Abstract
Induced pluripotent stem cell-derived neural stem cells (iNSCs) have led to cellular and functional recovery in ischemic stroke models. However, the therapeutic effects of iNSC treatment are limited by decreased cell survival in the cytotoxic stroke environment. Tanshinone IIA is a potential anti-inflammatory and antioxidative treatment that may modulate this harsh microenvironment and lead to improved iNSC survival in stroke tissue. To test this hypothesis, the combined effects of Tanshinone IIA-loaded nanoparticles (Tan IIA-NPs) and iNSCs were evaluated in a translational pig ischemic stroke model. 18 Yucatan pigs underwent middle cerebral artery occlusion and were assigned to the following treatment groups: PBS+PBS, PBS+iNSC, or Tan IIA-NP+iNSC. PBS or Tan IIA-NPs were administered intracisternally 1-hour post-stroke and either PBS or iNSCs were transcranially transplanted into the parenchyma 5 days post-stroke. Magnetic resonance imaging (MRI) was collected 24 hours post-stroke and 12 weeks post-transplantation. Immunohistochemistry was completed 12 weeks post-iNSC transplantation. MRI demonstrated that Tan IIA-NPs significantly reduced lesion volumes, midline shift, and intracerebral hemorrhage, while iNSCs improved white matter integrity. Immunohistochemistry revealed that Tan IIA-NP+iNSC treatment significantly increased NeuN+ neurons in the penumbra relative to PBS+iNSC and PBS+PBS treatment groups. Tan IIA-NP+iNSC treated pigs also showed significantly decreased Iba1+ immune cells and GFAP+ activated astrocytes in the penumbra relative to PBS+iNSC and PBS+PBS treated pigs. Tan IIA-NP+iNSC treated pigs showed significantly increased DCX+ neuroblasts at the lesion border and in the ventricular lining of the subventricular zone relative to PBS+iNSC and PBS+PBS pigs. In addition, PBS+iNSC treated pigs also showed significantly more DCX+ neuroblasts than PBS+PBS pigs. Collectively, Tan IIA-NPs in combination with iNSCs possess potential as a multifaceted neuroprotective and regenerative treatment for ischemic stroke patients. The robust tissue preservation and recovery responses in a predictive large animal model strongly support the continued evaluation of this novel combination therapy.
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