Abstract
Intra-arterial (IA) delivery of mesenchymal stem cells (MSCs) for acute ischemic stroke is attractive for clinical translation. However, studies using rat model of stroke have demonstrated that IA MSCs delivery can decrease middle cerebral artery (MCA) flow, which may limit its clinical translation. The goal of this study is to identify a dose of IA MSCs (maximum tolerated dose; MTD) that does not compromise MCA flow and evaluate its efficacy and optimal timing in a rat model of reversible middle cerebral artery occlusion (rMCAo). We sought to determine if there is a difference in efficacy of acute (1 h) versus sub-acute (24 h) IA MSCs treatment after rMCAo. Adult female Sprague-Dawley rats underwent rMCAo (90 min) and an hour later a single dose of MSCs (at de-escalating doses 1×106, 5×105, 2×105, 1×105 and 5×104) was given using IA route. MSCs were suspended in phosphate buffered saline (PBS) and PBS alone was used for control experiments. We measured the percent change in mean laser Doppler flow signal over the ipsilateral MCA in de-escalating doses groups to determine MTD. The results demonstrated that the lowering of IA MSC dose to 1×105 and below did not compromise MCA flow and hence an IA MSC dose of 1×105 considered as MTD. Subsequently, 1 h and 24 h after rMCAo, rats were treated with IA MSCs or PBS. The 24 h delivery of IA MSCs significantly improved neurodeficit score and reduced the mean infarct volume at one month as compared to control, but not the 1 h delivery. Overall, this study suggests that the IA delivery of MSCs can be performed safely and efficaciously at the MTD of 1×105 delivered at 24 hours in rodent model of stroke.
Highlights
Stroke is the main cause of long-term disability and the third leading cause of death in the United States
At the lowered dose level of 16105 mesenchymal stem cells (MSCs), the middle cerebral artery (MCA) flow compromise was significantly less as compared to 56105 dose group (LDFS decreased by 0.2% vs 45%, p = 0.01)
When we analyzed the maximum reduction in laser Doppler flow signal (LDFS) among the dose groups, the rats receiving 16106and 56105 MSCs had a maximum reduction of LDFS over 50%, whereas those receiving a dose at 16105 MSCs had a maximum reduction in LDFS of 23%, similar to 20% in placebo group (Figure 1C)
Summary
Stroke is the main cause of long-term disability and the third leading cause of death in the United States. Despite the approval of intravenous recombinant tissue plasminogen activator (rtPA) 18 years ago, and rapid growth in number of endovascular recanalization therapies for acute ischemic stroke (AIS), their impact on reducing strokerelated long-term disability is limited [2,3]. There continues to be a critical need for novel therapies for AIS. In this regard, over the last decade, various types of stem cell have been tested in several pre-clinical studies suggesting improved functional neurological outcomes after AIS [4,5,6,7]. The leading type of stem cell for clinical translation in stroke is the mesenchymal stem cell, which is an adult, non-hematopoietic progenitor cell with capacity to differentiate into a variety of cell lineages including osteoblasts, chondrocytes and neuron-like cells [8,9,10,11]
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