Promoting brain remodeling to aid in stroke recovery

Zhang, Zheng Gang; Chopp, Michael

doi:10.1016/j.molmed.2015.07.005

Cited by 67 publications

(36 citation statements)

References 86 publications

(103 reference statements)

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“…Exosomes, depending on their parental origin, contain a variety of proteins, lipids, noncoding RNAs, mRNA, and miRNA, collectively termed as “cargo” contents (Kalani et al, 2014). Contained among these constituents, miRNAs may play a key role in mediating biological function due to their prominent role in gene regulation, as we demonstrate that MSCs communicate with brain parenchymal cells and regulate neurite outgrowth by transfer of miR-133b to neural cells via exosomes (Xin et al, 2012; Xin et al, 2014; Xin et al, 2013c; Zhang and Chopp, 2015, 2016). In addition, we performed the control treatment with the artificial exosome membrane, which consists of the same lipid content as exosomes but lacks content of proteins and genetic materials.…”

Section: Discussionmentioning

confidence: 82%

Systemic administration of cell-free exosomes generated by human bone marrow derived mesenchymal stem cells cultured under 2D and 3D conditions improves functional recovery in rats after traumatic brain injury

Zhang

Chopp

Zhang

et al. 2017

Neurochemistry International

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322

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Multipotent human bone marrow derived mesenchymal stem cells (hMSCs) improve functional outcome after experimental traumatic brain injury (TBI). The present study was designed to investigate whether systemic administration of cell-free exosomes generated from hMSCs cultured in 2-dimensional (2D) conventional conditions or in 3-dimensional (3D) collagen scaffolds promote functional recovery and neurovascular remodeling in rats after TBI. Wistar rats were subjected to TBI induced by controlled cortical impact; 24 hours later tail vein injection of exosomes derived from hMSCs cultured under 2D or 3D conditions or an equal number of liposomes as a treatment control were performed. The modified Morris water maze, neurological severity score and footfault tests were employed to evaluate cognitive and sensorimotor functional recovery. Animals were sacrificed at 35 days after TBI. Histological and immunohistochemical analyses were performed for measurements of lesion volume, neurovascular remodeling (angiogenesis and neurogenesis), and neuroinflammation. Compared with liposome-treated control, exosome-treatments did not reduce lesion size but significantly improved spatial learning at 33-35 days measured by the Morris water maze test, and sensorimotor functional recovery, i.e., reduced neurological deficits and footfault frequency, observed at 14-35 days post injury (p < 0.05). Exosome treatments significantly increased the number of newborn endothelial cells in the lesion boundary zone and dentate gyrus, and significantly increased the number of newborn mature neurons in the dentate gyrus as well as reduced neuroinflammation. Exosomes derived from hMSCs cultured in 3D scaffolds provided better outcome in spatial learning than exosomes from hMSCs cultured in the 2D condition. In conclusion, hMSC-generated exosomes significantly improve functional recovery in rats after TBI, at least in part, by promoting endogenous angiogenesis and neurogenesis and reducing neuroinflammation. Thus, exosomes derived from hMSCs may be a novel cell-free therapy for TBI, and hMSC-scaffold generated exosomes may selectively enhance spatial learning.

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Section: Discussionmentioning

confidence: 82%

Systemic administration of cell-free exosomes generated by human bone marrow derived mesenchymal stem cells cultured under 2D and 3D conditions improves functional recovery in rats after traumatic brain injury

Zhang

Chopp

Zhang

et al. 2017

Neurochemistry International

Self Cite

322

247

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show abstract

“…That the brain remodels itself after stroke has been documented (Hermann et al, 2014; Tajiri et al, 2012; Watson et al, 2015; Zhang & Chopp, 2015), but this host repair mechanism is not sufficient to account for sustained relevant stroke recovery (Doeppner et al, 2009; Hess & Borlongan, 2008a; Hu et al, 2013; Kuge et al, 2009). Exogenous treatment, either pharmacologically or via stem cell transplantation, designed to enhance host brain regenerative process is needed to achieve clinically relevant functional outcomes in stroke (Kaneko et al, 2012; Matsukawa et al, 2009; Peña & Borlongan, 2015; Tajiri et al, 2012; Wang et al, 2014; Yasuhara et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

NSI‐189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats

Tajiri

Quach

Kaneko

et al. 2017

Journal Cellular Physiology

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Enhancing neurogenesis may be a powerful stroke therapy. Here, we tested in a rat model of ischemic stroke the beneficial effects of NSI‐189, an orally active, new molecular entity (mol. wt. 366) with enhanced neurogenic activity, and indicated as an anti‐depressant drug in a clinical trial (Fava et al., 2015, Molecular Psychiatry, DOI: 10.1038/mp.2015.178) and being tested in a Phase 2 efficacy trial (ClinicalTrials.gov, 2016, ClinicalTrials.gov Identifier: NCT02695472) for treatment of major depression. Oral administration of NSI‐189 in adult Sprague–Dawley rats starting at 6 hr after middle cerebral artery occlusion, and daily thereafter over the next 12 weeks resulted in significant amelioration of stroke‐induced motor and neurological deficits, which was maintained up to 24 weeks post‐stroke. Histopathological assessment of stroke brains from NSI‐189‐treated animals revealed significant increments in neurite outgrowth as evidenced by MAP2 immunoreactivity that was prominently detected in the hippocampus and partially in the cortex. These results suggest NSI‐189 actively stimulated remodeling of the stroke brain. Parallel in vitro studies further probed this remodeling process and demonstrated that oxygen glucose deprivation and reperfusion (OGD/R) initiated typical cell death processes, which were reversed by NSI‐189 treatment characterized by significant attenuation of OGD/R‐mediated hippocampal cell death and increased Ki67 and MAP2 expression, coupled with upregulation of neurogenic factors such as BDNF and SCF. These findings support the use of oral NSI‐189 as a therapeutic agent well beyond the initial 6‐hr time window to accelerate and enhance the overall functional improvement in the initial 6 months post stroke.

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“…Exosomes transfer their cargo miRNAs to recipient cells (120,121) and MSC-derived exosomes contain more than 700 miRNAs that are bound to argonaute2 (AGO2), a component of the RNAinduced silencing complex (RISC) (122,123). The effect of engineered MSC-derived exosomes that carry elevated miRNAs on brain remodeling after stroke has been investigated in vitro and in vivo (118,119).…”

Section: Hsc-exosomes and Therapiesmentioning

confidence: 99%