal cells promotes functional recovery and neuroplasticity after ischemic stroke in mice

Intravenous infusion of human bone marrow mesenchymal stromal cells promotes functional recovery and neuroplasticity after ischemic stroke in mice

Bone Marrow Mesenchymal Stromal Cells Drive Protective M2 Microglia Polarization After Brain Trauma

A close look at brain dynamics: Cells and vessels seen by in vivo two-photon microscopy

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