Cell Size and Velocity of Injection are Major Determinants of the Safety of Intracarotid Stem Cell Transplantation

Abstract

Intracarotid transplantation has shown potential for efficient stem cell delivery to the brain. However, reported complications, such as compromised cerebral blood flow (CBF), prompted us to perform further safety studies. Glial-restricted precursors (GRPs) and mesenchymal stem cells (MSCs) were transplanted into the internal carotid artery of rats (n ¼ 99), using a microcatheter. Magnetic resonance imaging was used to detect post-transplantation complications, including the development of stroke, for the following experimental variables: cell size, cell dose, cell infusion velocity, delay between artery occlusion and cell infusion, discordant versus concordant xenografting, and intracarotid transplantation with preserved versus compromised blood flow. Immunocompatibility and delayed infusion did not affect the number of complications. An infusion velocity over X1 mL/minute often resulted in stroke (27 out of 44 animals), even with an infusion of vehicle, whereas a lower velocity (0.2 mL/minute) was safe for the infusion of both vehicle and smaller cells (GRPs, diameter ¼ 15 mm). Infusion of larger cells (MSCs, diameter ¼ 25 mm) resulted in a profound decrease (75±17%) in CBF. Stroke lesions occurred frequently (12 out of 15 animals) when injecting 2 Â 10 6 MSCs, but not after lowering the dose to 1 Â 10 6 cells. The present results show that cell size and infusion velocity are critical factors in developing safe protocols for intracarotid stem cell transplantation. Journal of Cerebral Blood INTRODUCTIONThe intravascular route of stem cell delivery has met with increasing interest because of the minimally invasive nature of the procedure and the potential for broad cell distribution. Recent reports 1,2 have revealed positive effects of intravascular cell transplantation in animal models of neurologic disorders. The evaluation of neural cell distribution after intravenous cell transplantation has shown that most of the cells are initially entrapped within the lungs and do not travel to the brain.3 It has been hypothesized that an intraarterial approach would be a more efficient route of cell delivery to the brain, as this approach avoids the pulmonary circulation. This approach is particularly attractive when selecting and sorting cells for adhesion molecules, which can enhance cell homing and therapeutic outcome. 4 Moreover, it has been recently shown that transfection of adhesion molecules in progenitor cells results in a dramatic increase of their homing to inflamed brain endothelium.

Three-Dimensional Spheroid-Cultured Mesenchymal Stem Cells Devoid of Embolism Attenuate Brain Stroke Injury After Intra-Arterial Injection

“…In consistence with previous findings [18], we found that 3D spheroid culture significantly reduced the size of MSCs *40% (from average diameter 25 mm to average dimmer 15 mm). Cell size has been suggested as a critical parameter of vascular obstructions in a recent study [38]. Our results indicate that 3D-spheroid-cultured MSCs are safer and more effective than conventionally monolayer-cultured MSCs for intra-artery administration.…”

Intracoronary Injection of Large Stem Cells

“…One recent study that was performed in rats used intracarotid MSC injection for brain cell therapy and reported that cell size, injection speed, and the cell dose are the important factors that determine the occurrence of brain infarction. 17 In this study, 2×10 6 MSC with a diameter of 25 µm resulted in microinfarctions, whereas smaller cells (glialrestricted precursors) with same total cell volume did not cause infarctions. The importance of cell injection speed has also been shown in the pig model of recent myocardial infarction, and a slow rate of injection seems to be better in preventing microinfarctions.…”

Stem cell therapy in intracerebral hemorrhage rat model

“…Intracerebral and intracerebroventricular routes are very invasive alternatives, hardly representing the best clinical options. In this sense, intravascular injections are incomparably more feasible and less troublesome, and allows injections with higher cell doses [142] . However, due to their size, stem cells were reported to get trapped in the lungs, liver and spleen and to cause embolisms, following tail vein and intracarotid injections, respectively [143][144][145] .…”