Abstract 13444: Mechanism of Extravasation of Infused Regenerative Cells from Microvessels into Tissue Parenchyma
Background: In order for bloodborne stem cells to be effective in tissue regeneration, cells must cross vessel walls and enter the parenchyma. Although such transmigration does occur, the mechanism remains elusive. Leukocytes invade tissue by diapedesis; stem cells are commonly assumed to do likewise, but evidence is lacking.
Methods and Results: Cardiac-derived regenerative cells (CDC), multi-cellular cardiospheres (CSP), and inert polymer spheres (PSP; as control) were infused into rat coronary vessels. Membrane projections from adjacent endothelium (white arrowheads) surround a CDC (A; green) or CSP (B; green) to form “endothelial pockets” 24 hr after infusion. The adjacent vascular wall then undergoes breakdown to create a path for CDC and CSP extravasation (white arrows; A & B). Restoration of vessel patency is evident from circulating blood cell nuclei in the newly-recanalized lumen (B; yellow arrows). Endothelial pockets are started via endothelial cell projections (C; white arrowhead).The extravasation of CSP and CDC was evident 72 hr after infusion, while PSP remained in the blood vessels (D). The same process was confirmed in a mouse dorsal skin flap model with sequential live imaging (E). New vascular walls were formed (white arrows) and the opposing wall of the pocket was broken down (white arrow head) to allow the CDC to be expelled. Intact CSP (F; yellow arrow) were found in the extravascular space 72 hr after infusion. We further demonstrated that integrins are responsible for initial adhesion and endothelial pocket formation, while matrix metalloproteinases play critical roles in pocket breakdown and extravasation.
Conclusion: We report a novel mechanism of cell transmigration, “active vascular expulsion” (AVE). Unlike diapedesis, in AVE the vascular barrier undergoes extensive remodeling, while the cells themselves are relatively passive (G). In vitro models revealed that AVE is generalizable to other stem cell types and to cancer cells.
- © 2012 by American Heart Association, Inc.