Abstract
Advances on multiple scientific fronts have brought insights into mechanisms of tissue healing and uncovered new potential to cellular recovery and replacement. With the unabated rise in the prevalence of cardiovascular disease, the interventional community is increasingly faced with caring for patients with chronic coronary, peripheral vascular, myocardial, and conduction system diseases. The International Conference on Cell Therapy for Cardiovascular Diseases (IC3D) 2008 maintained its principal goal of integrating basic, translational, and clinical data and manuscripts for this special issue of Cell Transplantation were submitted by its faculty.
Several themes emerged from IC3D 2008. One in particular was the role played by tissue engineers in directing, and clarifying, important aspects of bedside-to-bench studies. The expertise of scientists in this multi-faceted discipline may be crucial to the rapid conduct of hypothesis testing. The following exemplify this trend.
Endothelial progenitor cell (EPC) characterization and function were subjects of extensive discussion. The influence of three-dimensional matrices on EPC biosecretory function had been previously reported. Not recognized until now, however, are the protective effects against host immune responses that are conferred by these structures to donor-derived EPCs. This process elicited is not simply a consequence of physical sheltering, but rather through modulation of molecules that regulate major histocompatibility class II expression (1). Moreover, our belief that autologous EPCs enjoy immunoprivileged status may be misplaced, as disease-related endothelial dysfunction is now recognized to generate anti-EC antibodies. Investigators from the same laboratory (6) provide data linking matrix embedding of EPCs to inhibition of the NF-κB pathway, known to be integral to chemoattraction of natural killer (NK) cells, local inflammation, and tissue repair.
In a more conventional role for the engineering community, reconstruction of diseased left ventricular wall, using a cardiac patch constructed of macroporous alginate scaffolds seeded with fetal cardiomyocytes, was reported (3). The performance of the novel cardiac patch was tested in a rat model of heterotopic heart transplant, which enables replacement of a full-thickness free wall and may be useful in screening or evaluating new tissue engineering strategies. A similar study by Thai et al. also used a novel three-dimensional fibroblast patch, which is already FDA approved for other uses, in the rat infarct model showing positive findings of postinfarct remodeling (12).
In situ polymerization of hydrogels to simulate, in a way, the construction of engineered tissue was proposed as a possible solution to address two weaknesses of catheter-based cell delivery: early cell loss and nutrient support. This was explored by testing the suitability of several cell delivery catheters to the passage of viscous solutions in order to define the limit for each device, and, having made this determination, demonstrating the ability of specific cell products to increase cell retention in an animal model of myocardial infarction (7).
The clinical experiences presented at IC3D, as with most studies, utilized progenitors derived from blood, bone marrow, or skeletal muscle. Considerable refinement and enhancement of the mechanisms of cell function and stability have occurred. However, reviewed by Sanz-Ruiz, a number of other cells types, such as adipose-derived stem cells, are seeing expanding use not only in prehuman but in clinical trials (9). Along with a technique described by Das et al., where umbilical cord stem cells are expanded using a three-dimensional nanofiber mesh, the spectrum of cells for cardiovascular disease is further widened (4). Safety profiles of cell products and delivery methods remain very important as we advance into larger clinical trials. Furlani et al. demonstrate that mesenchymal stem cells have the potential at early passage to transform and become nonfunctional. This surprising observation was seen after passage 3 in a rat infarct model and contradicts most data showing the safety of low passage cells in translational cell therapy (5). As to another safety parameter, arrhythmogenicity, Sherman et al. were able to demonstrate in a canine heart failure model that skeletal myoblasts did not promote disturbances in ventricular rhythm on ambulatory ECG monitoring. Interestingly, several parameters of heart rate variability were negatively affected in the treatment cohort (10). All such safety observations require substantiation.
As clinical trials advance, a number of issues persist related to route of delivery of cells. With respect to coronary delivery, Silva et al. demonstrate that anterograde is superior to retrograde (via the coronary sinus) (11). This still remains controversial as other groups have shown the opposite effect. The type of catheter, onset and duration of disease, along with a number of factors play a role in the outcomes. The role of adjunctive therapies is highlighted by Wehberg et al., who describe the use of transmyocardial laser revascularization along with platelet-rich plasma as a synergistic approach to the treatment of chronic angina (13).
That nearly all routes of delivery are safe is most important, and encourages the development (and rapid testing) of optimal cell subtypes. Once the cells are delivered improvement in imaging is required to better assess function. Nasseri et al. describe a noninvasive technique using strain, which appears to have early clinical merit but needs further validation (8). As we expand the cardiac cell therapy into cardiovascular cell therapy, the treatment of critical limb ischemic has rapidly expanded into clinical translation. Amann et al. present their early experience using a rapid bedside processing system to concentrate bone marrow mononuclear cells (2). Once the concentrate is obtained it is directly injected into the muscle during the same operative setting. We expect to see many other clinical trials in this rapidly expanding field, not only in cardiovascular disease, but also cerebrovascular and renovascular diseases.