In Vivo Tracking of Stem Cells for Clinical Trials in Cardiovascular Disease

Abstract

Abstract-Various stem cells hold promise for the treatment of human cardiovascular disease. Regardless of stem cell origin, future clinical trials will require that the location and number of such cells be tracked in vivo, over long periods of time. The problem of tracking small numbers of cells in the body is a difficult one, and an optimal solution does not yet exist. We review the many contrast agents and detectors that have been proposed for stem cell tracking during clinical trials, define the characteristics of an ideal imaging technology, and suggest future directions for research. For example, stem cell therapy for heart failure addresses an important problem in clinical medicine. Heart failure is a major cause of morbidity and mortality in the United States. The rates of new and recurrent heart failure events increase substantially with age. In patients aged 65 and older, congestive heart failure is the single most frequent cause of hospitalization in the United States. Despite substantial advances in the clinical management of heart failure, the diagnosis continues to carry a grave prognosis with an overall 5-year mortality rate of Ϸ50%. This rate is substantially worse in more severely affected patient subsets. An understanding of the role of stem cells in repopulating damaged areas in the heart would help target these diseased areas. 1 The problem of imaging small numbers of cells in the living subject is not limited to stem cell-based treatments in cardiology but has broad applicability in oncology, immunology, and transplantation. Ideal Imaging Technology for Stem Cell TrackingSuccessful in vivo imaging requires that a contrast agent associated with a stem cell exert an "effect size" sufficient for detection by imaging hardware. Although the most attractive contrast agents for tracking are endogenous ones (ie, normal components of the stem cell), their effect size is extremely small. This review will focus on exogenous contrast agents, which have a large and controllable effect size. It also will focus on imaging technology that has clinical relevance because many preclinical small animal studies in the field of stem cell tracking are not translatable to clinical practice. The 8 characteristics of an ideal imaging technology for stem cell tracking are presented in Table 1. First, and foremost, the exogenous contrast agent must be biocompatible, safe, and nontoxic. This is especially important when nanotechnology solutions to the tracking problem (mentioned below) are considered, because most solid-state devices will be composed of materials that do not have proven long-term safety in vivo.Another consideration is the need for genetic modification of the stem cell or perturbation of its genetic program by the contrast agent itself. Several imaging techniques, such as enzymatic conversion of an injected substrate and receptorbased binding, require stable integration of transgenes. This strategy may be combined with genetic manipulation of stem cell populations to enhance the viability, differentiatio...

Stem cell-derived cardiomyocytes after bone marrow and heart transplantation

“…11,12 The number of human studies on transfer of stem cells and subsequent tracing of these cells is still limited, 4,13,14 as tracking of stem cells in vivo is still difficult in humans. 15,16 Recent studies in patients after HTX or BMT have shown an influx, repopulation and differentiation of BMderived cells in the heart, originating from the cardiac recipient or the BMT donor, respectively. However, the reported number of invading stem cells that, evidently, differentiate into cardiomyocytes varied considerably between the various experimental and human studies.…”

“…However, the reported number of invading stem cells that, evidently, differentiate into cardiomyocytes varied considerably between the various experimental and human studies. 9,10,[14][15][16][17][18][19][20] This heterogeneity is most likely the result of an overestimation of host-derived cardiomyocytes, due to the presence of large number of infiltrating host-derived inflammatory cells and/or to the application of a variety of different detection techniques.…”

Tracking mesenchymal stem cells in the liver by magnetic resonance imaging

“…Recent progress in the isolation of stem cells along with improved understanding of their functions has extended the use of stem cells in cardiovascular and neurologic diseases [1]. The development of stem cell-based therapies requires a quantitative and qualitative assessment of initial stem cell distribution to target organs (homing) as well as engraftment and in situ differentiation.…”

“…The development of stem cell-based therapies requires a quantitative and qualitative assessment of initial stem cell distribution to target organs (homing) as well as engraftment and in situ differentiation. Several imaging techniques are proposed to track stem cells in vivo within individual organs over long periods of time [1]. However, tracking a small number of cells in the body is a difficult task and the ideal technique has not yet been delineated [1].…”

“…Several imaging techniques are proposed to track stem cells in vivo within individual organs over long periods of time [1]. However, tracking a small number of cells in the body is a difficult task and the ideal technique has not yet been delineated [1]. The need for high concentrations of contrast agents and high ionizing radiation preclude the use of computed tomography for such tracking.…”