Diffusion-Derived Magnetic Resonance Imaging Measures of Longitudinal Microstructural Remodeling Induced by Marrow Stromal Cell Therapy after Traumatic Brain Injury

Abstract

Using magnetic resonance imaging (MRI) and an animal model of traumatic brain injury (TBI), we investigated the capacity and sensitivity of diffusion-derived measures, fractional anisotropy (FA), and diffusion entropy, to longitudinally identify structural plasticity in the injured brain in response to the transplantation of human bone marrow stromal cells (hMSCs). Male Wistar rats (300-350g, n = 30) were subjected to controlled cortical impact TBI. At 6 h or 1 week postinjury, these rats were intravenously injected with 1 mL of saline (at 6 h or 1 week, n = 5/group) or with hMSCs in suspension (*3 · 10 6 hMSCs, at 6 h or 1 week, n = 10/group). In vivo MRI measurements and sensorimotor function estimates were performed on all animals pre-injury, 1 day post-injury, and weekly for 3 weeks post-injury. Bielschowsky's silver and Luxol fast blue staining were used to reveal the axon and myelin status, respectively, with and without cell treatment after TBI. Based on image data and histological observation, regions of interest encompassing the structural alterations were made and the values of FA and entropy were monitored in these specific brain regions. Our data demonstrate that administration of hMSCs after TBI leads to enhanced white matter reorganization particularly along the boundary of contusional lesion, which can be identified by both FA and entropy. Compared with the therapy performed at 1 week post-TBI, cell intervention executed at 6 h expedites the brain remodeling process and results in an earlier functional recovery. Although FA and entropy present a similar capacity to dynamically detect the microstructural changes in the tissue regions with predominant orientation of fiber tracts, entropy exhibits a sensitivity superior to that of FA, in probing the structural alterations in the tissue areas with complex fiber patterns.

Chronic global analysis of vascular permeability and cerebral blood flow after bone marrow stromal cell treatment of traumatic brain injury in the rat: A long-term MRI study

“…In agreement with the previous findings (Haus et al, 2016; Li et al, 2011; Li et al, 2012; Li et al, 2017), our long-term measurements demonstrate the significant improvement of neurological performance after transplantation of hMSCs (Fig. 6B) without lesion reduction (Fig.…”

“…Previous reports suggest that the grafted MSCs in the injured brain serve as in vivo local source of cytokines and trophic factors that activate endogenous restorative and regenerative processes (Chopp and Li, 2006; Parr et al, 2007), while recent investigations indicate that MSCs could also exert a systemic effect through the secretion of soluble factors that act in a global manner (Chen et al, 2015; Lee et al, 2009; Menge et al, 2012; Pati et al, 2011). In support of this premise, potent therapeutic benefits of MSCs on cerebral tissue repair have been observed without significant engraftment in the brain (Li et al, 2011; Li et al, 2012; Li et al, 2017; Mahmood et al, 2003). Since these soluble factors are systemically released by activated MSCs once intravenously infused, their influence may rely on the time when the intervention starts, instead of when the cells migrate into the brain.…”

“…6B) without lesion reduction (Fig. 6A), suggesting that improved functional recovery is attributed to cell-enhanced brain remodeling (Haus et al, 2016; Li et al, 2011; Li et al, 2012; Li et al, 2017), including neurovascular restoration, in the normal-appearing tissue region. No difference in mMWM performance between acute and delayed cell intervention may possibly be attributed to the similar effect of cell-enhanced hippocampal neuronal survival provided by the two treatment strategies (Xiong et al, 2009).…”

“…It has also been reported that intravenously delivered hMSCs after TBI lead to a widespread spatial modification of hemodynamic and structural impairments in the traumatized brain, despite the high concentration of the grafted cells around the contusional lesion compared to other areas in the brain (Li et al, 2011; Li et al, 2012; Mahmood et al, 2003). Based on these findings, we therefore conducted our long-term investigation in a broad region of normal-appearing cerebral tissue identified on MRI, where impact-induced damage (Pasco et al, 2007; Sidaros et al, 2009; Su et al, 2015; Wang et al, 2008) and post-injury remodeling by either spontaneous or treatment-derived action (Li et al, 2011; Li et al, 2012; Li et al, 2017) are taking place with time after TBI.…”

“…There is also a need to better elucidate the underlying mechanisms involved in cell-induced functional improvement after TBI. Treating TBI in the rat with human bone marrow stromal cells (hMSCs), we demonstrate that acute (e.g., 6 hours post-TBI) intravenous cell intervention exerts a potent therapeutic benefit in reducing cerebral atrophy, enhancing structural remodeling and improving neurological performance compared to delayed (e.g., 1 week post-TBI) intravenous cell administration (Li et al, 2011; Li et al, 2012; Li et al, 2017). However, whether this time-dependent therapeutic effect also modifies vascular and hemodynamic impairments is unknown.…”