Regenerative medicine for spinal cord injury: tissue engineering with focal magnetic stimulation to optimize endogenous stem cell recruitment and axon regrowth – AXOGRO

Human traumatic spinal cord injury (SCI) is a major public health problem because of lifelong disability, with loss of sensory, motor and autonomic functions. Despite advances in rehabilitation and neuromodulation treatments, that improve quality of life, patients with SCI continue to suffer ongoing dysfunction. There is currently no reparative clinical intervention or treatment, in either the acute or chronic phase. This is due to the limited repair capacity of the adult central nervous system (CNS). Barriers to repair include poor revascularization and resultant ischemia, the establishment of a fibroglial scar, and persistent inflammation, all of which inhibit axon growth. This detrimental cellular environment leads to progressive neurodegeneration and extension of the lesion beyond the initial impact, thereby aggravating neurological deficits. However, extensive studies conducted over the last three decades indicates that the mammalian CNS, the spinal cord in particular, retains a capacity for plasticity and structural reorganization. Fundamental research and preclinal strategies for SCI repair (mainly rodent) have brought important insights into the plasticity and restoration capacity of the CNS. However, application to clinical practice is still limited. Due to the complexity of SCI pathophysiology, the current consensus is that monotherapy is not sufficient and that functionally beneficial SCI treatment requires the combination of complementary approaches that address different aspects of the spinal pathology to create a synergistic effect.
Consequently, in the AXOGRO project, we propose to treat SCI with combined strategies (including those developed by consortium partners), each of which have proven beneficial effects on neural plasticity: (i) the implantation of a medical device (MD) composed of a natural biodegradable hydrogel that works as a scaffold capable of inducing tissue remodeling, potentiating axon growth and modulating inflammation; (2) repetitive low-intensity magnetic stimulation, which stimulates proliferation and recruitment of endogenous spinal ependymal stem cells (Endo-Ssc), and promotes axon growth and scar modulation after SCI; (3) cell therapy to optimize our MD with Schwann or olfactory ensheathing cells, whose preclinical effects has led to their use in clinical trials. Our program aims at treating acute and chronic spinal lesions. We will study in transgenic mice the ability of this combined treatment to stimulate the proliferation and recruitment of endogenous spinal cord stem cells, as well as their survival and differentiation following acute (AIM 1) and chronic (AIM 2) SCI. Subsequently, chronic thoracic injuries in rats will be performed by contusion in order to evaluate the results of this therapeutic combination on tissue repair and functional recovery (AIM 3). We will evaluate the effects of this therapeutic combination by sensorimotor, advanced imaging and molecular analyses. This project aims at both a better understanding of potential endogenous repair mechanisms after SCI and also to propose innovative treatments. It is based on well-established collaborations between the 3 teams and is located at the interface of neurobiology and material science with the aim of developing a state-of-the-art regenerative strategy for future clinical use.