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.
Highlights
Functional recovery in animal models of focal cerebral ischemia has been observed when MSCs were injected intravenously (i.v.) or intraarterially (i.a.)[17,18,19,20], there is not agreement yet about the optimal administration route
dextran-coated superparamagnetic nanoparticles (D-MNPs) were synthesized in the presence of dextran following the chemical co-precipitation method described in the Methods section
The core crystal structure determined by X-ray diffraction (XRD) (Fig. 1B) showed peaks at 2θpositions of ca. 30.2°, 35.6°, 43.2°, 57.1°, and 62.7°, corresponding to the (220), (311), (400), (511), and (440) planes of magnetite, respectively, with a lattice parameter of 8.33 ± 0.02 Å and a crystallite size of 4.8 ± 0.5 nm derived from the Scherrer equation
Summary
Functional recovery in animal models of focal cerebral ischemia has been observed when MSCs were injected intravenously (i.v.) or intraarterially (i.a.)[17,18,19,20], there is not agreement yet about the optimal administration route. Intravenous injections are minimally invasive, and cell tracking studies following that route have shown that most administered cells remain trapped in the lungs, liver, and spleen[21], indicating that a reduced number of cells reach the brain[22]. An in vivo analysis of the cellular fate and biodistribution of both administration routes is an important and necessary step towards the further development of minimally invasive stem cell therapy for central nervous system diseases, including stroke. To this end, the objective of this study was to perform an analysis of cell tagging by magnetic resonance imaging (MRI) contrast agents (CAs) and subsequent MRI analysis to address this challenge[26]. The therapeutic effects of MSCs administered through either route were compared in an animal model of ischemic stroke
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