Nicolas Guérout

Spinal cord injuries (SCI) are traumatic lesions of the spinal cord that commonly result from physical trauma. They can lead to severe and permanent impairments in motor, sensory, and/or autonomic functions, often resulting in paraplegia or tetraplegia. Despite advances in this field, effective restorative treatments for SCI remain limited. Over the past few years, several therapeutic strategies have been investigated to promote functional recovery after SCI, including neuromodulation approaches. Repetitive magnetic stimulation has emerged as a promising non-invasive strategy, with encouraging results when the stimulation is applied directly over the spinal cord. However, most studies have focused on high-intensity stimulation, while the key parameters underlying its therapeutic efficacy remain poorly understood. In this study, we investigated the effects of low-intensity repetitive trans-spinal magnetic stimulation (LI-rTSMS) following SCI in mice, using BMS, histological and RNA sequencing approaches. We aimed to determine the optimal protocol by comparing three stimulation patterns (10 Hz, iTBS and BHFS) and two coil sizes. Our results show that LI-rTSMS modulates the injured spinal cord in a pattern- and coil size-dependent manner, with distinct effects on fibrotic, neural, and inflammatory responses. Notably, the BHFS pattern produced the most marked tissue-remodeling effects, reducing fibrosis, reactive astrogliosis, and phagocytosis of myelin debris. This reduction in phagocytosis was also observed with a smaller coil, supporting an effect of LI-rTSMS on this process. We also identified distinct inflammatory signatures depending on the stimulation pattern and time after injury. Transcriptomic analyses revealed a common early inflammatory response to LI-rTSMS, whereas each stimulation pattern subsequently led to distinct molecular signatures after 2 weeks stimualtion. In addition, ependymal cells are known to retain endogenous regenerative potential following SCI. We found that LI-rTSMS increased ependymal cell proliferation and migration toward the lesion site, without detectable changes in their differentiation. Finally, we assessed c-Fos expression as a marker of early transcriptional changes in neurons. LI-rTSMS did not result in significant changes, suggesting that the observed effects were unlikely to be mediated by early, widespread neuronal activation. Altogether, this study provides mechanistic insights into the pattern-dependent effects of LI-rTSMS and highlights its potential role for future clinical translation.

Spinal cord injury (SCI) leads to irreversible loss of motor, sensory, and autonomic functions and currently has no cure. While cell therapies in animal models have shown benefits such as scar reduction and neuroprotection, their translation to humans remains limited, partly because clinical applications rely on autologous rather than healthy donor cells. This prompted us to investigate how the lesion context alters the neuro-reparative potential of olfactory ensheathing cells (OECs). OECs were cultured from healthy animals or from animals 1 week after SCI, and both populations were transplanted into recipient mice after SCI.Our results demonstrate for the first time that SCI-derived OECs display impaired therapeutic properties compared with healthy-donor OECs. Transplantation of post-injury cells failed to reduce fibrotic scar, demyelination, or astrocytic defects at the lesion epicenter, and did not promote sensory-motor recovery. In addition, SCI-derived OECs showed a markedly reduced ability to limit neuronal death, support axonal survival, and preserve synaptic integrity, whereas transplantation of healthy-donor OECs significantly improved all these outcomes. At the molecular level, SCI-derived OECs secreted pro-inflammatory mediators that polarized microglia toward a pro-inflammatory phenotype, thereby exacerbating the hostile lesion environment. Altogether, these combined in vivo and in vitro findings reveal that the lesion-induced context profoundly compromises OEC reparative functions. They highlight a previously unrecognized limitation of autologous OEC transplantation and underscore the importance of considering the lesion context when designing cell-based strategies for SCI.

