Mesenchymal Stem Cell Therapy Modulates Peripheral-Central Immune Interactions and Attenuates Neuroinflammation-Driven Cognitive Dysfunction.

Abstract

Peripheral inflammation is increasingly recognized as a critical driver of sustained neuroinflammation and cognitive dysfunction in neurodegenerative and inflammation-associated disorders. Systemic inflammatory mediators can compromise blood-brain barrier integrity, activate glial cells, and initiate maladaptive neuroimmune cascades that disrupt hippocampal-prefrontal circuits underlying learning and memory. Here, we investigated whether early systemic administration of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) mitigates inflammation-driven cognitive deficits in a chronic lipopolysaccharide (LPS) mouse model. Adult mice received daily LPS injections for seven days to induce persistent systemic and central inflammation, which was confirmed by serum and hippocampal cytokine analyses in a separate cohort at the time of MSC administration, followed by intravenous MSC treatment immediately after cessation of the inflammatory insult. Behavioral testing revealed significant impairments in spatial working memory, recognition memory, and associative learning. These deficits were accompanied by pronounced microglial activation, immune cell accumulation, astrocytosis, and a shift toward a pro-inflammatory cytokine milieu with suppression of IL-10 in the hippocampal CA1 region and medial prefrontal cortex. Early MSC treatment attenuated glial reactivity, reduced pro-inflammatory cytokines, restored IL-10 expression, and partially rescued cognitive performance. Collectively, these findings identify a post-inflammatory therapeutic window in which early MSC-based immunomodulation can rebalance neuroimmune signaling and limit inflammation-induced hippocampal-prefrontal circuit dysfunction, highlighting a clinically relevant strategy for targeting cognitive impairment associated with chronic systemic inflammation.