Contribution of Circulating Cells to Cardiac Repair

Abstract

Coronary artery occlusion is accompanied by extensive cardiomyocyte death which subsequently leads to intensive inflammatory response Accumulating studies have reported that early inflammation is critical for recruitment of immune cells to the injured myocardium and it has been implicated in tissue regeneration In addition to immune cells numerous studies have suggested that bone marrow served as a reservoir of stem cell populations for cardiomyocyte repopulation However this remains a controversial issue It is observed that the bone marrow-borne cells can only adopt to the cells of hematopoietic lineage in the injured heart The controversy may arise from a problematic methodology In previous study we discovered that cardiomyocyte replenishment was initiated in 7 days post- myocardial injury Administration of immune modulator prostaglandin E2 (PGE2) not only promoted endogenous stem cell-mediated cardiomyocyte replenishment but also changed inflammatory microenvironment at day 3 post-infarction by altering percentage of the M2 macrophages The finding implies that the time point is an important parameter to examine contribution of circulating cells to heart repair Furthermore a PGE2-related downstream signal particularly acting through the EP2 receptor is involved in cardiac repair by modulating macrophage activities Therefore the main theme of current study is to examine the role of two distinct circulating cell populations the bone marrow-borne stem cells and immune cells in heart repair To evaluate the contribution of bone marrow-borne cells in myocardial regeneration we combined two approaches pulse-trace labeling and a parabiosis model to examine the fate of circulating cells in the injured myocardium under normal physiological conditions In the parabiosis model we observed scattered circulating cells derived from the parabiotic partner expressed cardiac-specific markers throughout the myocardium Genetic tracing revealed that circulating hematopoietic cells acquired cardiac cell fate by means of cell fusion and trans-differentiation In contrast to the previous report that bone marrow-borne circulating cells only adopt hematopoietic cell fate in the injured myocardium we showed that circulating hematopoietic cells participate in cardiomyocyte regeneration in a mouse model of parabiosis To examine how PGE2-related immune response contributes to cardiac repair EP2-deficient transgenic mice were used In the EP2 knocked out mice we detected a reduction in number of macrophages at day 3 post-infarction suggesting the EP2 receptor involved in acute inflammatory response Lineage tracing revealed that EP2 deficiency effectively blocked endogenous stem cell-dependent cardiomyocyte replenishment Furthermore cardiac function of EP2 knocked out mice was also impaired In conclusion our findings reveal the contribution of two different bone marrow-borne cell populations the stem cells and immune cells in cardiac repair Detailed mechanistic studies are required to uncover how functions of these cells populations could be modulated to boost their power to repair injured tissue

Date of Award	2015 Feb 3
Original language	English
Supervisor	Li-Wha Wu (Supervisor)