Human and animal studies are adding to the growing body of research investigating the role of stem cell therapies in cardiac disease. With inconsistent results emerging from clinical studies over the last decade, a close examination of cellular mechanisms via imaging is critical.
Skeletal myoblasts (SKMs) were one of the earliest cell types investigated for their applications in cardiac regeneration; however, their potential for arrhythmogenicity and failure to differentiate into cardiomyoctyes led the field to seek out other cell types (5
Embryonic stem cells (ESCs) are, theoretically, ideal candidates for cardiac regeneration because of their ability for unlimited self-renewal and pluripotency (6
). Human embryonic stem cell-derived cardiomyocytes have been transplanted into the murine heart following ischemia-reperfusion injury and these pre-differentiated cells can promote short-term functional recovery (7
). However, ESC use has been hindered by teratoma formation in vivo,
with intramyocardial teratoma formation observed following transplantation of ~1×105
). Nevertheless, because of their potential advantages, ESC therapy is an active field of investigation. Prior to clinical use of these cells, researchers must therefore develop techniques that can pre-differentiate these cells reliably to lessen the likelihood of teratoma formation.
Another potential cell source is mesenchymal stem cells (MSCs), which are adult stem cells purified from whole bone marrow following in vitro
expansion. One important characteristic of MSCs is that they are potentially “immunoprivileged”--they cannot stimulate T-cells proliferation because they do not express HLA class II antigens, B7 costimulatory molecules, or CD40 (9
). These immunoprivileged properties, the ability to home in on the heart following infarct, and anti-inflammatory benefits (10
) make these cells attractive candidates for allogenic transplantation. In 2009, Osiris Therapeutics announced the completion of the Phase I Osiris Prochymal study (11
). This study looked at the safety of allogeneic MSC transplantation in patients with acute MI and found that over the two-year study, 47.4% of placebo patients had cardiac arrhythmia compared to only 11.8% of Prochymal patients (p=0.006). The patients who received MSCs also had a higher LVEF at 2 years (12
Bone marrow mononuclear cells have been used in both animal models and human clinical trials, and this work has stirred both controversy and excitement. Being free from formation of arrhythmias or teratomas, these cells came into the spotlight of the field of cardiac regenerative medicine after initial reports of transdifferentiation following transplantation in mice in 2001 (13
), results which have not been reproduced by later studies (14
). Although transdifferentiation remains controversial, significant neomyogenesis is unlikely to be a major contributor given that <1% of the bone marrow cells survive 8 weeks following transplantation (16
). Transplantation of autologous bone marrow stem cells has also been tested in pigs, and transplantation of cells expressing pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) has been shown to increase cardiac contractility and perfusion, suggesting that some benefit may be due to paracrine effects (17
). Translation to human clinical trials of cardiac bone marrow cell transplant post-infarct has thus far shown mixed results. Two large trials found that bone marrow cell transfusion within 6 days after myocardial infarction had no effect on left ventricular function at six months (18
). By contrast, the Bone Marrow Transfer to Enhance ST-Elevation Infarct Regeneration (BOOST) trial found that left ventricular ejection function (LVEF) did improve with bone marrow cell infusion at 6 months (20
), though this improvement was not present at the 18-month follow-up (21
). The Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial showed increased LVEF in the bone-marrow cell infusion group vs. placebo (5.5±7.3% vs. 3.0±6.5%; P=0.01) at four months, and reported greatest improvement in those with poorest baseline LVEF (22
). These same patients later had a reduced risk for repeat MI or death. A meta-analysis of clinical trials through 2007 found that cell therapy in an acute MI setting increased LVEF, and reduced risk for death and rehospitalization from heart failure (23
). However, results from these studies suggest that if bone marrow mononuclear stem cells could provide functional benefit and reduce mortality, they do so by accelerating recovery in the acute stages post-MI. Early cell engraftment may be a key indicator of functional outcome, necessitating sensitive noninvasive imaging of stem cell therapies for clinical use.
The contradictory results from many pre-clinical and clinical studies employing diverse patient populations, delivery methods, and cell types highlight the need for more basic research into mechanisms of stem cell repair. Functional benefit could be due to factors as diverse as paracrine effects, progenitor cell mobilization, or neovascularization (24
). Though cell therapies are singularly useful, it may also be important to reduce cell injury through other mechanisms, such as reducing reperfusion injury post-ischemia by mediating chemokine activity (26
) or by preconditioning (27
). Molecular imaging that provides information about cell behavior in vivo
can elucidate the mechanisms of cell therapy and possibly settle, or clarify, the contradictory reports of functional outcomes. Given the diverse mechanisms that underlie functional effects of cardiac stem cell therapies, the urgent need to improve, validate, and evaluate current techniques of tracking stem cells must be met.