Brief Report: Mechanism of Extravasation of Infused Stem Cells

Abstract

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. Cardiac-derived regenerative cells and multi-cellular cardiospheres were infused into the coronary vessels of rat hearts. Serial histology revealed a novel mechanism of cell transmigration, “active vascular expulsion”, which underlies the extravasation of infused cells and cell aggregates. In this mechanism, the vascular barrier undergoes extensive remodeling, while the cells themselves are relatively passive. The mechanism was confirmed in vivo by serial intravital microscopy of cardiosphere extravasation in a dorsal skin flap model. Integrins and matrix metalloproteinases play critical roles in active vascular expulsion. In vitro models reveal that active vascular expulsion is generalizable to other stem cell types and to breast cancer cells. Recognition of active vascular expulsion as a mechanism for transvascular cell migration opens new opportunities to enhance the efficacy of vascularly-delivered cell therapy.

The effect of encapsulation of cardiac stem cells within matrix-enriched hydrogel capsules on cell survival, post-ischemic cell retention and cardiac function

“…This notion is supported by several recent papers demonstrating early CSC engraftment predicts later cardiac recovery from myocardial infarction while methods targeted towards boosting the early retention of transplanted cells enhance cells-mediated cardiac repair [6][7][8][9]. These measures address the challenge to acutely retain injected cells within a vascular organ by reducing mechanical extrusion from the myocardium and clearance through lymphatic or venous drainage [10,11]. But once cells are acutely retained in damaged myocardium, ongoing cell death ensues as the suspended cells have lost vital integrin-dependent attachments to the extracellular matrix (ECM) (12) which reduces stimulation of pro-survival pathways and results in detachment-induced programmed cell death (or anoikis) [13,14].…”

Targeted repair of heart injury by stem cells fused with platelet nanovesicles

“…We previously described the sequence of non-PNV modified CSC adhesion and extravasation after vascular delivery in MI hearts. Our data indicate that by 24 hrs post-injection CSCs are found adhering to the blood vessels and surrounded by endothelial projections 21 . By 72 hrs, the infused cells have extravasated into the extravascular space via a process we recently termed angiopellosis 22 .…”

Letter by Gallet and Marbán Regarding Article, “Intracoronary Injection of Large Stem Cells: Size Matters”

“…Cardiospheres undergo active extravasation; 5 after infusion, they first lodge within the microvasculature, causing vessel occlusion. Afterwards, CSp transmigrate via the creation of endothelial pockets and breakdown of the adjacent vessel wall.…”