Establishment of immortalized mesenchymal stromal cells with red fluorescence protein expression for in vivo transplantation and tracing in the rat model with traumatic brain injury

Multipotent mesenchymal stromal cells (MSC) represent a promising strategy for a variety of medical applications. Although only a limited number of MSC engraft and survive after in vivo cellular infusion, MSC have shown beneficial effects on immunomodulation and tissue repair. This indicates that the contribution of MSC exists in paracrine signaling, rather than a cell-contact effect of MSC. In this review, we focus on current knowledge about tumor necrosis factor (TNF)-stimulated gene-6 (TSG-6) and mechanisms based on extracellular vesicles (EV) that govern long-lasting immunosuppressive and regenerative activity of MSC. In this context, in particular, we discuss the very robust set of findings by Jha and colleagues, and the opportunity to potentially extend their research focus on EV isolated in concentrated conditioned media (CCM) from adipose tissue derived MSC (ASC). Particularly, the authors showed that ASC-CCM mitigated visual deficits after mild traumatic brain injury in mice. TSG-6 knockdown ASC were, then, used to generate TSG-6-depleted CCM that were not able to replicate the alleviation of abnormalities in injured animals. In light of the presented results, we envision that the infusion of much distilled ASC-CCM could enhance the alleviation of visual abnormalities. In terms of EV research, the advantages of using size-exclusion chromatography are also highlighted because of the enrichment of purer and well-defined EV preparations. Taken together, this could further delineate and boost the benefit of using MSC-based regenerative therapies in the context of forthcoming clinical research testing in diseases that disrupt immune system homeostasis.

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Systematic review and meta-analysis of preclinical studies testing mesenchymal stromal cells for traumatic brain injury

npj Regenerative Medicine ◽

10.1038/s41536-021-00182-8 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Francesca Pischiutta ◽

Enrico Caruso ◽

Alessandra Lugo ◽

Helena Cavaleiro ◽

Nino Stocchetti ◽

...

Keyword(s):

Systematic Review ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Mesenchymal Stromal Cells ◽

Effect Size ◽

Stromal Cells ◽

Meta Analysis ◽

Similar Efficacy ◽

Post Injury ◽

Neurological Improvement

AbstractMesenchymal stromal cells (MSCs) are widely used in preclinical models of traumatic brain injury (TBI). Results are promising in terms of neurological improvement but are hampered by wide variability in treatment responses. We made a systematic review and meta-analysis: (1) to assess the quality of evidence for MSC treatment in TBI rodent models; (2) to determine the effect size of MSCs on sensorimotor function, cognitive function, and anatomical damage; (3) to identify MSC-related and protocol-related variables associated with greater efficacy; (4) to understand whether MSC manipulations boost therapeutic efficacy. The meta-analysis included 80 studies. After TBI, MSCs improved sensorimotor and cognitive deficits and reduced anatomical damage. Stratified meta-analysis on sensorimotor outcome showed similar efficacy for different MSC sources and for syngeneic or xenogenic transplants. Efficacy was greater when MSCs were delivered in the first-week post-injury, and when implanted directly into the lesion cavity. The greatest effect size was for cells embedded in matrices or for MSC-derivatives. MSC therapy is effective in preclinical TBI models, improving sensorimotor, cognitive, and anatomical outcomes, with large effect sizes. These findings support clinical studies in TBI.

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

Journal of Neurosurgery ◽

10.3171/2014.11.jns14770 ◽

2015 ◽

Vol 122 (4) ◽

pp. 856-867 ◽

Cited By ~ 292

Author(s):

