Bystander Effect Fuels Human Induced Pluripotent Stem Cell-Derived Neural Stem Cells to Quickly Attenuate Early Stage Neurological Deficits After Stroke

: Present therapies for stroke rest with tissue plasminogen activator (tPA), the sole licensed antithrombotic on the market; however, tPA's effectiveness is limited in that the drug not only must be administered less than 3-5 hours after stroke but often exacerbates blood-brain barrier (BBB) leakage and increases hemorrhagic incidence. A potentially promising therapy for stroke is transplantation of human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSCs). To date, the effects of iPSCs on injuries that take place during early stage ischemic stroke have not been well studied. Consequently, we engrafted iPSC-NSCs into the ipsilesional hippocampus, a natural niche of NSCs, at 24 hours after stroke (prior to secondary BBB opening and when inflammatory signature is abundant). At 48 hours after stroke (24 hours after transplant), hiPSC-NSCs had migrated to the stroke lesion and quickly improved neurological function. Transplanted mice showed reduced expression of proinflammatory factors (tumor necrosis factor-α, interleukin 6 [IL-6], IL-1β, monocyte chemotactic protein 1, macrophage inflammatory protein 1α), microglial activation, and adhesion molecules (intercellular adhesion molecule 1, vascular cell adhesion molecule 1) and attenuated BBB damage. We are the first to report that engrafted hiPSC-NSCs rapidly improved neurological function (less than 24 hours after transplant). Rapid hiPSC-NSC therapeutic activity is mainly due to a bystander effect that elicits reduced inflammation and BBB damage.

Significance: Clinically, cerebral vessel occlusion is rarely permanent because of spontaneous or thrombolytic therapy-mediated reperfusion. These results have clinical implications indicating a much extended therapeutic window for transplantation of human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSCs; 24 hours after stroke as opposed to the 5-hour window with tissue plasminogen activator [tPA]). In addition, there is potential for a synergistic effect by combining hiPSC-NSC transplantation with tPA to attenuate stroke's adverse effects.