Abstract 1109: Fate Of Mesenchymal Stem Cells Following Intravascular Delivery
Background: Several clinical trials are currently exploring intravascular delivery of mesenchymal stem cells (MSC) as a form of therapy following myocardial ischemic injury. Little is known, however, about the fate and kinetics of these cells in the microcirculation, and their capacity for tissue integration.
Methods and Results: Intravital microscopy of rat cremaster muscle was used to visualize intra-arterially delivered MSCs within the microcirculation in real time. A total of 1–2x106 5-chloromethylfluorescein diacetate-labeled rat MSCs (mean diameter in suspension 20 μm) were bolused into the common iliac artery ipsilateral to the exteriorized cremaster. Microvascular red cell velocity was measured with optical Doppler velocimetry. Continuous interrogation of an arteriole-venule pair (diameter <200 μm) following cell injection (inj) (n = 6 rats) revealed that 90 ± 7% of cells arrested in the tissue during the first pass. The entrapment occurred at the precapillary level (mean vessel diameter 11.5 ± 1.2 μm), interrupting flow in these vessels. This led to decreased flow in the feeding arteriole (velocity pre-inj 6.3 ± 1.0 mm/s, post-inj 4.6 ± 1.3 mm/s, p<0.001, n=6). No MSC migration outside the vasculature was seen up to 2 hr after inj. However, when intravital microscopy was performed 24 hours after MSC inj (n=3), fluorescent cells were also identified in the perivascular space, with restoration of flow in the respective microvessel. In separate in vitro studies (n=8), rat MSC and leukocyte deformability (cortical tension) were each derived by measuring mean pressures required to advance the cells through Nuclepore membranes. MSC cortical tension (0.49 ± 0.08 dynes/cm) was comparable to that of leukocytes (0.36 ± 0.05 dynes/cm, p=0.34).
Conclusion: Although they deform comparably to leukocytes, intra-arterially delivered MSCs entrap at the precapillary level during the first pass due to their size, impeding microvascular flow. This effect appears transient, as entrapment diminishes within 24 hrs, and may relate to MSC exit from the microvascular space. These phenomena have important implications for intravascular delivery of MSCs, and should inform approaches to cell culture which affect cell dimensions.