Double-Injected Human Stem Cells Enhance Rehabilitation in TBI Mice Via Modulation of Survival and Inflammation

Abstract

Traumatic brain injury (TBI), a complicated form of brain damage, is a major cause of mortality in adults. Following mechanical and structural primary insults, a battery of secondary insults, including neurotransmitter-mediated cytotoxicity, dysregulation of calcium and macromolecule homeostasis, and increased oxidative stress, exacerbate brain injury and functional deficits. Although stem cell therapy is considered to be an alternative treatment for brain injuries, such as TBI and stroke, many obstacles remain. In particular, the time window for TBI treatment with either drugs or stem cells and their efficacy is still vague. Human placenta-derived mesenchymal stem cells (hpMSCs) have received extensive attention in stem cell therapy because they can be acquired in large numbers without ethical issues and because of their immune-modulating capacity and effectiveness in several diseases, such as Alzheimer’s disease and stroke. Here, we tested the feasibility of hpMSCs for TBI treatment with an animal model and attempted to identify appropriate time points for cell treatments. Double injections at 4 and 24 h post-injury significantly reduced the infarct size and suppressed astrocyte and microglial activation around the injury. With reduced damage, double-injected mice showed enhanced anti-inflammatory- and TNF-α receptor 2 (TNFR2)-associated survival signals and suppressed pro-inflammatory and oxidative responses. In addition, double-treated TBI mice displayed restored sensory motor functions and reduced neurotoxic Aβ42 plaque formation around the damaged areas. In this study, we showed the extended therapeutic potentials of hpMSCs and concluded that treatment within an appropriate time window is critical for TBI recovery.

The Effect of Oral Mucosal Mesenchymal Stem Cells on Long-Term Brain Edema and Lesion, Anxiety-Like Behavior, and Cognitive and Motor Outcomes in Experimental Traumatic Brain Injury

“…In another study, exosome injection of MSCs after 15 minutes from the TBI could inhibit the in ammation by disturbing the injury cycle [41]. On the other hand, other studies stated that early administration of SC could not be effective due to the tissue in ammation, and delayed administration or repeating the dose may result in more effective outcomes [2,42]. This study investigated repeating the injection of OMSCs in 1 and 24 hours after the injury.…”

“…Traumatic brain injury (TBI) is one of the major causes of death and disability worldwide [1,2]. Despite the effective therapeutic options available, TBI treatment remains a challenge for scientists and physicians [3].…”

“…Based on the absence of successful and effective treatment for TBI patients [8], the existence of evidence which shows that neuroprotective effects of MSCs on neurodegenerative diseases including TBI [2], and also the bene ts of using OMSCs in nervous diseases [22], the present study set out to assess the effect of OMSCs on TBI. In this investigation, the effect of OMSCs administration on brain edema, anxiety-like behavior, and pathological, neurological, cognitive, and motor outcomes induced by moderate diffuse TBI in male rats in long-term were evaluated.…”

Neuroprotection in Traumatic Brain Injury: Mesenchymal Stromal Cells can Potentially Overcome Some Limitations of Previous Clinical Trials

“…Both central ( 49 – 60 ) and systemic ( 60 – 75 ) administration of MSCs 24 h post-TBI have resulted in early and persistent improvements of functional and structural outcomes. It was recently shown that a double systemic infusion of MSC (at 4 and 24 h) post-TBI was more effective than a single dose at 24 h ( 76 ). The authors showed 4 and 24 h post-TBI peaks of IL1β, TNFα, and IFNγ, suggesting that a shorter lag time between TBI and treatment may be important to counteract early pro-inflammatory changes.…”

Time-Dependent Effect of 3d Biodegradable Scaffold Transplantation on the Functional Outcome of C57bl/6 Mice in the Therapy of Severe Open Traumatic Brain Injury

“…Показано, что активация иммунного ответа достигает максимума между 5 и 7 днями по-МЕЖДУНАРОДНЫЙ ЖУРНАЛ ПРИКЛАДНЫХ И ФУНДАМЕНТАЛЬНЫХ ИССЛЕДОВАНИЙ № 12, 2017 99  БИОЛОГИЧЕСКИЕ НАУКИ  сле ЧМТ и остается повышенной в течение 2 недель, что дает временной интервал для терапевтического вмешательства [1]. Нако-нец, ЧМТ приводит к апоптозу и ишемии ткани головного мозга и функциональному дефициту [2].…”