There is a great need for therapeutic strategies that aid in the repair or regeneration of ischemic tissue following myocardial infarction, especially therapies that can improve the engraftment of therapeutic cells (i.e. stem cells). Myocardial infarction typically leads to death of cardiomyocytes in the infarct zone that culminates in pathological remodeling of the heart. This can cause severe consequences such as cardiac dilation, wall thinning and deterioration of contractile function leading to congestive heart failure. Therapeutic strategies that aim to harness or enhance (with an exogenous cell source) natural stem cell homing mechanisms show promise to preserve and restore cardiac output following myocardial infarction. Although results in human trials are mixed, certain negative results may be explained by inefficient homing mechanisms. We have recently developed a simple platform strategy that can be used to effectively incorporate potentially any homing receptor onto a cell surface for systemic cell targeting. We have shown that incorporation of homing receptors onto the surface of mesenchymal stem cells (MSCs) can lead to a robust homing response which we have characterized via in vitro cell rolling experiments under physiologically simulated conditions. We have also shown that our approach can be used to significantly enhance the homing of systemically infused MSCs within a murine model of inflammation. Importantly, we have determined modification conditions that maintain MSC viability, cell adhesion, proliferation, and multi-differentiation capacities. The goal of this work is to engineer the surface of MSCs to enhance their trafficking efficiency to site of cardiovascular disease, and improve the homogeneity of the homing response without affecting their native properties, including their ability to transmigrate through vascular endothelium. Our initial efforts will focus on attaching biotinylated ligands to induce a robust cell rolling response. To emigrate to extravascular spaces, circulating cells must rapidly develop strong adhesion to, and arrest on specific sites of vascular endothelium while resisting continuous shear forces at the vessel walls. Since selecting-dependent adhesion of leukocytes does not lead to firm adhesion and transmigration unless another set of adhesion molecules, the integrins, are engaged, we plan to co-immobilize rolling ligands with antibodies that target integrins that are expressed on endothelium at sites of inflammation or within ischemic tissue.

Public Health Relevance

The aim of this proposal is to engineer the surface of mesenchymal stem cells to enhance their trafficking efficiency to sites of cardiovascular disease, and improve the homogeneity of the homing response without affecting their native properties, including their ability to transmigrate through vascular endothelium and capacity for multi-lineage differentiation. The development of this novel approach will have broad implications for wound repair and treatment of many tissues where cell based therapies is appropriate. Potential benefits for treatment of ischemic tissue following myocardial infarction include increased cardiac output leading to increased survival and improved quality of life.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL095722-05
Application #
8669801
Study Section
Intercellular Interactions Study Section (ICI)
Program Officer
Thomas, John
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
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Levy, Oren; Anandakumaran, Priya; Ngai, Jessica et al. (2013) Systematic analysis of in vitro cell rolling using a multi-well plate microfluidic system. J Vis Exp :e50866

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