Diffuse white matter response in trauma-injured brain to bone marrow stromal cell treatment detected by diffusional kurtosis imaging

Abstract

Diffuse white matter (WM) response to traumatic brain injury (TBI) and transplantation of human bone marrow stromal cells (hMSCs) after the injury were non-invasively and dynamically investigated. Male Wistar rats (300-350 g) subjected to TBI were intravenously injected with 1 ml of saline (n = 10) or with hMSCs in suspension (∼3 × 10⁶ hMSCs, n = 10) 1-week post-TBI. MRI measurements of T2-weighted imaging and diffusional kurtosis imaging (DKI) were acquired on all animals at multiple time points up to 3-months post-injury. Functional outcome was assessed using the Morris water maze test. DKI-derived metrics of fractional anisotropy (FA), axonal water fraction (AWF) and radial kurtosis (RK) longitudinally reveal an evolving pattern of structural alteration post-TBI occurring in the brain region remote from primary impact site. The progressive structural change is characterized by gradual disruption of WM integrity at an early stage (weeks post-TBI), followed by spontaneous recovery at a later stage (months post-TBI). Transplantation of hMSCs post-TBI promotes this structural plasticity as indicated by significantly increased FA and AWF in conjunction with substantially elevated RK at the later stage. Our long-term imaging data demonstrate that hMSC therapy leads to modified temporal profiles of these metrics, inducing an earlier presence of enhanced structural remodeling, which may contribute to improved functional recovery.

Keywords: Bone marrow stromal cells; DKI; MRI; Structural change; Traumatic brain injury.

Fig. 1.. A representative image slice of T2 and FA maps (cell-treated animal, 3-weeks post-TBI) illustrating the creation of ROIs.

A: T2 map showing the contusional lesion (hyperintense area in the cortical region) which extends to the subcortical region underneath, causing the damage to corpus callosum (CC) and external capsule (EC) as well as an enlarged lateral ventricle in the ipsilaleral side of the brain. B: FA map correspondingly reflecting the impact-induced FA reduction in the cortex and underlying CC+EC region while depicting this principal WM structure in the brain (as bright). C: Direction-encoded color FA map further distinguishing CC+EC (with distinct edge) from surrounding tissue regions (such as cingulum and striatum) by revealing additional structural details, which therefore serves as reference to accurately create the regions of interest (ROIs). D: Schematic anatomical diagram (bregma −0.8) illustrating the cortex (light blue shading) and CC+EC regions in the contralateral side of the brain that are chosen for MRI assessment (cg: cingulate cortex. Fr: frontal cortex. HL: hindlimb area of cortex. FL: forelimb area of cortex. Par1: parietal cortex area 1. Par2: parietal cortex area 2). E: FA map with ROIs separately encompassing the selected cortex and CC+EC regions. Referring to the anatomical diagram (D), ROIs are manually delineated on color FA map (C) and copied onto the different parametric maps (including FA, AWF, MK, AK and RK) for quantitative evaluation.

Fig. 2.. Temporal profiles of FA in CC+EC (A) and cortex (B) regions.

Compared to the preinjury, a significant reduction of FA after TBI in CC+EC region (A) is observed in both groups. This situation persists in the saline-treated group throughout the experimental period, whereas the significantly decreased FA is absent in the cell-treated group at later stage (2-months and 3-months) due to an earlier and greater recovery of FA (starting from 3-weeks for the cell-treated group vs. 2-months for the saline-treated group). Statistical group differences are found at 5-weeks and 3-months post-TBI. Regardless of cell or saline intervention, however, similar temporal profiles of FA are shown in cortex region (B) with no significant differences between two groups at all time points and no significant changes with time after TBI compared to the preinjury status for each group.

Fig. 3.. Temporal profiles of AWF in CC+EC region.

After TBI, the significant decrease of AWF at an earlier stage (2-weeks to 3-weeks) and reversal of AWF at a later stage in CC+EC region are present in both groups. Cell administration results in an earlier and stronger recovery of AWF (starting from 3-weeks for the cell-treated group vs. 5-weeks for the saline-treated group). Statistical group differences are found at 3-weeks, 2-months and 3-months post-TBI.

Fig. 4.. Changes of Kurtosis in CC+EC (A-C) and cortex (D-F) regions.

In CC+EC region (A-C), higher MK (A) values in the cell-treated group than in the saline-treated group at most observation time points exhibit with significant group difference present at 3-weeks post-TBI. Compared to the pre-injury, significantly increased MK at a later stage of TBI is found in the cell-treated group (A, 2-momths post-TBI). TBI leads to increased AK (B) during the experimental period regardless of cell or saline intervention afterwards, while cell engraftment after TBI substantially reverses the reduction of RK (C) at the later stage of TBI despite the dramatically decreased RK present in both groups at the earlier stage of TBI (1-weeks to 3-weeks). In the cortex region (D-F), similar temporal profiles for the cell- and saline-treated groups in MK (D), AK (E) and RK (F) are found with no significant differences between two groups at all observation time points and no significant changes with time after TBI compared to the pre-injury status for each group.

Fig. 5.. Functional outcome (mMWM).

Improved neurological performance, as evidenced by spending significantly longer time in the correct quadrant, was detected in the cell-treated group compared to the saline-treated group.