OBJECTIVE Reperfusion
therapy with intravenous recombinant
tissue plasminogen activator (rtPA) is the standard of care for
acute ischemic stroke. However, hemorrhagic complications can result.
Intravenous infusion of mesenchymal stem cells (MSCs) reduces stroke volume and improves behavioral function in experimental
stroke models. One suggested therapeutic mechanism is inhibition of vascular endothelial dysfunction. The objective of this study was to determine whether MSCs suppress hemorrhagic events after rtPA
therapy in the acute phase of transient
middle cerebral artery occlusion (tMCAO) in rats. METHODS After induction of tMCAO, 4 groups were studied: 1)
normal saline [NS]+vehicle, 2) rtPA+vehicle, 3) NS+MSCs, and 4) rtPA+MSCs. The incidence rate of
intracerebral hemorrhage, both hemorrhagic and ischemic volume, and behavioral performance were examined.
Matrix metalloproteinase-9 (
MMP-9) levels in the brain were assessed with zymography. Quantitative analysis of regional cerebral blood flow (rCBF) was performed to assess hemodynamic change in the ischemic lesion. RESULTS The MSC-treated groups (Groups 3 and 4) experienced a greater reduction in the incidence rate of
intracerebral hemorrhage and hemorrhagic volume 1 day after tMCAO even if rtPA was received. The application of rtPA enhanced activation of
MMP-9, but MSCs inhibited
MMP-9 activation. Behavioral testing indicated that both MSC-infused groups had greater improvement than non-MSC groups had, but rtPA+MSCs provided greater improvement than MSCs alone. The rCBF ratio of rtPA groups (Groups 2 and 4) was similar at 2 hours after reperfusion of tMCAO, but both were greater than that in non-rtPA groups. CONCLUSIONS Infused MSCs may inhibit endothelial dysfunction to suppress hemorrhagic events and facilitate functional outcome. Combined
therapy of infused MSCs after rtPA
therapy facilitated early behavioral recovery.