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The initiating IL-10 production dominates the therapy of mesenchymal stem cell scaffold in spinal cord injury

ABSTRACT: spinal cord injury (SCI) is an acute damage to central nevous system, resulting in severe morbidity and permanent disability. Locally implanting scaffold system immobilized mesenchymal stem cellshas been widely proven to promote the locomotor function recovery of SCI rat, but the underlying mechanism remains elusive. Here we constructed a hyaluronic acid scaffold system (HA-MSC) to accelerates human MSC adhesive growth and prolongs the survival time of MSC in the lesion of SCI rats. And the residual MSCs regulate the local immune responses by upregulating anti-inflammatory cytokines. Interestingly, the dramatically increased but transient expression of IL-10 is found secreted by MSCs in the first week. Blocking the function of the initiating produced IL-10 by antibody totally abolishes the neurological and behavioral recovery of SCI rats, indicating a core role of IL-10 in SCI therapy of HA-MSC implantation. Transcriptome analyses indicate that IL-10 selectively promotes the migration and cytokine secretion programs of MSC, which in turn help MSC to exert its anti-inflammatory therapeutic effects. Our findings thus highlight a novel role of IL-10 in regulating MSC migration and cytokine secretion and determine the vital role of IL-10 in the domination of MSC treatment for spinal cord repair.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240755 | GEO | 2024/01/16

REPOSITORIES: GEO

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Project description:The inflammatory response after spinal cord injury (SCI) is an important contributor to secondary damage. Infiltrating macrophages can acquire a spectrum of activation states, however, the microenvironment at the SCI site favors macrophage polarization into a pro-inflammatory phenotype, which is one of the reasons why macrophage transplantation has failed. In this study, we investigated the therapeutic potential of the macrophage secretome for SCI recovery. We investigated the effect of the secretome in vitro using peripheral and CNS-derived neurons and human neural stem cells. Moreover, we perform a pre-clinical trial using a SCI compression mice model and analyzed the recovery of motor, sensory and autonomic functions. Instead of transplanting the cells, we injected the paracrine factors and extracellular vesicles that they secrete, avoiding the loss of the phenotype of the transplanted cells due to local environmental cues. We demonstrated that different macrophage phenotypes have a distinct effect on neuronal growth and survival, namely, the alternative activation with IL-10 and TGF-β1 (M(IL-10+TGF-β1)) promotes significant axonal regeneration. We also observed that systemic injection of soluble factors and extracellular vesicles derived from M(IL-10+TGF-β1) macrophages promotes significant functional recovery after compressive SCI and leads to higher survival of spinal cord neurons. Additionally, the M(IL-10+TGF-β1) secretome supported the recovery of bladder function and decreased microglial activation, astrogliosis and fibrotic scar in the spinal cord. Proteomic analysis of the M(IL-10+TGF-β1)-derived secretome identified clusters of proteins involved in axon extension, dendritic spine maintenance, cell polarity establishment, and regulation of astrocytic activation. Overall, our results demonstrated that macrophages-derived soluble factors and extracellular vesicles might be a promising therapy for SCI with possible clinical applications.

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The initiating IL-10 production dominates the therapy of mesenchymal stem cell scaffold in spinal cord injury

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