The impact of enriched environment and transplantation of murine cortical embryonic stem cells on recovery from controlled cortical contusion injury

Abstract

Purpose: The effectiveness of embryonic stem cell (eSC) therapy has been explored in many models of neurological disease and several research groups have shown that eSC treatment leads to improved outcomes in pre-clinical models of traumatic brain injury (TBI). Though functional recovery occurs, few surviving eSCs appear to develop neuronal characteristics; instead the majority of the surviving eSC express glial phenotypes. Additionally, researchers have shown that enriching the post-surgical environment of the subject promotes functional recovery following TBI. The purpose of the current project was to determine if post-surgical environmental enrichment (EE) impacts the survival, migration, and integration of eSCs in a rodent model of TBI and if the presence of these cells lead to improved outcomes. Methods: In the current study, the medial frontal cortex (MFC) of rats was injured using a controlled cortical impact (CCI) device. Immediately following injury the rats were placed into either EE or standard environment (SE) housing and then seven days post-injury rats received either murine cortical eSC or media. Behavioral testing consisted of the Morris water maze (MWM), Barnes Maze (BM), and Rotarod tasks (RR). Results: On the MWM task, TBI/eSC/EE animals performed as well as the Sham/SE and Sham/EE groups. The TBI/eSC/SE, TBI/Media/EE, and TBI/Media/SE groups were impaired compared to the controls. By the end of training on the BM there were no differences between the Sham, TBI/Media/EE, and TBI/eSC/EE groups. On the RR task all animals placed in the EE performed equally well and significantly better than their SE housed counterparts. By the end of training on the RR task, the TBI/eSC/EE group performed as well as the sham counterparts, and though not significant they also surpassed the performance of the injured animals that received enrichment or eSC treatment alone. Conclusions: Combing therapeutic strategies with enriching the post-injury environment is likely to be an important addition to determining the efficacy of pre-clinical therapies.

Post-operative environmental enrichment improves spatial and motor deficits but may not ameliorate anxiety- or depression-like symptoms in rats following traumatic brain injury

“…The FST seems to have changed the behaviors of the sham animals in this study. Behavior of the sham animals on the sucrose consumption task, BM and EPM are not consistent with those previously recorded in our lab (Crane et al, 2012;Peruzzaro et al, 2013), although the procedures with the exception of the FST are the same. These results indicate that in order to be able to correctly utilize the FST, it should either 1) be the only behavioral task completed with that subset of animals, 2) be used as the final behavior test or 3) be used as a single, 5 minute trial task, rather than the 2-trial extended time task.…”

“…Much pre-clinical and clinical research supports post-injury environmental stimulation as a primary treatment strategy for brain injury (Galani et al, 1997;Grealy et al, 1999;Sterr et al, 2002). EE has often been used as an experimental treatment where the animal is forced to move and interact with its environment, which facilitates functional recovery (Hoffman et al, 2008;Kline et al, 2007;Peruzzaro et al, 2013). EE has been shown to beneficially affect behavioral plasticity through affecting brain function and structure, whereby moderating mechanisms of cell loss when administered to subjects with TBI, resulting in a more efficacious functional recovery in animals that have sustained closed head injuries .…”

Transplantation of mesenchymal stem cells genetically engineered to overexpress interleukin-10 promotes alternative inflammatory response in rat model of traumatic brain injury

“…Controlled cortical impact (CCI) model was performed according to procedures previously described by Peruzzaro and colleagues [24]. Rats were anesthetized using a mixture of 1–3% isoflurane (Henry Schein Co., Melville, NY) and 500-mL-1 L/min oxygen and maintained throughout surgery.…”

“…Rats were tested on the accelerating rotarod to assess gross locomotor performance [24, 28]. The task consists of an elevated rotating rod (Columbus Instruments, Columbus, OH) that gradually accelerated from 6 to 30 RPMs over the course of 240 s. The rod was approximately 0.6 m from the padded floor of the apparatus and has a circumference of 24.13 cm.…”

Traumatic Brain Injury and Stem Cell: Pathophysiology and Update on Recent Treatment Modalities

“…In each group, two arms of the study emerged; the rats were treated with either murine cortical embryonic stem cells or did not receive such treatment. The enriched environment animals performed statistically as well as the sham group, compared to groups with just embryonic stem cells or only an enriched environment [ 72 ]. This trial highlighted the importance of an enriched postsurgical environment in the healing process.…”