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

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

Induced Pluripotent Stem Cells for Ischemic Stroke Treatment

“…Moreover, long-term survival and widespread distribution of NSCs were detected following intra-arterial delivery in an ischemic stroke rodent model, and cell differentiation was evident at 4 weeks ( Zhang et al, 2020 ). In a cortical stroke model, stable graft survival and neuronal differentiation were successfully monitored, and human NSC transplantation was found to have a profound effect on network stability ( Minassian et al, 2020 ). In addition, neural progenitor cells derived from human iPSCs were found to be more effective than mesenchymal stromal cells obtained from human placenta in suppressing the progression of experimental ischemic stroke by improving animal survival in the most acute period and accelerating the recovery of neurological deficit and body weight ( Cherkashova et al, 2019 ).…”

The Effects Of Stem Cells On Recovery After Stroke

“…MSCs have also been shown to differentiate into neural cells and to migrate toward the ischemic brain [3]. Since MSCs are non-tumorigenic and show no ethical issues and concerns with tissue rejection, they show promise for clinical therapy after stroke [3,27]. Their therapeutic effects are mediated through paracrine activity by their trophic factors [15].…”

“…The nontumorigenic and easily accessible properties of mesenchymal stem cells (MSCs) has allowed them to be considered as another potential treatment for stroke. One study looked at the effects of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) compared to MSCs that were delivered to mice with focal cerebral ischemia [27]. Motor coordination, histology, immune response, and cerebral angiogenesis and neurogenesis were analyzed for 28 days after ischemia.…”

“…The study showed that MSC-EVs and MSCs improve neurological impairment similarly after ischemia. Since EVs have been reported to be well tolerated in humans, researchers predicted that MSC-EVs could be translated into human patients [27].…”

Reactive Astrocytes Prevent Maladaptive Plasticity after Ischemic Stroke

“…Loss and gain of sensorimotor deficit–related functional connectivity and the spontaneous reorganization of functional neuronal networks can be monitored longitudinally by resting-state functional magnetic resonance imaging (rs-fMRI). In vivo rs-fMRI shows blood oxygen level–dependent signal fluctuations related to synchronized networks of spatially distinct brain regions at rest and is widely used to noninvasively monitor functional network changes after stroke in clinical studies (Thiel and Vahdat, 2015) and also in studies in rodents (Grandjean et al, 2020; Green et al, 2018; Mandino et al, 2019; Minassian et al, 2020). Reactive astrocytes are important cellular players in stroke (Li et al, 2008; Pekny and Nilsson, 2005; Pekny et al, 2019).…”