Phase-dependent efficacy of intravenous amniotic mesenchymal stem cells in a rat spinal cord injury model

Abstract

Abstract Background Spinal cord injury results in profound neurological disability driven initially by primary mechanical damage and subsequently by secondary injury processes characterized by progressive neuroinflammation. Intravenous administration of human amniotic mesenchymal stem cells (MSC) has emerged as a promising therapeutic approach; however, the optimal timing of administration and its relationship to dynamic immune responses remain unclear. Methods A rat contusion model of spinal cord injury was used to evaluate the effects of intravenous MSC administration at three post-injury time points: days 1, 3, and 7. Functional and histological assessments were performed for each group. Systemic inflammatory responses were evaluated through blood analysis of neutrophil and macrophage counts, systemic inflammation index (SII), and plasma proteomics. Local immune responses were assessed by quantifying infiltrating immune cells within the injured spinal cord. Results The most substantial improvement in locomotor function was observed in the day-1 treatment group, followed by the day-7 group, whereas the day-3 group showed minimal benefit. The day-3 group also demonstrated a trend toward greater lesion length and increased macrophage infiltration 28 days after injury. MSC administration reduced SII in the day-1 and day-7 groups but not in the day-3 group, which instead showed an increased systemic inflammatory response. Analysis of spinal cord tissue demonstrated that MSC treatment on day-1 effectively reduced neutrophil infiltration, which peaks at this time point, while day-7 administration reduced macrophage infiltration during its peak phase. In contrast, MSC administration on day-3 failed to attenuate either neutrophil or macrophage accumulation. Plasma proteomic profiling revealed enhanced complement and coagulation pathway activation specifically on day-3. Conclusions The therapeutic efficacy of intravenously administered MSC is highly dependent on the timing of intervention. Optimal benefit is achieved when treatment coincides with peak activation of a dominant target immune cell population and avoids the peak of complement and coagulation signaling. These findings support a phase-matched therapeutic strategy to maximize MSC effectiveness following spinal cord injury.

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