Intravenous Administration of Human Adipose Derived-Mesenchymal Stem Cells Is Not Efficient in Diabetic or Hypertensive Mice Subjected to Focal Cerebral Ischemia.

Gabrielle Mangin,Philippe Bonnin,Nathalie Kubis,Anaïck Moisan,Adrien Cogo,Benjamin Maïer,On Behalf Of The Resstore Consortium

doi:10.3389/fnins.2019.00718

Abstract

As the second cause of death and cognitive decline in industrialized countries, stroke is a major burden for society. Vascular risks factors such as hypertension and diabetes are involved in most stroke patients, aggravate stroke severity, but are still poorly taken into account in preclinical studies. Microangiopathy and sustained inflammation are exacerbated, likely explaining the severity of stroke in those patients. We sought to demonstrate that intravenous administration of human adipose derived-mesenchymal stem cells (hADMSC) that have immunomodulatory properties, could accelerate sensorimotor recovery, prevent long-term spatial memory impairment and promote neurogenesis, in diabetic or hypertensive mice, subjected to permanent middle cerebral artery occlusion (pMCAo). Diabetic (streptozotocin IP) or hypertensive (L-NAME in drinking water) male C57Bl6 mice subjected to pMCAo, were treated by hADMSC (500,000 cells IV) 2 days after cerebral ischemia induction. Infarct volume, neurogenesis, microglial/macrophage density, T-lymphocytes density, astrocytes density, and vessel density were monitored 7 days after cells injection and at 6 weeks. Neurological sensorimotor deficit and spatial memory were assessed until 6 weeks post-stroke. Whatever the vascular risk factor, hADMSC showed no effect on functional sensorimotor recovery or cognitive decline prevention at short or long-term assessment, nor significantly modified neurogenesis, microglial/macrophage, T-lymphocytes, astrocytes, and vessel density. This work is part of a European program (H2020, RESSTORE). We discuss the discrepancy of our results with those obtained in rats and the optimal cell injection time frame, source and type of cells according to the species stroke model. A comprehensive understanding of the mechanisms preventing recovery should help for successful clinical translation, but first could allow identifying good and bad responders to cell therapy in stroke.

Highlights

Stroke is currently the second cause of death and cognitive decline worldwide (Snyder et al, 2015; World Health Organization [WHO], 2018)
Mesenchymal stem cells (MSCs) are attractive. They are multipotent cells capable of differentiating into at least one differentiated cell type depending on environmental conditions (Chamberlain et al, 2007). These cells improve neurological deficit after stroke in both mice (Chen et al, 2003) and rats (Li et al, 1999; Cho et al, 2012) but their mechanism of action is still poorly understood, neurogenesis, angiogenesis and immunomodulation, all contributing to new neuronal networks formation, have been associated to improved neurological recovery (Chen et al, 2014)
Stroke volume measured after Cresyl violet staining was assessed at day 9 (7 days after human adipose derivedmesenchymal stem cells (hADMSC) delivery) and neuroblasts density, microglia/macrophages cells density, T-Lymphocytes density, astrocytes density, and vessels density assessment were performed 1-week post-hADMSC delivery (9 days post-stroke, D9) or 40 days post-stroke (D40), i.e., at the end of the cognitive assessment period, to evaluate the histological consequences of hADMSC injection

Summary

Introduction

Stroke is currently the second cause of death and cognitive decline worldwide (Snyder et al, 2015; World Health Organization [WHO], 2018). They are multipotent cells capable of differentiating into at least one differentiated cell type depending on environmental conditions (Chamberlain et al, 2007). These cells improve neurological deficit after stroke in both mice (Chen et al, 2003) and rats (Li et al, 1999; Cho et al, 2012) but their mechanism of action is still poorly understood, neurogenesis, angiogenesis and immunomodulation, all contributing to new neuronal networks formation, have been associated to improved neurological recovery (Chen et al, 2014)

Objectives

Methods

Results

Discussion

Conclusion