Neurorestorative Responses to Delayed Human Mesenchymal Stromal Cells Treatment of Stroke in Type 2 Diabetic Rats

Abstract

Background and Purpose Co-morbidity of diabetes mellitus and stroke results in worse functional outcome, poor long term recovery and extensive vascular damage. We investigated the neurorestorative effects and mechanisms of stroke treatment with human bone marrow derived mesenchymal stromal cells (hMSCs) in type two diabetes mellitus (T2DM) rats. Methods Adult male Wistar rats were induced with T2DM, subjected to 2 hours of middle cerebral artery occlusion (MCAo) and treated via tail-vein injection with: 1) PBS (n=8); 2) hMSCs (n=10, 5×106) at 3 days after MCAo. Results In T2DM rats, hMSCs administered at 3 days after MCAo significantly improves neurological function without affecting blood glucose, infarct volume and incidence of brain hemorrhage in comparison to T2DM-MCAo PBS treated rats. Delayed hMSC treatment of T2DM stroke significantly improves blood brain barrier integrity, increases vascular and arterial density and cerebral vascular perfusion, and promotes neuroblast cell migration and white matter remodeling as indicated by increased doublecortin, axon, myelin and neurofilament density, respectively. Delayed hMSC treatment significantly increases platelet-derived growth factor (PDGF) expression in the ischemic brain, decreases pro-inflammatory M1 macrophage and increases anti-inflammatory M2 macrophage compared to PBS treated T2DM-MCAo rats. In vitro data show that hMSCs increase sub-ventricular zone explant cell migration and primary cortical neuron neurite outgrowth while inhibition of PDGF decreases hMSCs induced SVZ cell migration and axonal outgrowth. Conclusion In T2DM stroke rats, delayed hMSC treatment significantly improves neurological functional outcome, and increases neurorestorative effects and M2 macrophage polarization. Increasing brain PDGF expression may contribute to hMSC induced neurorestoration.

Cell-Based and Exosome Therapy in Diabetic Stroke

“…However, at delayed time points such as 48 hours after stroke, VEGF administration was found to enhance angiogenesis in the ischemic penumbra and contribute to neurological recovery in non‐DM rats 38. Compared to non‐DM rats, in the ischemic brain of type 2 DM rats VEGF follows a trend of increase by day 1 and decrease by day 3 after stroke 23. In concert, these studies indicate that treatment initiation time point is critical and requires optimization when treating DM stroke.…”

“…In concert, these studies indicate that treatment initiation time point is critical and requires optimization when treating DM stroke. MSC treatment in DM stroke rats was found to increase cerebral artery wall thickness while decreasing artery internal diameter indicating that MSC treatment may increase atherosclerosis-like vascular changes [15,23].…”

“…In non‐DM rodents, intravenous, intra‐arterial, intra‐carotid or intra‐striatal administration of BMSCs at 1 or 7 days after stroke improves functional outcome, enhances synaptogenesis, stimulates nerve regeneration, mediates immunomodulatory effects, and reduces inflammation 34, 35, 36, 37. Human BMSCs administered intravenously at 3 days after stroke in type 2 DM rats, significantly improves neurological function, increases neurovascular remodeling and decreases inflammatory responses without increasing BBB leakage or cerebral hemorrhage 23. However, intravenous administration of BMSCs at 1 day after stroke in type 1 DM rats does not improve neurological function, and instead increases brain hemorrhage and BBB leakage 15, 21.…”

“…Since DM stroke induces extensive neural and vascular damage, it is critical for therapeutic interventions to promote remodeling of the neurovascular unit, which fundamentally describes the structural and functional interactions between neurons, capillaries and glia in the brain. Pre-clinical studies in animal models of stroke and DM stroke have shown that cell therapies have long treatment time windows ranging from several hours to days after stroke onset and improve neurological functional outcome by amplifying endogenous brain repair mechanisms such as neurovascular remodeling, white matter remodeling, and attenuating local and systemic inflammatory and immune responses [17][18][19][20][21][22][23].…”

Blood–Brain Barrier Disruption, Vascular Impairment, and Ischemia/Reperfusion Damage in Diabetic Stroke

“…Additional complications such as hypertension can exacerbate cerebral edema after stroke in patients with DM 23. Understanding the mechanism and consequences of BBB disruption after stroke and in particular diabetic stroke are essential to developing therapeutics 24, 25…”