Transatlantic Network of Excellence for Cardiac Regeneration

European Coordinator:

• Stefanie DIMMELER, J.W. Goethe-University, Frankfurt (Germany)

North American Coordinator:

• Michael D. SCHNEIDER, formerly Baylor College of Medicine, Houston (USA); now Imperial College, London (UK)

Members:

Heart muscle has a limited capacity to repair itself in the event of injury, such as that suffered in a heart attack. One of the great challenges in current cardiovascular research is to identify cells, already existing within the body or engineered externally, which can repair an injured or diseased heart. This network focuses on progenitor cells, which are like stem cells in that they have the capacity, with the right stimuli, to differentiate into specific types of cell. The network is centered around 4 aims:

1.  To define the developmental origin and lineage of adult cardiac progenitor cells
2. To study how progenitor cells make their way into a target tissue, a process called “homing”
3. To identify the signals that regulate the differentiation of progenitor cells into cardiac cells
4. To translate the findings into clinical trials of adult progenitor cells for human cardiac repair

Aim 1: One cell type studied by network investigators is mesoangioblasts, progenitor cells associated with blood vessels which are able to differentiate into both skeletal and cardiac muscle cells. Injection of mesoangioblasts into mice with heart attacks is associated with an improvement in heart function, perhaps due to the production of factors that promote blood vessel development (angiogenesis) or inhibit cell death (apoptosis). Mesoangioblasts have been also isolated from human adult tissues, but, importantly, patients with progressive heart disease have very low numbers of mesoangioblasts, suggesting that this cell population has been exhausted by the disease.

Aim 2: Several signals affecting the mobilization and homing of progenitor cells to target tissues have been pursued:

• IGF-1, or insulin-like growth factor-1, appears to have a regenerative effect in injured heart. Possible mechanisms of this effect include IGF-1’s action on myelocytic cells and signaling pathways involving calcineurin, SGK1 and SIRT1, all of which are being studied.
• Notch1 signaling is known to be important in embryonic development of cardiovascular and neural systems. Interestingly, this pathway is also activated in conditions of low oxygen, such as occurs with a heart attack. Treatment with an antibody stimulating the Notch-1 receptor results in improvement after heart attacks, and the investigators hypothesize that Notch1 may improve the homing of progenitor cells to the affected heart tissue. However, while high Notch1 activity appears advantageous after a heart attack, the investigators have found that over-expression of Notch-1 during mouse embryonic development leads to severe cardiac defects, reinforcing the importance of the timing of these signals.
• Other pathways that have been studied for their effects on cell homing and migration are IL-10, VEGF, SDF-1, NF-κB, and eNOS.

Aim 3: Serum response factor (SRF) is a transcription factor, a protein that binds to DNA to regulate the expression of different genes, that is very important for heart formation in the embryo. Network investigators have shown that knocking out SRF in mice embryos prevents the development of rhythmic beating muscle cells in the heart. Furthermore, they have determined that binding of SRF with co-factor proteins is critical for its function and have identified specific regions involved in these interactions. Other pathways studied include Wnt11, Wnt5a, PKC, CRP2, Map4k4, and Dicer.

Aim 4: The investigators have performed clinical trials testing the efficacy of bone-marow derived or circulating progenitor cells for the treatment of cardiac dysfunction due to coronary artery disease or non-coronary artery disease related conditions.