Intra-Arterial Delivery of Cell Therapies for Stroke

Guzman, Raphael; Janowski, Mirosław; Walczak, Piotr

doi:10.1161/strokeaha.117.018288

Cited by 74 publications

(60 citation statements)

References 59 publications

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“…We followed up the animals for up to 3 months. Important advantages of our endovascular model of stroke compared to other reported large animal models include minimally invasive access, assessment of the very early stroke-related tissue changes with imaging, and potential for exploiting IA catheter placement to locally deliver adjuvant therapies, including stem cells 36 . The last feature is very attractive in the era of growing use of thrombectomy 37 .…”

Section: Discussionmentioning

confidence: 99%

Endovascular model of ischemic stroke in swine guided by real-time MRI

Gołubczyk

Kalkowski

Kwiatkowska

et al. 2020

Sci Rep

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Modeling stroke in animals is essential for testing efficacy of new treatments; however, previous neuroprotective therapies, based on systemic delivery in rodents failed, exposing the need for model with improved clinical relevance. The purpose of this study was to develop endovascular approach for inducing ischemia in swine. To achieve that goal, we used intra-arterial administration of thrombin mixed with gadolinium and visualized the occlusion with real-time MRI. Placement of the microcatheter proximally to rete allowed trans-catheter perfusion of the ipsilateral hemisphere as visualized by contrast-enhanced perfusion MR scans. Dynamic T2*w MRI facilitated visualization of thrombin + Gd solution transiting through cerebral vasculature and persistent hyperintensities indicated occlusion. Area of trans-catheter perfusion dynamically quantified on representative slice before and after thrombin administration (22.20 ± 6.31 cm2 vs. 13.28 ± 4.71 cm2 respectively) indicated significantly reduced perfusion. ADC mapping showed evidence of ischemia as early as 27 min and follow-up T2w scans confirmed ischemic lesion (3.14 ± 1.41 cm2). Animals developed contralateral neurological deficits but were ambulatory. Our study has overcome long lasting challenge of inducing endovascular stroke model in pig. We were able to induce stroke using minimally invasive endovascular approach and observe in real-time formation of the thrombus, blockage of cerebral perfusion and eventually stroke lesion.

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Section: Discussionmentioning

confidence: 99%

Endovascular model of ischemic stroke in swine guided by real-time MRI

Gołubczyk

Kalkowski

Kwiatkowska

et al. 2020

Sci Rep

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“…In the lower row, double staining of HuNu for the engrafted cells and NeuN for mature neurons was negative, indicating that most stem cells differentiating into the neuronal lineage (see further electrophysiological data on Figure 9) had not yet reached differentiation state of fully mature neurons at 12 weeks. (Guzman et al, 2018). We have investigated the stabilizing effect of intracortical implantation of hNSCs on the stroke-induced functional hyperconnectivity.…”

Section: Monitoring the Graft Fatementioning

confidence: 99%

Human Neural Stem Cell Induced Functional Network Stabilization After Cortical Stroke: A Longitudinal Resting-State fMRI Study in Mice

Minassian

Green

Diedenhofen

et al. 2020

Front. Cell. Neurosci.

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Most stroke studies dealing with functional deficits and assessing stem cell therapy produce extensive hemispheric damage and can be seen as a model for severe clinical strokes. However, mild strokes have a better prospect for functional recovery. Recently, anatomic and behavioral changes have been reported for distal occlusion of the middle cerebral artery (MCA), generating a well-circumscribed and small cortical lesion, which can thus be proposed as mild to moderate cortical stroke. Using this cortical stroke model of moderate severity in the nude mouse, we have studied the functional networks with resting-state functional magnetic resonance imaging (fMRI) for 12 weeks following stroke induction. Further, human neural stem cells (hNSCs) were implanted adjacent to the ischemic lesion, and the stable graft vitality was monitored with bioluminescence imaging (BLI). Differentiation of the grafted neural stem cells was analyzed by immunohistochemistry and by patch-clamp electrophysiology. Following stroke induction, we found a pronounced and continuously rising hypersynchronicity of the sensorimotor networks including both hemispheres, in contrast to the severe stroke filament model where profound reduction of the functional connectivity had been reported by us earlier. The vitality of grafted neural stem cells remained stable throughout the whole 12 weeks observation period. In the stem cell treated animals, functional connectivity did not show hypersynchronicity but was globally slightly reduced below baseline at 2 weeks post-stroke, normalizing thereafter completely. Our resting-state fMRI (rsfMRI) studies on cortical stroke reveal for the first time a hypersynchronicity of the functional brain networks. This hypersynchronicity appears as a hallmark of mild cortical strokes, in contrast to severe strokes with striatal involvement where exclusively hyposynchronicity has been reported. The effect of the stem cell graft was an early

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“…Although osmotic BBBO has been an established method for decades, the parameters for inducing BBBO are highly variable and inconsistent. The infusion speed, in particular, is one of the most critical parameters in small animals and many published reports recommend an infusion that highly exceeds the physiological perfusion rate in the carotid artery, leading to brain damage ( 17 , 22 , 23 ). For example, in different preclinical studies, the infusion velocity of mannitol into the carotid artery for some rat studies was as low as 3.0 ml/min ( 14 ) or as high as 7.2 ml/min ( 13 ).…”

Section: Discussionmentioning

confidence: 99%

Real-Time MRI Guidance for Reproducible Hyperosmolar Opening of the Blood-Brain Barrier in Mice

et al. 2018

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The blood-brain barrier (BBB) prevents effective delivery of most therapeutic agents to the brain. Intra-arterial (IA) infusion of hyperosmotic mannitol has been widely used to open the BBB and improve parenchymal targeting, but the extent of BBB disruption has varied widely with therapeutic outcomes often being unpredictable. In this work, we show that real-time MRI can enable fine-tuning of the infusion rate to adjust and predict effective and local brain perfusion in mice, and thereby can be allowed for achieving the targeted and localized BBB opening (BBBO). Both the reproducibility and safety are validated by MRI and histology. The reliable and reproducible BBBO we developed in mice will allow cost-effective studies on the biology of the BBB and drug delivery to the brain. In addition, the IA route for BBBO also permits subsequent IA delivery of a specific drug during the same procedure and obtains high targeting efficiency of the therapeutic agent in the targeted tissue, which has great potential for future clinical translation in neuro-oncology, regenerative medicine and other neurological applications.

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Intra-Arterial Delivery of Cell Therapies for Stroke

Cited by 74 publications

References 59 publications

Endovascular model of ischemic stroke in swine guided by real-time MRI

Endovascular model of ischemic stroke in swine guided by real-time MRI

Human Neural Stem Cell Induced Functional Network Stabilization After Cortical Stroke: A Longitudinal Resting-State fMRI Study in Mice

Real-Time MRI Guidance for Reproducible Hyperosmolar Opening of the Blood-Brain Barrier in Mice

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