Cardiophere-Derived Cells Embedded in Platelet Gel Increases Heart Function and Improves Heart Structure After a Heart Attack

Biomaterials are organic compounds that can be molded into the shape of a particular organ or tissue, and can be seeded with cells that will form the shape of the organ or tissue and degrade the it, while using the biomaterial as a scaffold for their growth and development.

One organ where biomaterials can make a great difference is the heart, since implanted cells tend to either die to move away from the heart. By implanting cells into the heart that are embedded in biomaterials, the implanted cells stay put, are protected from cell death induced by the inhospitable environment of the heart after a heart attack, and tend to differentiate into heart-specific cells at the site at which they were implanted.

Injectable biomaterials are preferable for the heart, since non-injectable biomaterials require that the surgeon crack the chest and implant the biomaterial, which is a much more invasive procedure. One of the most appealing injectable biomaterials is platelet gel (also known as platelet fibrin scaffold).

The body naturally generates platelet gel after injury, however, it can be engineered as a tissue substitute to speed healing. The scaffold for platelet gel consists of naturally occurring biomaterials composed of a cross-linked fibrin network.

Platelet gel polymerization requires the enzyme thrombin and its substrate fibrinogen. Thrombin degrades fibrinogen to fibrin, which self-assembles to form the fibrin meshwork that composes the ground substance for platelet gel.  This reaction is affected primarily by the concentration of thrombin and temperature. Platelet gels are composed of fibers whose thicknesses vary according to the reaction conditions, and can be enriched by addition of other molecules (fibronectin, vitronectin, laminin, and collagen). Linking these molecules to the fibrin scaffold greatly affects the properties of the platelet gel, and the gel can also serve as a reservoir for growth factors and other molecules that speed healing.

Injection of platelet gel into a heart that has just experienced a heart attack prevents remodeling. Can stem cells that have a documented ability to heal damaged hearts have their healing capacities increased by implanting them in platelet gel?

A paper published workers in Eduardo Marban’s lab at Cedars-Sinai Medical Center in Los Angeles in the journal Biomaterials asks this very question, using rats as a model. In this article, Marban’s group used cardiosphere-derived cells (CDCs), which were successfully used in the CADUCEUS clinical trial to heal the hearts of human patients who have suffered a heart attack. The strategy used in these experiments was relatively simple (in principle): Induce heart attacks in the rats, treat once group with platelet gel alone, and the other group with CDCs embedded in platelet gel. Then compare the structural and functional integrity of the hearts in each group.

The results of these experiments come in several categories. First of all, the CDCs grown in platelet gel showed increased viability (reduced death) in comparison to CDCs grown on standard tissue culture plates. Furthermore, platelet gel-grown CDCs also differentiated into three-dimensional structures such as blood vessels. The CDCs also degraded the platelet gel and by two weeks of culture, two-thirds of the platelet gel was degraded. Furthermore, CDCs in platelet gel spread out and began to beat. Far more CDCs spread out and beat when grown in platelet gel than those grown in tissue culture plates. The contraction of the CDC-formed heart muscle cells was also much more robust in platelet gel than in tissue culture plates. Overall, the CDCs did much better in platelet gel than in standard tissue culture plates. They grew better, survived better, formed more heart-specific structures, and differentiated in more mature heart cell types when grown in platelet gel.

Another bonus to the platelet gel consists in its ability to trap growth factors. The CDCs in the platelet gel secrete a wide variety of growth factors, and these growth factors bind to the platelet gel and are concentrated by it. This recruits other cells to the platelet gel. That increases the ability of the platelet gel to facilitate stem cell-mediated healing.

Implanting platelet gel alone and platelet gel seeded with CDCs into damaged hearts caused increased heart wall thickness, decreased infarct size, and improved cardiac function. However in all cases, the CDC-seeded platelet gel causes even greater improvements than platelet gel alone.

These experiments show that stem cell-mediated healing is improved by the use of biomaterials. Furthermore, platelet gel is a very easily manufactured biomaterial that improves the growth and heart-specific differentiation of CDCs. Give the demonstrated healing capacities of CDCs, augmenting those capabilities with biomaterials such as platelet gel should be a priority for future clinical trials.