Abstract
Spinal cord injury triggers irreversible loss of motor and sensory functions. Numerous strategies aiming at repairing the injured spinal cord have been studied. Among them, the use of bone marrow-derived mesenchymal stem cells (BMSCs) is promising. Indeed, these cells possess interesting properties to modulate CNS environment and allow axon regeneration and functional recovery. Unfortunately, BMSC survival and differentiation within the host spinal cord remain poor, and these cells have been found to have various adverse effects when grafted in other pathological contexts. Moreover, paracrine-mediated actions have been proposed to explain the beneficial effects of BMSC transplantation after spinal cord injury. We thus decided to deliver BMSC-released factors to spinal cord injured rats and to study, in parallel, their properties in vitro. We show that, in vitro, BMSC-conditioned medium (BMSC-CM) protects neurons from apoptosis, activates macrophages and is pro-angiogenic. In vivo, BMSC-CM administered after spinal cord contusion improves motor recovery. Histological analysis confirms the pro-angiogenic action of BMSC-CM, as well as a tissue protection effect. Finally, the characterization of BMSC-CM by cytokine array and ELISA identified trophic factors as well as cytokines likely involved in the beneficial observed effects. In conclusion, our results support the paracrine-mediated mode of action of BMSCs and raise the possibility to develop a cell-free therapeutic approach.
Highlights
Spinal cord injury (SCI) is characterized by the primary lesion, rapidly followed by a cascade of cellular and molecular events that trigger the development of the secondary lesion, known to be deleterious for axonal regeneration and functional recovery
In vitro, bone marrow-derived mesenchymal stem cells (BMSCs)-conditioned medium (CM) provides protection against neuronal apoptosis, is pro-angiogenic and confers a proinflammatory phenotype to macrophages
We demonstrate for the first time that BMSC-released molecules are able to reduce cystic cavity size along the ventro-dorsal axis at the lesion epicentre, to favour large blood vessel growth and to improve locomotor recovery in a spinal cord contusion injury model
Summary
Spinal cord injury (SCI) is characterized by the primary lesion, rapidly followed by a cascade of cellular and molecular events that trigger the development of the secondary lesion, known to be deleterious for axonal regeneration and functional recovery. The initiated spontaneous axonal regeneration is repressed by the inhibitory environment composed of astroglial scar, and myelin-derived inhibitory molecules [11] In this context, numerous experimental studies have been performed to improve functional recovery, focusing on various parameters: control of inflammation [12,13], rescue of neural tissue [14,15], stimulation of axonal regeneration by modulation of the lesioned environment [16,17,18] or promotion of remyelination [19,20]. Olfactory ensheathing cells, schwann cells, macrophages, fibroblasts, neural stem cells or BMSCs have been transplanted in various spinal cord injured contexts [21,22,23,24,25,26,27,28,29]
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