Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury

Abstract

Object Transplanted multipotent mesenchymal stromal cells (MSCs) improve functional recovery in rats after traumatic brain injury (TBI). Here, we test a novel hypothesis that systemic administration of cell-free exosomes generated from MSCs promotes functional recovery and neurovascular remodeling in rats after TBI. Methods Wistar rats were subjected to TBI followed by tail vein injection of 100 μg protein of exosomes derived from MSCs or an equal volume of vehicle phosphate-buffered saline (n = 8/group) 24 hours later. To evaluate cognitive and sensorimotor functional recovery, the modified Morris water maze, neurological severity score and footfault tests were performed. Animals were sacrificed at 35 days after TBI. Histopathological and immunohistochemical analyses were performed for measurements of lesion volume, neurovascular remodeling (angiogenesis and neurogenesis), and neuroinflammation. Results Compared with saline-treated controls, exosome-treated TBI rats showed significant improvement in spatial learning at 34-35 days measured by the Morris water maze test (p < 0.05), and sensorimotor functional recovery, i.e., reduced neurological deficits and footfault frequency, observed at 14-35 days post injury (p < 0.05). Exosome treatment significantly increased the number of newborn endothelial cells in the lesion boundary zone and dentate gyrus, and significantly increased the number of newborn immature and mature neurons in the dentate gyrus as well as reduced neuroinflammation. Conclusions We, for the first time, demonstrate that MSC-generated exosomes effectively improve functional recovery, at least in part, by promoting endogenous angiogenesis and neurogenesis and reducing inflammation in rats after TBI. Thus, MSC-generated exosomes may provide a novel cell-free therapy for TBI and possibly other neurological diseases.

Stem cell drugs: the next generation of pharmaceutical products

“…Arslan et al (2013) showed that a single intravenous administration of exosomes was effective in enhancing cardiac function and geometry after myocardial infarction due to bioenergetics re-establishment (increased ATP production), oxidative stress reduction and prosurvival signaling activation (enhanced PI3K/Akt signaling) (Arslan et al, 2013 (Nakamura et al, 2015). In the nervous system, MSC derived exosomes have been evaluated in the treatment of neurological and neurodegenerative diseases; they have been shown to enhance angiogenesis and neurogenesis, reduce inflammation and improve spatial learning and sensorimotor function (Kim et al, 2016;Zhang et al, 2015).…”

Traumatic Penumbra: Opportunities for Neuroprotective and Neurorestorative Processes

“…Exosomes play an important role in intercellular communication and are promising therapeutic agents because their complex cargo of proteins and genetic materials has diverse biochemical potential to participate in multiple biochemical and cellular processes, an important attribute in the treatment of complex diseases with multiple secondary injury mechanisms involved [45]. The refinement of MSC therapy from a cell-based therapy to cell-free exosome-based therapy offers several advantages, as it eases the arduous task of preserving cell viability and function, storage, and delivery to patient [175][176][177][178]. Further exploring the mechanisms by which the secretion-based paracrine effect of MSCs participates in neurorestoration and functional recovery following TBI is an outstanding opportunity for research.…”

“…However, previous studies show that only a small proportion of transplanted MSCs actually survive and few MSCs differentiate into neural cells in injured brain tissues. It seems that the predominant mechanisms by which MSCs participate in brain remodeling and functional recovery are likely related to their secretion-based paracrine effect rather than a cell replacement effect [45,[175][176][177][178] ( Figure 2).…”

“…In contrast to transplanted exogenous MSCs, nanosized exosomes derived from MSCs do not proliferate and are less immunogenic and easier to store and deliver than MSCs [181][182][183]. Exosomes generated from MSCs improved functional recovery in rats after TBI [45,175]. Exosomes play an important role in intercellular communication and are promising therapeutic agents because their complex cargo of proteins and genetic materials has diverse biochemical potential to participate in multiple biochemical and cellular processes, an important attribute in the treatment of complex diseases with multiple secondary injury mechanisms involved [45].…”

Mesenchymal stem cell-based therapy for ischemic stroke

“…Several studies demonstrate that small cellularly secreted vesicles called exosomes mediate much of MSCs' tissue healing capabilities [15][16][17][18][19][20][21][22][23][24][25][26][27][28]. MSC derived exosomes are internalized by target cells and transfer proteins, RNA, lipids and metabolites [29].…”