Spinal cord injury (SCI) causes irreversible loss of motor, sensory, and autonomic functions and currently has no cure. Beyond local damage, SCI induces systemic inflammation, including cerebral inflammation that impairs neurogenesis. While cell therapies show promising effects in animal models, such as scar reduction and neuroprotection, their benefits in humans remain limited. One key difference lies in the transplantation strategy: animals receive healthy donor cells, whereas humans require autologous transplants. This led us to investigate how the lesion context affects the neuro-reparative potential of olfactory ensheathing cells (OECs) harvested from olfactory bulbs. To this end, we cultured OECs from healthy animals and from animals that had undergone SCI one week earlier. We then transplanted both types of OECs into recipient animals after SCI for therapeutic purposes. Using functional sensory-motor studies, histological and gene expression analyses, we were able to demonstrate for the first time that the lesion negatively affects the therapeutic properties of cells used to treat SCI. Indeed, transplantation of cells from previously injured animals does not modulate the fibrotic and glial scar, or the demyelinated areas at the lesion site, and therefore fails to improve functional recovery; unlike cells derived from healthy donors. Moreover, our in vitro studies show that cells derived from SCI animals secrete pro-inflammatory molecules that promote the polarization of microglia toward a pro-inflammatory phenotype. Altogether, these innovative findings provide new insights into the potential of cell transplantation in the context of autologous therapy after SCI. Graphical

Neuromodulation has experienced significant growth in recent years. This technique modulates the activity of the central or peripheral nervous system via electrical or magnetic fields. It can be applied to peripheral nerves, the spinal cord, or the brain. Historically, spinal cord stimulation has been used for chronic pain management, with electrodes surgically placed around the spinal cord via a method known as epidural spinal cord stimulation. Recently, this technique has been improved for the treatment of spinal cord injuries. In the brain, deep brain stimulation targets the basal ganglia and is used primarily to treat Parkinson’s disease. Over time, less invasive methods, such as transcutaneous electrical nerve stimulation and magnetic stimulation (including repetitive magnetic stimulation), have emerged. Transcutaneous electrical nerve stimulation operates similarly to epidural spinal cord stimulation but stimulates the skin surface, whereas repetitive magnetic stimulation uses magnetic fields to noninvasively induce electrical currents. Repetitive magnetic stimulation has been used clinically for decades, particularly to target specific cortical areas in the brain. Although neurostimulation techniques have long been applied clinically, the precise mechanisms involved have only recently been partially understood. This review aims to explore the role of magnetic stimulation in treating central nervous system pathologies, with a focus on its cellular and molecular mechanisms. The comprehensive literature on magnetic stimulation underscores its evolving role in clinical and research settings, highlighting the continuous advancement of these technologies in treating neurological disorders and suggesting a potential revolution in the treatment of patients with neurodegenerative or traumatic diseases.

Spinal cord injuries (SCIs) affect between 250,000 and 500,000 people worldwide each year, most commonly due to road accidents or falls. These injuries result in permanent disabilities, the severity and impact of which are directly related to the extent and location of the injury. Recent studies have also shown that SCIs can lead to cognitive disorders due to inflammation in the brain. From a therapeutic perspective, numerous treatments have been explored, including cell therapy. It has been established that a common mechanism across various cellular transplant models is the modulation of inflammation at the injury site. However, it remains unclear whether the immunomodulatory effects observed in the spinal cord also extend to the brain. To test this hypothesis, we induced SCI in wild-type mice and treated them with transplants of differentiated cells, specifically olfactory ensheathing cells, or stem cells, such as mesenchymal stem cells. Our results demonstrate that both types of transplants can reverse cognitive disorders induced by SCI. Additionally, we found that these cellular transplants modulate brain inflammation and increase neuronal density in the hippocampus. To our knowledge, this is the first study to show that cells transplanted into the spinal cord can modulate the inflammatory response in the brain, thereby reversing the negative effects of injury on brain function following SCI. These findings underscore the complex interactions between the brain and spinal cord under both physiological and pathological conditions.

Traumatic injuries of the spinal cord (SCIs) are still pathologies with a disastrous outcome