Overcoming the persistent axon inhibitory environment following a functionally debilitating incomplete spinal cord lesion has long proven to be an elusive dilemma, especially months to years after the initial spinal injury. Our exciting pre-clinical findings will begin to enhance our understanding of the basic mechanisms underlying functionally beneficial regenerative events occurring at chronic injury stages for clinically relevant translational benefits. Following a three-month upper cervical spinal hemi-lesion using adult female Sprague Dawley rats, we show that the combined treatment has a profound effect on functional recovery of the chronically paralyzed forelimb and paw, specifically during walking as well as precision movements of the digits. However, instead of using ChABC, we utilized a novel and more clinically relevant systemic, non-invasive combinatorial treatment strategy designed to both reduce and overcome inhibitory CSPGs simultaneously and spatially extensively. In the present study, we sought to further optimize and elucidate the capacity for nerve sprouting and/or regeneration to restore gross as well as fine motor control of the forearm and digits at lengthy chronic stages post injury. Importantly, ChABC treatment at cervical level 4 in this chronic model also elicited rapid, albeit modest, improvements in upper arm function. Recently, we discovered that targeted enzymatic modulation of the potently inhibitory chondroitin sulfate proteoglycan (CSPG) component of the extracellular and perineuronal net (PNN) matrix via Chondroitinase ABC (ChABC) can rapidly restore robust respiratory function to the previously paralyzed hemi-diaphragm after remarkably long times post-injury (up to 1.5 years) following a cervical level 2 lateral hemi-transection. Spinal cord injuries, for which there are limited effective clinical treatments, result in enduring paralysis and hypoesthesia due, in part, to the inhibitory microenvironment that develops and limits regeneration/sprouting, especially during chronic stages. This non-invasive system is expected to help elucidate the therapeutic mechanism of cell transplantation treatment for SCI. Through the use of this system, we found that the activity of grafted cells was integrated with host behaviour and driven by host neural circuit inputs. We introduced Akaluc, a newly engineered luciferase, under the control of enhanced synaptic activity-responsive element (E-SARE), a potent neuronal activity-dependent synthetic promoter, into NS/PCs and engrafted the cells into SCI model mice. The aim of this project was to establish a novel non-invasive in vivo imaging system to visualize the activity of neural grafts by which we can simultaneously demonstrate the circuit-level integration between the graft and host and the contribution of graft neuronal activity to host behaviour. However, whether and how grafted cells are incorporated into the host neural circuit and contribute to motor function recovery remain unknown. Perfusion and diffusion offer complementary and clinically relevant insight to physiological and structural abnormalities following spinal cord injury beyond those afforded by T1 or T2 contrasts.Įxpectations for neural stem/progenitor cell (NS/PC) transplantation as a treatment for spinal cord injury (SCI) are increasing. Spinal cord perfusion has unique spatiotemporal dynamics compared with diffusion measures of axonal damage and highlights the importance of acute perfusion abnormalities. At 48 hours, SCBF (R2 = 0.41, padj < 0.01) became less associated with outcome, and DWI (R2 = 0.38, padj < 0.01) lesion volume became more closely related to outcome. At 4 hours, the volume of the SCBF deficit (R2 = 0.56, padj < 0.01) was significantly correlated with 12-week locomotor outcome, while DWI (R2 = 0.30, padj < 0.01) was less predictive of outcome. At 4 hours, the deficit in SCBF was larger than the DWI lesion, and while SCBF partially recovered by 48 hours, the DWI lesion expanded. Locomotor outcome was assessed up to 12-weeks post injury. MRI at 4-hours, 48-hours, and 12-weeks post injury included T1, T2, perfusion, and DWI. Adult Sprague-Dawley rats received a cervical contusion injury of varying severity (injured = 30, sham = 9). This study examined the progression of MRI biomarkers after spinal cord injury and their ability to predict long-term neurological outcomes in a rodent model, with an emphasis on diffusion-weighted imaging (DWI) markers of axonal injury and perfusion-weighted imaging of spinal cord blood flow (SCBF). Traumatic spinal cord injury causes rapid neuronal and vascular injury, and predictive biomarkers are needed to facilitate acute patient management.
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