The multiple migratory mechanisms of systemically infused mesenchymal stem cells to sites of inflammation

Systemically infused mesenchymal stem cells (MSC) are being explored for their immunomodulatory therapeutic potential in multiple inflammatory pathologies. This therapeutic potential has been associated with the ability of MSC to accumulate at sites of inflammation following infusion. However, there is a poor understanding of the mechanisms that mediate MSC trafficking to inflamed tissue. Here, we first introduce key concepts in MSC biology and cellular trafficking, and highlight the relevance of MSC trafficking. We also introduce key concepts in cellular trafficking, particularly the leukocyte homing cascade, as a framework to approach MSC trafficking. Then, we review the field of MSC trafficking in the second chapter, particularly the methods employed to study MSC trafficking and associated challenges. In the third chapter, we study MSC ability to perform transendothelial migration, a specific step in the process of MSC trafficking, using high resolution confocal and dynamic imaging techniques. We found that MSC transmigration is associated with both leukocyte-like and novel mechanisms, including nonapoptotic migratory blebbing. In the fourth chapter, we address the importance of non-endothelial factors in MSC trafficking to inflamed tissues, including mechanical trapping in small vessels, secondary interactions with endogenous immune cells and vascular permeability. Finally, we conclude by proposing an integrated model of mesenchymal trafficking versus hematopoietic trafficking, and highlight the potential role of the intravascular compartment as a major site of MSC immunomodulation. We believe that this body of work has a broad impact on our understanding of MSC biology and therapeutic potential, our comprehension of mesenchymal cell trafficking (including metastasis) and the design of cell delivery strategies for clinical translation.

Department dc:contributor.department

Harvard--MIT Program in Health Sciences and Technology.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2014

Author dc:creator

• Teo, Grace Sock Leng

Advisor dc:contributor.advisor

• Jeffrey M. Karp, Christopher V. Carman, and Charles P. Lin.

• Harvard--MIT Program in Health Sciences and Technology.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/90176

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/90176