Abstract
Objective: Treatment of stroke with bone-marrow-stromal cells (BMSCs) derived from normal rats (Nor-BMSCs) at 24h after stroke onset improves functional recovery in non-DM rats, but not in type-one DM (T1DM) rats. In the present study, we tested the differential therapeutic effects and mechanisms of action of the treatment of T1DM stroke with BMSCs derived from DM rats (DM-BMSCs) or Nor-BMSCs. Methods: T1DM rats were subjected to 2h of middle cerebral artery occlusion (MCAo) and were treated with DM-BMSCs, Nor-BMSCs or vehicle control (n=8/group) initiated at 24h after MCAo. A battery of functional tests, and vascular and white matter (WM) changes and in vitro cell culture experiments were performed. Results: Compared with Nor-BMSCs, treatment of stroke in T1DM rats with DM-BMSCs significantly improved functional outcome. DM-BMSCs increased vascular remodeling identified by cerebral vascular density and cerebral artery density, increased Bielschowsky silver (axon marker) and Luxol fast blue (myelin marker) expression in the ischemic border zone (IBZ) compared to T1DM-MCAo rats (p<0.05). However, DM-BMSC treatment also increased artherosclerosis-like changes identified by an increased internal carotid wall thickness, artery intimae thickness, and decreased cerebral artery diameter (p<0.05) compared to T1DM-MCAo control. DM-BMSCs treatment significantly increased PDGF, but decreased RhoA and ROCK expression in the IBZ. In vitro, DM-BMSCs have higher miR133b (1.9 fold) expression compared to Nor-BMSCs. DM-BMSC conditioned medium increased brain endothelial cell, smooth muscle cell and oligodendrocyte progenitor cell survival, as well as increased subventricular zone explant cell migration and primary cortical neuron axon outgrowth compared to Nor-BMSC conditioned or control medium. Conclusion: Treatment of stroke in T1-DM rats with DM-BMSCs have dual effects on stroke, i.e. significantly increases neurovascular remodeling, improves neurological recovery, and induces artherosclerosis-like vascular changes. The miR133b/RhoA/ROCK pathway may play a role in the DM-BMSC induced neurorestorative effects.
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