Preconditioning with interleukin-1 alpha is required for the neuroprotective properties of mesenchymal stem cells after ischaemic stroke in mice

Abstract

Abstract Mesenchymal stem cells (MSCs) pre-conditioning with interleukin-1 alpha (IL-1ɑ) drives MSCs toward a potent anti-inflammatory and pro-trophic phenotype. The aim of this study was to assess the therapeutic potential of IL-1ɑ preconditioning of MSCs, administered intra-arterially (a clinically relevant approach in the setting of thrombectomy) after experimental cerebral ischaemia in mice. Focal ischaemic stroke was induced by filament occlusion of the middle cerebral artery in mice. After 3 h from start of occlusion, animals were treated with vehicle, 9.1x104 non-conditioned or IL-1ɑ preconditioned MSCs by intra-arterial administration. Animals were allowed to recover for 3 days or 14 days post-stroke and lesion volume and functional outcomes were evaluated. To assess reperfusion cerebral blood flow was measured at 1.5 h after treatment using laser speckle imaging in a separate cohort of animals. Preconditioned MSCs reduced lesion volume and neurological deficits compared to vehicle by 67%, while non-conditioned MSCs had no effect, at 3 days post-stroke. A separate cohort of animals recovered to 14 days post-stroke also showed reduced infarct volume at 48 h (assessed by MRI) when treated with preconditioned MSCs, along with lower neurological deficits at 14 days and better weight recovery compared to vehicle treated mice. Cerebral blood flow was increased by preconditioned MSCs compared to vehicle by 32%. Preconditioning MSCs with IL-1α increases their neuroprotective capability and improves functional recovery after delayed intra-arterial administration in a mouse model of focal cerebral ischaemia. With increasing use of thrombectomy the adjunct use of preconditioned MSCs therefore represents a highly relevant therapy to improve outcomes in ischaemic stroke.