Neonatal hypoxia-ischemia occurs in 1-3 per 1,000 full-term births, resulting in approximately 12,000 patients per year given a prognosis of developmental delay. Stem cell therapy is a very promising strategy in regenerative medicine. Our team established a porcine model of neonatal hypoxia/ischemia, with a detailed evaluation of behavioral and histopathological outcomes. In addition, immunodeficient rag2-/- animals are ideal recipients of human grafts. In this project, we evaluate whether cell labeling using iron oxide nanoparticles compromises cell migration and differentiation after transplantation in a highly translational large animal model with distances traveled by the cells relevant to the clinical setting. We further perform studies to evaluate the appropriate stem cell dose; assess if positive therapeutic effect results from indirect mechanisms, mostly based on trophic factor release; and evaluate if cell replacement is feasible in large, gyrencephalic brain, and how much it contributes to the behavioral recovery using long-term animal survival. If our study confirms therapeutic efficacy, the protocol will be ready to be applied in an early phase clinical trial, as well as provide preliminary data for cell engineering and delivery modifications for further outcome improvement.

Public Health Relevance

Neonatal hypoxia-ischemia results with life-long developmental delay, that can hinder self-reliance and educational and workplace opportunities. Immunodeficient rag2-/- piglets in concert with FDA-approved stem cells and a minimally invasive, image-guided transplantation strategy create a unique platform to introduce a regenerative medicine approach to neonatal care.

One of the many critical questions concerning stroke treatment is deciphering the ideal route of delivery in terms of efficacy, safety, timing of delivery, and methods by which to monitor the process. With an increasing number of intra-arterial catheter interventions for stroke performed, it would seem that intra-arterial cell injection would be ideally suited and feasible for use in the stroke setting. Preclinical data suggest that intra-arterial cell injection leads to a greater number of cells targeting the ischemia. Cell sorting or cell engineering to improve the targeted delivery needs to be further investigated. The mechanistic theories about transendothelial migration and the safety concerns have led to an additional important consideration, which is the monitoring of cell delivery.

Adapted from: Guzman R, Janowski M, Walczak M. Intra-Arterial Delivery of Cell Therapies for Stroke. Stroke, 2018;49:1075–1082.