Mesenchymal Stem Cells Induce Recovery After Stroke by Regulation of Inflammation and Oligodendrogenesis

BACKGROUND: Brain repair mechanisms fail to promote recovery after stroke and approaches to induce brain regeneration are scarce. Mesenchymal stem cells (MSC) are thought to be a promising therapeutic option. However, their efficacy is not fully elucidated and the mechanism underlying their effect is not known. METHODS: The middle cerebral artery occlusion (MCAO) model was utilized to determine the efficacy of interferon-γ-activated mesenchymal stem cells (aMSCγ) as an acute therapy for stroke. aMSCγ were intravenously administered to rats three hours after MCAO and functional recovery was assessed using the modified Neurological Severity Score (mNSS), open field analysis, and magnetic resonance imaging. Alterations in post-stroke inflammation, neurogenesis, and oligodendrogenesis were analyzed using biochemical, immunofluorescence, and stereological techniques. Mass spectrometry was used to analyze the MSC secretome. RESULTS: Here we show that treatment with aMSCγ is a more potent therapy for stroke than naïve MSC (nMSC). aMSCγ treatment results in significant functional recovery assessed by the mNSS and open field analysis compared to vehicle-treated animals. aMSCγ-treated animals showed significant reductions in infarct size and inhibition of microglial activation. We show that aMSCγ treatment suppresses the hypoxia-induced microglial pro-inflammatory phenotype more effectively than treatment with nMSC. Importantly, treatment with aMSCγ induces recruitment and differentiation of oligodendrocyte progenitor cells to myelin-producing oligodendrocytes in vivo. To elucidate the mechanism underlying high efficacy of aMSCγ therapy, we examined the secretome of aMSCγ and compared it to nMSC. Intriguingly, we found that aMSCγ but not nMSC upregulate neuron-glia antigen 2, (NG2), an important extracellular signal and a hallmark protein of oligodendrocyte progenitor cells (OPCs). CONCLUSIONS: These results suggest that activation of MSC with interferon-γ induces a potent pro-regenerative, pro-myelinating, and anti-inflammatory phenotype of these cells, which increases the potency of aMSCγ as an effective therapy for ischemic stroke. The unraveling of the secretome of aMSCγ may help move the field towards a better understanding of the potential of MSCs as a therapy for stroke.