Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association · 2025
White matter injury in young rats with cerebral palsy: the role of massage in regulating exosomes via the chemokine axis.
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Yiping Chen, Suyu Chen, Min Li, Yongli Li, Yujing Zhang, Sihan Liu, Chenggui Xu, Tinghui Zhang, Yong Liao, Ji Zhang, Xinghe Zhang, Xiantao Tai
Аннотация
BACKGROUND: Massage is kown to effectively alleviate symptoms of Cerebral Palsy (CP), yet its specific mechanism in CP remains unclear. Cerebral white matter damage is a primary consequence of hypoxia-ischemia (HI) in CP rats. This study aims to explore the potential of massage in facilitating the migration of bone marrow mesenchymal stem cells (BMSCs-Exo) to the brain through the chemokine axis, with the goal of moderating cerebral white matter injury in CP rats.
METHOD: Forty-eight rats were randomized to Sham, Model, Massage, and Inhibition groups. HI injury was induced in 3-day-old rat pups and confirmed through righting reflex assessment and cerebral blood flow imaging. The Massage group received daily massage therapy from postnatal day 5 for 28 days. The Inhibition group was treated with a CXCR4 inhibitor (AMD3100), while the remaining groups were administered saline. Behavioral assessments were conducted at 2 and 4 weeks post-treatment. The homing efficiency of BMSCs-Exo was monitored using small animal live imaging, and cerebral oxygen saturation was measured noninvasively through photoacoustic imaging. Neuronal morphology was evaluated using Nissl staining, and immunofluorescence was employed to co-label oligodendrocytes with CXCR4/SDF-1. SDF-1/CXCR4 expression in bone marrow, serum, and brain white matter was assessed using PCR. In vitro experiments involved co-culturing BMSCs with oligodendrocytes under hypoxic and low glucose conditions. The cell groups included Normal control, DMSO control, Massage, and Massage + GW4869 Group. Viability of BMSCs and oligodendrocytes was determined using CCK-8 assays. Additionally, immunofluorescence staining was performed to visualize exosomes in oligodendrocytes.
RESULTS: HI injury prolonged righting reflex latency and decreased cerebral blood flow. Massage intervention was linked to improved blood flow, increased brain homing of BMSCs-Exo, and enhanced limb function, particularly evident after 4 weeks. Histological analysis using Nissl staining and immunofluorescence demonstrated that massage was coincided with reduced neuronal injury and the upregulation of SDF-1/CXCR4 expression in oligodendrocytes. Initially reduced following HI, SDF-1/CXCR4 levels were restored by massage, with the CXCR4 inhibitor significantly abrogating the therapeutic effects of massage. CCK-8 assays indicated that massage was associated with promoted viability of BMSCs and oligodendrocytes, which was attenuated in the presence of exosome inhibition. Furthermore, the uptake capacity of oligodendrocyte cells for exosomes was superior in the Massage group compared to the DMSO control group.
CONCLUSION: Massage is associated with enhanced motor function and white matter restoration in cerebral palsy, potentially through mechanisms involving the SDF-1/CXCR4 axis, increased homing of BMSCs-Exo to the brain, and enhanced oligodendrocyte attachment.
METHOD: Forty-eight rats were randomized to Sham, Model, Massage, and Inhibition groups. HI injury was induced in 3-day-old rat pups and confirmed through righting reflex assessment and cerebral blood flow imaging. The Massage group received daily massage therapy from postnatal day 5 for 28 days. The Inhibition group was treated with a CXCR4 inhibitor (AMD3100), while the remaining groups were administered saline. Behavioral assessments were conducted at 2 and 4 weeks post-treatment. The homing efficiency of BMSCs-Exo was monitored using small animal live imaging, and cerebral oxygen saturation was measured noninvasively through photoacoustic imaging. Neuronal morphology was evaluated using Nissl staining, and immunofluorescence was employed to co-label oligodendrocytes with CXCR4/SDF-1. SDF-1/CXCR4 expression in bone marrow, serum, and brain white matter was assessed using PCR. In vitro experiments involved co-culturing BMSCs with oligodendrocytes under hypoxic and low glucose conditions. The cell groups included Normal control, DMSO control, Massage, and Massage + GW4869 Group. Viability of BMSCs and oligodendrocytes was determined using CCK-8 assays. Additionally, immunofluorescence staining was performed to visualize exosomes in oligodendrocytes.
RESULTS: HI injury prolonged righting reflex latency and decreased cerebral blood flow. Massage intervention was linked to improved blood flow, increased brain homing of BMSCs-Exo, and enhanced limb function, particularly evident after 4 weeks. Histological analysis using Nissl staining and immunofluorescence demonstrated that massage was coincided with reduced neuronal injury and the upregulation of SDF-1/CXCR4 expression in oligodendrocytes. Initially reduced following HI, SDF-1/CXCR4 levels were restored by massage, with the CXCR4 inhibitor significantly abrogating the therapeutic effects of massage. CCK-8 assays indicated that massage was associated with promoted viability of BMSCs and oligodendrocytes, which was attenuated in the presence of exosome inhibition. Furthermore, the uptake capacity of oligodendrocyte cells for exosomes was superior in the Massage group compared to the DMSO control group.
CONCLUSION: Massage is associated with enhanced motor function and white matter restoration in cerebral palsy, potentially through mechanisms involving the SDF-1/CXCR4 axis, increased homing of BMSCs-Exo to the brain, and enhanced oligodendrocyte attachment.