Journal article
Mesenchymal stem cells transmigrate between and directly through tumor necrosis factor-α-activated endothelial cells via both leukocyte-like and novel mechanisms
Stem cells (Dayton, Ohio), Vol.30(11), pp.2472-2486
11/2012
DOI: 10.1002/stem.1198
PMCID: PMC3479371
PMID: 22887987
Abstract
Systemically administered adult mesenchymal stem cells (MSCs), which are being explored in clinical trials to treat inflammatory disease, exhibit the critical ability to extravasate at sites of inflammation. We aimed to characterize the basic cellular processes mediating this extravasation and compare them to those involved in leukocyte transmigration. Using high-resolution confocal and dynamic microscopy, we show that, like leukocytes, human bone marrow-derived MSC preferentially adhere to and migrate across tumor necrosis factor-α-activated endothelium in a vascular cell adhesion molecule-1 (VCAM-1) and G-protein-coupled receptor signaling-dependent manner. As several studies have suggested, we observed that a fraction of MSC was integrated into endothelium. In addition, we observed two modes of transmigration not previously observed for MSC: Paracellular (between endothelial cells) and transcellular (directly through individual endothelial cells) diapedesis through discrete gaps and pores in the endothelial monolayer, in association with VCAM-1-enriched "transmigratory cups". Contrasting leukocytes, MSC transmigration was not preceded by significant lateral migration and occurred on the time scale of hours rather than minutes. Interestingly, rather than lamellipodia and invadosomes, MSC exhibited nonapoptotic membrane blebbing activity that was similar to activities previously described for metastatic tumor and embryonic germ cells. Our studies suggest that low avidity binding between endothelium and MSC may grant a permissive environment for MSC blebbing. MSC blebbing was associated with early stages of transmigration, in which blebs could exert forces on underlying endothelial cells indicating potential functioning in breaching the endothelium. Collectively, our data suggest that MSC transmigrate actively into inflamed tissues via both leukocyte-like and novel mechanisms.
Details
- Title: Subtitle
- Mesenchymal stem cells transmigrate between and directly through tumor necrosis factor-α-activated endothelial cells via both leukocyte-like and novel mechanisms
- Creators
- Grace S L Teo - Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts, USAJames A AnkrumRoberta MartinelliSarah E BoettoKayla SimmsTracey E SciutoAnn M DvorakJeffrey M KarpChristopher V Carman
- Resource Type
- Journal article
- Publication Details
- Stem cells (Dayton, Ohio), Vol.30(11), pp.2472-2486
- Publisher
- United States
- DOI
- 10.1002/stem.1198
- PMID
- 22887987
- PMCID
- PMC3479371
- ISSN
- 1066-5099
- eISSN
- 1549-4918
- Grant note
- P40RR017447 / NCRR NIH HHS HL095722 / NHLBI NIH HHS R01 HL104006 / NHLBI NIH HHS DE019191 / NIDCR NIH HHS HL097172 / NHLBI NIH HHS R03 DE019191 / NIDCR NIH HHS P40 RR017447 / NCRR NIH HHS R01 HL095722 / NHLBI NIH HHS HL104006 / NHLBI NIH HHS R21 HL097172 / NHLBI NIH HHS
- Language
- English
- Date published
- 11/2012
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering
- Record Identifier
- 9984000933002771
Metrics
19 Record Views