Abstract
Induced pluripotent stem cell-derived neural stem cells (iNSCs) have significant potential as an autologous, multifunctional cell therapy for stroke, which is the primary cause of long term disability in the United States and the second leading cause of death worldwide. Here we show that iNSC transplantation improves recovery through neuroprotective, regenerative, and cell replacement mechanisms in a novel ischemic pig stroke model. Longitudinal multiparametric magnetic resonance imaging (MRI) following iNSC therapy demonstrated reduced changes in white matter integrity, cerebral blood perfusion, and brain metabolism in the infarcted tissue. The observed tissue level recovery strongly correlated with decreased immune response, enhanced neuronal protection, and increased neurogenesis. iNSCs differentiated into neurons and oligodendrocytes with indication of long term integration. The robust recovery response to iNSC therapy in a translational pig stroke model with increased predictive potential strongly supports that iNSCs may be the critically needed therapeutic for human stroke patients.
Highlights
Studies have demonstrated that upon transplantation, Induced pluripotent stem cell-derived neural stem cells (iNSCs) have a dual mode of therapeutic action: 1) serving as a cell replacement therapy by differentiating into neurons and glia that integrate into surrounding tissues and 2) producing neuroprotective and regenerative growth factors that stabilize and promote healing of damaged parenchyma[13,14,15,16]
magnetic resonance imaging (MRI) performed 24 hours post-stroke confirmed the presence of cytotoxic ischemia and cerebral infarction
A smaller degree of atrophy was observed in iNSC treated animals, there was no statistical difference between the two treatment groups (Fig. 2G)
Summary
Studies have demonstrated that upon transplantation, iNSCs have a dual mode of therapeutic action: 1) serving as a cell replacement therapy by differentiating into neurons and glia that integrate into surrounding tissues and 2) producing neuroprotective and regenerative growth factors that stabilize and promote healing of damaged parenchyma[13,14,15,16]. INSCs were tested in a rodent brain which, when compared to the human, possesses many cerebral anatomical and physiological differences; these results may not be directly translatable to clinical applications. The pig brain has greater anatomical and physiological similarities to humans with respect to gray to white matter composition, blood flow, gyral patterning, metabolism, and size - key factors that directly affect injury evolution, tissue recovery and treatment development[18,19,20,21,22,23,24,25]. Transplanted iNSCs survived for 12 weeks in the pig brain and differentiated into neuronal and glial cells These results demonstrate that iNSCs have significant potential as a regenerative and cell replacement therapy in a robust translational large animal model, providing further insight into the potential of these cells as a therapeutic for patients
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