From homing to repair: Synergistic mechanisms of peripherally administered mesenchymal stem cells for central nervous system diseases.

Central nervous system (CNS) diseases remain a major challenge in neuroscience research due to their complex pathophysiology and the limited effectiveness of current therapies. Mesenchymal stem cells (MSCs), adult multipotent stem cells, have attracted growing interest for CNS disorders because of their homing-related trafficking, paracrine effects, and immunomodulatory capabilities. Evidence from experimental studies suggests that peripherally administered MSCs can respond to lesion-associated inflammatory cues and exert neuroprotective and reparative effects through the release of extracellular vesicles and other bioactive factors. In addition, MSCs can modulate inflammatory responses and immune cell functions, thereby improving the microenvironment relevant to tissue repair. Although preclinical studies support the therapeutic potential of MSCs, their mechanisms of action remain incompletely defined, and multiple obstacles hinder clinical translation. Therefore, this review summarizes three synergistic mechanisms by which peripherally administered MSCs may influence CNS disease outcomes, including homing, paracrine signaling, and immunomodulation. By integrating recent advances, we discuss mechanistic rationales and translational considerations that may help explain how peripheral MSC delivery contributes to CNS repair.