Abstract
Introduction: Intraparenchymal stem cell transplantation shows therapeutic promise for chronic ischemic stroke patients. Our previous phase 1/2a trial revealed a transient T2-FLAIR (fluid-attenuated inversion recovery) MRI signal in the premotor cortex following intraparenchymal stem cell transplantation, the size of which positively correlated with the extent of clinical recovery. We sought to elucidate the underlying molecular mechanisms in this FLAIR region that may facilitate post-stroke recovery using spatial transcriptomic profiling in stroke-injured rat brains. Methods: Adult male SD rats underwent 30 min transient middle cerebral artery occlusion followed at 1 month by transplantation of human ES-derived neural stem cells (NR1) or buffer into the ipsilesional striatum. Whisker paw test and various MRI sequences (T2, FLAIR, DWI) were performed at multiple time points. The Visium platform (10X Genomics) was used for unbiased spatial transcriptome analysis in two stem-cell and two vehicle-treated brains at the peak of FLAIR. Results: We successfully replicated transplant-induced FLAIR after chronic stroke in rats and found a positive correlation between FLAIR and improved neurological outcomes. Visium identified specific gene clusters for the stroke injury, transplant/needle-track, stem cell graft, and the cortical ‘FLAIR’ region. The latter consisted of a central core containing the gene signature of the needle track and blood, and a wider region around this core which encompassed the FLAIR lesion seen by MRI. This wider FLAIR region displayed a predominantly microglia/inflammation-associated signature and was best characterized by the upregulation of apoptosis-associated genes. Pathway analysis of the differentially-expressed genes in the FLAIR cluster revealed a significant representation of immune cell responses (e.g. phagocytosis, immune cell migration, cytokine signaling), as well as ER stress mechanisms. Conclusion: This pilot study provides initial evidence that altered immune responses in the stem cell transplant-induced FLAIR region may promote recovery after chronic stroke. Further research on the role of microglia/neuroinflammation is needed to understand the mechanisms of stem cell-mediated brain repair.
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