To explore the initial steps by which transplanted mesenchymal stem cells (MSCs) interact with the vessel wall in the course of extravasation, we studied binding of human MSCs to endothelial cells (ECs). In a parallel plate flow chamber, MSCs bound to human umbilical vein ECs (HUVECs) similar to peripheral-blood mononuclear cells (PBMCs) or CD34 ؉ hematopoietic progenitors at shear stresses of up to 2 dynes/cm 2 . This involved rapid extension of podia, rolling, and subsequent firm adhesion that was increased when ECs were prestimulated with TNF-␣. MSC binding was suppressed when ECs were pretreated with function-blocking anti-P-selectin antibody, and rolling of MSCs was induced on immobilized P-selectin, indicating that P-selectin was involved in this process. IntroductionIn recent years, mesenchymal stem cells (MSCs) have been characterized as adherent-cell populations originating from bone marrow, capable of expanding in vitro as undifferentiated cells or differentiating into osteocytes, chondrocytes, tenocytes, adipocytes, or smooth muscle cells. [1][2][3] MSCs have been used in a number of preclinical models to mediate the regeneration of muscle, endothelial, neuronal, skin, or renal epithelial tissue. [4][5][6][7] In vitro differentiation studies have demonstrated the potential of MSCs to also form alveolar and airway epithelial cells or cardiac pacemaker cells. 8,9 Moreover, MSCs have been transplanted intravenously and shown to distribute to spleen, bone, lung, and cartilage in several rodent models. [10][11][12] Intravenously injected MSCs have already been used in patients to accelerate hematopoietic reconstitution after hematopoietic stem cell transplantation, to overcome the molecular defect in children with osteogenesis imperfecta, or to alleviate the outcome after myocardial infarction. [13][14][15][16][17] Transplantation experiments in mice and primates have shown that intravenously applied MSCs distribute to several tissues and may accumulate in the lungs. 10,12,18,19 However, currently it is poorly understood to what degree MSCs use specific adhesion mechanisms for egress from the bloodstream and whether they home in a tissue-specific manner. To leave the bloodstream, mature leukocytes and hematopoietic progenitor cells (HPCs) have been shown to undergo a coordinated sequence of adhesion steps, initiated by tethering events, which are mainly mediated by selectins and their ligands. 20,21 Subsequently, the captured cells roll and encounter chemokines, which eventually activate integrins, resulting in firm arrest and subsequent transendothelial migration.To elucidate the potential of MSCs to undergo coordinated steps of interaction with endothelial cells (ECs), we investigated human MSCs under shear flow using a parallel plate flow chamber and by intravital microscopy in mice. We show here that human MSCs home to different tissues and display coordinated rolling and adhesion behavior on ECs. Although P-selectin glycoprotein ligand 1 (PSGL-1) is not expressed by MSCs, MSCs bind to ECs in a P-sele...

Mesenchymal stem/stromal cells (MSCs) are increasingly used as an intravenously applied cellular therapeutic. They were found to be potent in situations such as tissue repair or severe inflammation. Still, data are lacking with regard to the biodistribution of MSCs, their cellular or molecular target structures, and the mechanisms by which MSCs reach these targets. This review discusses current hypotheses for how MSCs can reach tissue sites. Both preclinical and clinical studies using MSCs applied intravenously or intra-arterially are discussed in the context of our current understanding of how MSCs might work in physiological and pathological situations.