Umbilical cord mesenchymal stem cell-conditioned medium inhibits microglial activation to ameliorate neuroinflammation in amyotrophic lateral sclerosis mice and cell models

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease for which few effective therapeutic strategies are available. Increasing evidence indicates that neuroinflammation plays a significant role in ALS pathogenesis. Mesenchymal stem cell (MSC)-based therapy has been proposed for the treatment of neurodegenerative diseases, including ALS. In this study, we first demonstrated that systemic administration of conditioned medium derived from umbilical cord MSCs (UCMSC-CM) extends the lifespan of transgenic SOD1-G93A mice, a well-characterized model of familial ALS. Moreover, UCMSC-CM inhibits microglial activation and astrogliosis and alleviates the inflammatory milieu by reducing the release of proinflammatory cytokines and the expression of iNOS in the spinal cord. Using BV-2 cells overexpressing the SOD1-G93A mutant as an ALS cellular model, we uncovered that UCMSC-CM also suppresses the lipopolysaccharide (LPS)-induced inflammatory response, including reduced expression of proinflammatory cytokines and iNOS. Importantly, by culturing astrocytes alone in microglia-conditioned medium (MCM) or together with microglia in a transwell coculture system, we found that UCMSC-CM modulates the secretome of microglia exposed to inflammatory stimuli, thereby preventing the conversion of astrocytes to the A1 neurotoxic phenotype. This study revealed the anti-inflammatory properties of UCMSC-CM and its regulatory effect on glial activation in the treatment of neuroinflammation in ALS, providing strong evidence for the clinical application of UCMSC-CM.