[Frontiers in Bioscience 13, 2421-2434, January 1, 2008]

Cellular cardiomyoplasty: routes of cell delivery and retention

Adil Al Kindi1, Yin Ge1, Dominique Shum-Tim1, Ray C-J Chiu1

1Divisions of and Experimental Surgery, Faculty of Medicine, McGill University, Montreal, Quebec, Canada

TABLE OF CONTENTS

1. Abstract 2. Introduction 3. Cell delivery 3.1. Intramyocardial injection 3.2. Intracoronary injection 3.3. Retrograde coronary venous injection 3.4. Systemic intravenous injection 4. Cellular Retention and Engraftment 4.1. Cell loss due to “washout” 4.2. Factors affecting cell survival and engraftment 4.3. Comparative studies on cell delivery techniques 5. On enhancing cell retention and survival 6. Summary and conclusions 7. References

1. ABSTRACT 2. INTRODUCTION

Experimental and clinical studies have proven the During the past several years, there have been feasibility of cellular cardiomyoplasty in treating the many experimental and clinical studies on progenitor/stem damaged myocardium following ischemic injury. Over the cell therapies for myocardial damage and failure. In years, this field has exploded with different investigators view of continuous and forceful contraction of the heart, trying different routes of cell delivery ranging from direct effective delivery of the therapeutic cells effectively into cell injection into the heart to peripheral intravenous the target tissue has been quite challenging. Here, we will delivery utilizing the various signaling mechanisms known. review the routes of cell delivery to the heart and explore These different routes have resulted in a wide range of the advantages and limitations of each mode of delivery. retention and engraftment of cells in the target tissues. In This will be followed by evidence of cell retention and this review, we will explore the different modalities of cell engraftment and methods of improvement of the delivery, the pros and cons of each route and the cellular methodologies used. Finally, we will look at factors that retention and therapeutic efficacy of these routes. We will decrease cell retention and how they could be inhibited. then look into the different theories that try to explain the observed retention and engraftment of cells in the target 3. CELL DELIVERY tissues. Finally, we will discuss various methods that can improve cellular retention and engraftment and hence better Physiological mobilization of bone marrow stem improvement in myocardial function. cells (BMSCs) occurs after Acute Myocardial Infarction

2421 Cellular cardiomyoplasty: routes of cell delivery and retention

(AMI) (1-3). This mobilization, although limited, is a proven very beneficial in cases of chronic ischemia, when natural process by which the body attempts to heal the dead the patient is excluded from any revascularization (5, 6), or cardiac cells by replacing them with multipotent BMSCs in diffuse pathology of the myocardium such as in viral that are capable of differentiating into cardiac cells. cardiomyopathy, where diffuse cell delivery into the entire Therefore, attempts to deliver more cells to the heart would ventricular wall is desirable. Transcatheter techniques augment this natural process and, in theory, amplify the require mapping of the ischemic areas in order to achieve healing response. Thus, different methods were developed accurate delivery. Thus, this approach results in prolonged in order to deliver the cells to the heart in a more controlled procedure times that may not be tolerated by sick patients fashion. The optimal route of cell delivery is currently still (5, 6). under investigation. It should be able to deliver the maximum cell quantity with the best precision to the As in the development of other biotherapeutics, targeted site. It should also be easily reproducible, safe to early studies in cardiac cell therapy were conducted in the patient, with minimal unwanted ad