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

Anuka Minassian; Claudia Green; Michael Diedenhofen; Stefanie Vogel; Simon Hess; Maren Stoeber; Marina Dobrivojevic Radmilovic; Dirk Wiedermann; Peter Kloppenburg; Mathias Hoehn

doi:10.3389/fncel.2020.00086

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

Front Cell Neurosci. 2020 Apr 7:14:86. doi: 10.3389/fncel.2020.00086. eCollection 2020.

Authors

Anuka Minassian¹, Claudia Green¹, Michael Diedenhofen¹, Stefanie Vogel¹, Simon Hess^{2

3}, Maren Stoeber¹, Marina Dobrivojevic Radmilovic^{1

4}, Dirk Wiedermann¹, Peter Kloppenburg^{2

3}, Mathias Hoehn^{1

5}

Affiliations

¹ In-Vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Cologne, Germany.
² Biocenter, Institute for Zoology, University of Cologne, Cologne, Germany.
³ Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
⁴ Department of Histology and Embryology, School of Medicine, University of Zagreb, Zagreb, Croatia.
⁵ Department of Radiology, Leiden University Medical Center, Leiden University, Leiden, Netherlands.

Abstract

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 and persistent normalization of the functional sensorimotor networks across the whole brain. These novel functional results may help interpret future outcome investigations after stroke and demonstrate the highly promising potential of stem cell treatment for functional outcome improvement after stroke.

Keywords: distal MCA occlusion; functional connectivity; human neural stem cells; moderate severity stroke model; mouse; neuronal differentiation; resting-state fMRI; stroke-induced hyperconnectivity.