Abstract WP115: Transplanted Induced Neural Stem Cells Differentiate and Integrate Into the Brain Parenchyma of Ischemic Stroke Pigs Leading to Improved Tissue Recovery

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Abstract

Studies in rodents have provided evidence that induced pluripotent stem cell derived neural stem cells (iNSCs) have a multifunctional role in stroke recovery. iNSCs mitigate tissue loss due to secondary injury, promote tissue recovery through angiogenesis, and differentiate into mature neural cell types resulting in recovery and replacement of lost and damaged brain tissue. However, many stroke therapies developed in the rodent have failed in clinical trials, suggesting that iNSC therapy should be tested in a more translatable large animal model such as the pig. The objective of this study was to assess the ability of iNSCs to differentiate into mature neural cell types and characterize the effects of iNSCs on brain tissue recovery utilizing non-invasive magnetic resonance imaging (MRI) and spectroscopy approaches in a pig model. Eight male landrace pigs underwent middle cerebral artery occlusion stroke surgery. After 5 days, 4 pigs received iNSC intraparenchymal injections and 4 pigs received vehicle only injections. Pigs underwent MRI assessment at 24 hrs post-stroke and 1, 4, and 12 wks post-injection, and brain tissues were collected 12 wks post-injection. At 12 wks post-injection, iNSC treated pigs showed significant improvement in white matter integrity with recovery of fractional anisotropy being 4-fold higher in treated pigs relative to non-treated pigs. Perfusion weighted imaging demonstrated significant improvement in cerebral blood volume (13%), time to peak (36%), and mean transit time (41%) in treated pigs at 12 wks post-injection vs. non-treated pigs. In addition, treated pigs showed significant improvement in neurometabolites NAA, Cr, and Cho at 12 wks post-injection relative to non-treated pigs. Gene expression analysis established significant increases in neurotrophic and angiogenic factors including BDNF and ANG1, respectively, in brain tissue of treated pigs vs. non-treated pigs suggesting potential modes of action. iNSCs were located in the brain parenchyma 12 wks post-injection, and the majority were positive for the mature neuronal marker NeuN. These results demonstrated that iNSCs are capable of neuronal differentiation and long term integration while promoting tissue recovery in a preclinical pig ischemic stroke model.

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