Regional modulation of neurodegeneration and microglial activation by intravenous Wharton’s jelly mesenchymal stromal cell therapy in a mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative condition characterized by rapid degeneration of motoneurons (MNs), leading to progressive muscle atrophy and, ultimately, mortality within a few years of diagnosis. Although the precise mechanisms initiating MN degeneration are not fully understood, the involvement of non-neuronal cells, including microglia, in ALS pathophysiology is increasingly recognized. Mesenchymal stromal cell (MSC)-based therapies have emerged as a promising avenue for ALS treatment, yet clinical outcomes remain variable, underscoring the necessity for additional pre-clinical investigations. This study evaluated the therapeutic potential of human MSCs derived from Wharton’s jelly (WJMSC) in the female SOD1^G93A mouse model of ALS. Our results indicated that intravenous administration of WJMSC during the presymptomatic phase of the disease notably delayed the onset of motor deficits and extended the lifespan. This functional benefit was associated with the preservation of MNs in the cervical spinal cord. In the lumbar spinal cord, we did not observe MN neuroprotection, but we noted a temporary increase in microgliosis following WJMSC treatment. Our results supported the therapeutic benefits of human MSC in ALS, while also highlighting the differential responses of spinal-cord regions to the treatment during the disease progression. This study underscores the importance of targeting specific disease stages and regions for MSC therapy in ALS, paving the way for refined and potentially more effective therapeutic strategies.