Exosomes in stroke pathogenesis and therapy

Chopp

Neurochemistry International

et al. 2017

Self Cite

300

247

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.

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

Chopp

Neurochemistry International

et al. 2017

Self Cite

300

247

“…C-F) Quantitative data showed proteins of DNMT3A (C ), NUMB (D), SNAP25 (E ), and GAP43 (F ) in the SN and DRG tissues of db/m or db/db mice (n = 4 mice/group). *P , 0.05. and that exosomal miRs in distal axons locally regulate axonal growth (35).…”

Section: Discussionmentioning

confidence: 99%

Exosomes derived from high‐glucose‐stimulated Schwann cells promote development of diabetic peripheral neuropathy

et al. 2018

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Schwann cells actively interact with axons of dorsal root ganglia (DRG) neurons. Exosomes mediate intercellular communication by transferring their biomaterials, including microRNAs (miRs) into recipient cells. We hypothesized that exosomes derived from Schwann cells stimulated by high glucose (HG) exosomes accelerate development of diabetic peripheral neuropathy and that exosomal cargo miRs contribute to this process. We found that HG exosomes contained high levels of miR-28, -31a, and -130a compared to exosomes derived from non-HG-stimulated Schwann cells. In vitro, treatment of distal axons with HG exosomes resulted in reduction of axonal growth, which was associated with elevation of miR-28, -31a, and -130a and reduction of their target proteins of DNA methyltransferase-3α, NUMB (an endocytic adaptor protein), synaptosome associated protein 25, and growth-associated protein-43 in axons. In vivo, administration of HG exosomes to sciatic nerves of diabetic db/db mice at 7 wk of age promoted occurrence of peripheral neuropathy characterized by impairment of nerve conduction velocity and induction of mechanic and thermal hypoesthesia, which was associated with substantial decreases in intraepidermal nerve fibers. Our findings demonstrate a functional role of exosomes derived from HG-stimulated Schwann cells in mediating development of diabetic peripheral neuropathy.-Jia, L., Chopp, M., Wang, L., Lu, X., Szalad, A., Zhang, Z. G. Exosomes derived from high-glucose-stimulated Schwann cells promote development of diabetic peripheral neuropathy.

Journal of Clinical Investigation

“…EV communication also appears to be an important determinant of the outcome of CNS pathologies, such as brain ischemia. In this issue, Zhang et al detail EV signaling within the CNS, emphasizing its involvement in mediating neurorestorative events following stroke and neural injury (18).…”

Section: Evs As Regulators Of Neuronal Immune and Inflammatory Procmentioning

confidence: 99%

Extracellular vesicles: masters of intercellular communication and potential clinical interventions

Pitt¹,

Kroemer²,

Zitvogel³

2016

396

314

Intercellular signaling via extracellular vesicles (EVs) is an underappreciated modality of cell-cell crosstalk that enables cells to convey packages of complex instructions to specific recipient cells. EVs transmit these instructions through their cargoes of multiple proteins, nucleic acids, and specialized lipids, which are derived from their cells of origin and allow for combinatorial effects upon recipient cells. This Review series brings together the recent progress in our understanding of EV signaling in physiological and pathophysiological conditions, highlighting how certain EVs, particularly exosomes, can promote or regulate infections, host immune responses, development, and various diseases -notably cancer. Given the diverse nature of EVs and their abilities to profoundly modulate host cells, this series puts particular emphasis on the clinical applications of EVs as therapeutics and as diagnostic biomarkers.