Yanlu Zhang ◽

Michael Chopp ◽

Yuling Meng ◽

Mark Katakowski ◽

Hongqi Xin ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Dentate Gyrus ◽

Morris Water Maze ◽

Mesenchymal Stromal Cells ◽

Functional Recovery ◽

Stromal Cells ◽

Water Maze ◽

Morris Water Maze Test ◽

Neurovascular Remodeling

OBJECT Transplanted multipotent mesenchymal stromal cells (MSCs) improve functional recovery in rats after traumatic brain injury (TBI). In this study the authors tested a novel hypothesis that systemic administration of cell-free exosomes generated from MSCs promotes functional recovery and neurovascular remodeling in rats after TBI. METHODS Two groups of 8 Wistar rats were subjected to TBI, followed 24 hours later by tail vein injection of 100 μg protein of exosomes derived from MSCs or an equal volume of vehicle (phosphate-buffered saline). A third group of 8 rats was used as sham-injured, sham-treated controls. To evaluate cognitive and sensorimotor functional recovery, the modified Morris water maze, modified Neurological Severity Score, and foot-fault tests were performed. Animals were killed 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 the saline-treated group, exosome-treated rats with TBI showed significant improvement in spatial learning at 34–35 days as measured by the modified Morris water maze test (p < 0.05), and sensorimotor functional recovery (i.e., reduced neurological deficits and foot-fault frequency) was observed at 14–35 days postinjury (p < 0.05). Exosome treatment significantly increased the number of newly generated endothelial cells in the lesion boundary zone and dentate gyrus and significantly increased the number of newly formed immature and mature neurons in the dentate gyrus as well as reducing neuroinflammation. CONCLUSIONS The authors demonstrate for the first time that MSC-generated exosomes effectively improve functional recovery, at least in part, by promoting endogenous angiogenesis and neurogenesis and by reducing inflammation in rats after TBI. Thus, MSC-generated exosomes may provide a novel cell-free therapy for TBI and possibly for other neurological diseases.

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Propranolol and Mesenchymal Stromal Cells Combine to Treat Traumatic Brain Injury

Stem Cells Translational Medicine ◽

10.5966/sctm.2015-0065 ◽

2015 ◽

Vol 5 (1) ◽

pp. 33-44 ◽

Cited By ~ 32

Author(s):

Daniel J. Kota ◽

Karthik S. Prabhakara ◽

Alexandra J. van Brummen ◽

Supinder Bedi ◽

Hasen Xue ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Mesenchymal Stromal Cells ◽

Stromal Cells

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Combination therapy with Treg and mesenchymal stromal cells enhances potency and attenuation of inflammation after traumatic brain injury compared to monotherapy

Stem Cells ◽

10.1002/stem.3320 ◽

2020 ◽

Vol 39 (3) ◽

pp. 358-370

Author(s):

Henry W. Caplan ◽

Karthik S. Prabhakara ◽

Naama E. Toledano Furman ◽

Soheil Zorofchian ◽

Akshita Kumar ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Combination Therapy ◽

Mesenchymal Stromal Cells ◽

Stromal Cells

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Evaluation of the neuroprotective activity of a new allylmorpholine derivative in a rat model of traumatic brain injury

Drug development & registration ◽

10.33380/2305-2066-2021-10-4(1)-179-187 ◽

2021 ◽

Vol 10 (4) ◽

pp. 179-187

Author(s):

V. A. Prikhodko ◽

A. V. Kan ◽

Yu. I. Sysoev ◽

I. A. Titovich ◽

N. A. Anisimova ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Rat Model ◽

Neurological Deficit ◽

Elevated Plus Maze ◽

Neuroprotective Activity ◽

Drug Candidates ◽

Plus Maze

Introduction. The search for and development of new drugs capable of reducing the severity of neurological deficit in traumatic brain injury are a critical task for investigational pharmacology. Chromone-containing allylmorpholines are a new group of neuroprotective drug candidates that have been shown to inhibit acetylcholinesterase and butyrylcholinesterase, and block N-methyl-D-aspartate receptors in vitro.Aim. This study aimed to evaluate the neuroprotective activity of the allylmorpholine derivative (E)-4-[3-(8-bromo-6-methyl-4-oxo-4H-chromen- 3-yl)-1-cyclohexylallyl]morpholin-4-ium chloride (33b) in vivo using a rat model of traumatic brain injury.Materials and methods. Traumatic brain injury was induced using the controlled cortical impact model. The allylmorpholine derivative was administered intraperitoneally at 1, 10, or 50 mg × kg-1 b.w. at 1 h after trauma induction, and then daily for the next 6 d. The neurological deficit was assessed using the Limb Placing, Open Field, Elevated Plus Maze, Beam Walking, and Cylinder tests.Results and discussion. At all doses administered, the allylmorpholine derivative had no positive effect on the motor function or exploratory behavior following traumatic brain injury. In the Elevated Plus Maze, 10 mg × kg-1 b.w. of the compound further suppressed exploratory behaviour in the injured animals, which appears to be consistent with its sedative properties observed previously in zebrafish.Conclusion. Despite the previously described in vitro affinity of allylmorpholines towards several molecular targets crucial for the pathogenesis of brain trauma and posttraumatic functional recovery, an allylmorpholine derivative had no neuroprotective effect in a rat model of traumatic brain injury in this study. These results further emphasize the importance of in vivo evaluation of potential neuroprotective drug candidates.

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