Abstract TP247: Tanshinone IIA Loaded Nanoparticles Enhance Induced Pluripotent Stem Cell-derived Neural Stem Cell Recovery Responses In A Porcine Ischemic Stroke Model

Abstract

Induced pluripotent stem cell-derived neural stem cells (iNSCs) have shown significant therapeutic promise in rodent stroke models with neuroprotective, regenerative, and cell replacement effects. However, the therapeutic potency of iNSCs has been largely limited by low iNSC survivability in the cytotoxic stroke environment. In this study, we examined the potential of Tanshinone IIA, an anti-inflammatory and antioxidative agent, loaded nanoparticles (Tan IIA-NPs) to improve iNSC survival, engraftment, and recovery responses in a porcine ischemic stroke model. Eighteen Yucatan pigs underwent middle cerebral artery occlusion (MCAO) surgery and were assigned to PBS+PBS, PBS+iNSC, or Tan IIA-NP+iNSC treatment groups. PBS or Tan IIA-NPs were administered intracisternally 1 hour post-stroke and PBS or iNSCs were transcranially transplanted into the penumbra stroke region 5 days post-stroke. Porcine adapted Modified Rankin Scale (mRS) neurologic scores were recorded pre- and post-stroke. Magnetic resonance imaging (MRI) and immunohistochemistry were performed 12 weeks post-iNSC transplantation. mRS evaluations demonstrated that Tan IIA-NP+iNSC treatment led to faster and improved (p<0.05) recovery at 1, 4, and 12 weeks post-transplantation relative to PBS+PBS and PBS+iNSC treatments. MRI results at 12 weeks showed a stepwise decrease in lesion volume and midline shift in PBS+PBS, PBS+iNSC, and Tan IIA-NP+iNSC groups with the Tan IIA-NP+iNSC group showing a significant decrease (p<0.05) relative to the PBS+PBS group. Immunohistochemistry analysis showed that Tan IIA-NPs resulted in increased (p<0.05) iNSC survival and differentiation into NeuN+ neurons and decreased (p<0.05) differentiation into GFAP+ astrocytes. These promising results indicate that the combined Tan IIA-NP+iNSC therapy leads to improved iNSC survival and engraftment, tissue and functional recovery, and may be a viable treatment for human stroke patients.