Intra-Arterial Transplantation of Low-Dose Stem Cells Provides Functional Recovery Without Adverse Effects After Stroke

Abstract

Cell transplantation therapy for cerebral infarction has emerged as a promising treatment to reduce brain damage and enhance functional recovery. We previously reported that intra-arterial delivery of bone marrow mesenchymal stem cells (MSCs) enables superselective cell administration to the infarct area and results in significant functional recovery after ischemic stroke in a rat model. However, to reduce the risk of embolism caused by the transplanted cells, an optimal cell number should be determined. At 24 h after middle cerebral artery occlusion and reperfusion, we administered human MSCs (low dose: 1 × 10(4) cells; high dose: 1 × 10(6) cells) and then assessed functional recovery, inflammatory responses, cell distribution, and mortality. Rats treated with high- or low-dose MSCs showed behavioral recovery. At day 8 post-stroke, microglial activation was suppressed significantly, and interleukin (IL)-1β and IL-12p70 were reduced in both groups. Although high-dose MSCs were more widely distributed in the cortex and striatum of rats, the degree of intravascular cell aggregation and mortality was significantly higher in the high-dose group. In conclusion, selective intra-arterial transplantation of low-dose MSCs has anti-inflammatory effects and reduces the adverse effects of embolic complication, resulting in sufficient functional recovery of the affected brain.

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

“…Several studies have reported that the i.a. administration of stem cells is not a trivial issue, with high risk of secondary embolisms and high mortality23253771727374757677 as we have confirmed in our study. However, despite the risk of secondary embolisms, herein we have also observed that relatively small variation in carotid arteries occlusion, during tMCAo and i.a.…”

“…and i.v. administration in animal models of ischemic stroke with different degrees of success in terms of outcome373839 and brain engraftment23404142, but only a few have established a relationship between them434445. In this study, we administered MSCs labeled with D-MNPs to address the relationship between cell allocation and animal recovery after stroke.…”

Comparison of MSC-Neurogenin1 administration modality in MCAO rat model

“…However, the major issue of IA administration is microembolization due to aggregation of the cells in the blood vessels [31]. The major determinants of the safety of IA stem cell administration are cell size, velocity of injection, and cell dose [22, 32]. Janowski et al .…”

Optical fluorescence imaging with shortwave infrared light emitter nanomaterials for in vivo cell tracking in regenerative medicine

“…Surprisingly, low‐dose cell delivery for treatment of ischaemic stroke through intra‐arterial pathway leads to the improvement of inflammation and decreases rate of embolus formation in vessels …”

“…29 Surprisingly, low-dose cell delivery for treatment of ischaemic stroke through intra-arterial pathway leads to the improvement of inflammation and decreases rate of embolus formation in vessels. 30 Another undesirable side effect of intra-arterial cell administration is the fragmentation of infused cells due to the shear forces of arterial blood flow. These damaged cells may be rapidly removed from the circulation through the liver and spleen, causing shorter blood half-life of infused cells.…”