Intraarterial route increases the risk of cerebral lesions after mesenchymal cell administration in animal model of ischemia

Abstract

Mesenchymal stem cells (MSCs) are a promising clinical therapy for ischemic stroke. However, critical parameters, such as the most effective administration route, remain unclear. Intravenous (i.v.) and intraarterial (i.a.) delivery routes have yielded varied outcomes across studies, potentially due to the unknown MSCs distribution. We investigated whether MSCs reached the brain following i.a. or i.v. administration after transient cerebral ischemia in rats, and evaluated the therapeutic effects of both routes. MSCs were labeled with dextran-coated superparamagnetic nanoparticles for magnetic resonance imaging (MRI) cell tracking, transmission electron microscopy and immunohistological analysis. MSCs were found in the brain following i.a. but not i.v. administration. However, the i.a. route increased the risk of cerebral lesions and did not improve functional recovery. The i.v. delivery is safe but MCS do not reach the brain tissue, implying that treatment benefits observed for this route are not attributable to brain MCS engrafting after stroke.

Human intracerebroventricular (ICV) injection of autologous, non-engineered, adipose-derived stromal vascular fraction (ADSVF) for neurodegenerative disorders: results of a 3-year phase 1 study of 113 injections in 31 patients

“…Intra-arterial delivery was also investigated. It provides a better biodistribution of the stem cells through the brain, but increases the risk of cerebral lesions/microstrokes [66].…”

Inclusion criteria update for the rat intraluminal ischaemic model for preclinical studies

“…We have also established an arbitrary inclusion interval (between 25% and 45%) for DWI hemispheric infarct volume that could be a topic for discussion. We established this threshold based on previous studies (Argibay et al, 2017; Campos et al, 2011; Pérez-Mato et al, 2014; Vieites-Prado et al, 2016) in which the same inclusion protocol was used, and in which DWI volumes <25% during MCAo were associated with small subcortical ischaemia or no ischaemia at 24 h, and DWI volumes >45% were associated with a malignant infarct that affected all hemispheres and resulted in a high mortality rate. Finally, this study was performed in Sprague-Dawley rats because this is the most common strain used in studies on cerebral ischaemia; however, we are aware that this protocol should be validated in other strains and species of rat, as well as in a permanent MCAo model.…”

Inclusion Criteria Update of the Intraluminal Ischemic Model in Rat for Preclinical Studies

“…We have also established an arbitrary inclusion interval between 25 and 45% for DWI hemispheric infarct volume that could be discussed. We have established this threshold because, based on previous studies (Argibay et al, 2017;Campos et al, 2011;Pérez-Mato et al, 2014;Vieites-Prado et al, 2016) where same inclusion protocol was used, we observed that DWI volumes under 25% during MCAo were associated with small subcortical ischemia or no ischemia at 24 hours, while DWI volumes above 45% were associated with malignant infarct that affected all hemisphere and caused a high rate of mortality. Therefore, based on this experience, we established this threshold for DWI.…”