Abstract 20152: Human Neural Stem Cell Transplantation Ameliorates Hemorrhagic Transformation Caused by Delayed Antithrombotic Treatment in Aged Stroke Brains
Background: Despite aging being a strong risk factor, most preclinical stroke studies employ young animals instead of aged animals. tPA dissolves clots and restores blood flow. Yet, while tPA’s role within blood vessels can be beneficial, reports of harmful effects within the CNS have been reported. Issues surrounding tPA are two-fold: (1) Treatment requires the patient receive recombinant tPA quickly (<4.5 hours) after stroke onset, and (2) there is the probability of ischemic reperfusion (IR) damage, a destabilization of the blood-brain barrier (BBB) that leads to bleeding into the brain (hemorrhagic transformation, HT). While age alone is not a barrier for tPA treatment (within 4.5 h), the effect of delayed tPA treatment (e.g., 6h) on aged stroke brains has not been well studied. In this study, we explore the effect of aging as it affects the BBB and HT in a delayed tPA-treated stroke mice.
Methods and Results: One day post-stroke, we injected human neural stem cells (hNSCs) into the ipsilesional hippocampus of a mouse model of stroke with middle cerebral artery occlusion to induce focal ischemia followed by reperfusion (MCAO/R). The time frame for NSC transplantation corresponded to the upregulation of endogenous proinflammatory cytokines. We examined the effect of hNSC transplantation on pathological processes 48h post-stroke. Previously, we reported for the first time that NSCs (both mouse and human) transplanted into the brain 24h post-IR rapidly improve neurological function and reduce BBB damage at 48h post-IR (24h post-transplant) in young-adult mice (4-5mo). In this study, consistent with others’ findings, tPA administered within 4.5h post-stroke benefits both young-adult and aged mice. However, we found differential effects of aging after delayed tPA treatment (6h post-stroke): no severe HT in young mice but severe, prominent HT in aged mice (13-18 mo). Greater MCP-1 upregulation is linked with tPA-induced HT. Importantly, transplanted hNSCs ameliorated tPA-induced HT, decreased expression of proinflammatory factors (TNF-α and MCP-1), and consequently improved BBB integrity.
Conclusions: Our findings implicate that combining hNSC transplantation after delayed tPA injection improves tPA’s efficacy and safety in aged stroke brains.
Author Disclosures: A.D. Eckert: None. J. Lee: None.
- © 2016 by American Heart Association, Inc.