Abstract 007: Platelet Derived Growth Factor-AA Promotes Migration of Resident Cardiac Stem Cells

Abstract

Bone marrow mesenchymal stem cells modulate cardiac healing via the release of paracrine factors. Although the exact mechanisms are not yet understood, one promising approach is through the mobilization of endogenous cardiac stem cells. Recently, we reported the existence of a new type of cardiac stem cell, named Cardiac Atrial appendage Stem Cells (CASCs), that is characterized by a high aldehyde dehydrogenase expression. In this study, we hypothesized that conditioned medium from mesenchymal stem cells (MSC-CM) is able to promote migration of resident cardiac stem cells. Therefore, human cardiac fragments were cultured inside a collagen type I matrix and subjected to serum-free DMEM (control) or MSC-CM. By analysis of cell counts, perimeter and area measurements, we found that MSC-CM promoted migration of cells from cardiac fragments throughout the matrix. These migrating cells possessed stem cell properties, as shown by a clonogenicity of 21.6±4.3% (n=3) and pluripotency associated genes like Oct-4, Nanog, Dppa-3, Tbx-3, c-Myc and Klf-4. Flow cytometrical analysis showed that these cells expressed a CSC-phenotype. Further investigation demonstrated that, comparable to CASCs, migrating cells had a high aldehyde dehydrogenase activity and were able to differentiate towards cardiomyocytes. In addition, we demonstrated an extensive activation of the platelet derived growth factor receptor-α (PDGFRα) in migrating cells subjected to MSC-CM. Subsequent collagen assays indicated that pure PDGF-AA was sufficient to produce migration effects similar to MSC-CM, albeit higher PDGF-AA concentrations than measured in MSC-CM were necessary. Imatinib mesylate, a PDGFR inhibitor, was partially able to attenuate MSC-CM induced migration, pointing out that PDGF-AA might work synergistically with other factors to promote migration. In conclusion, these data demonstrate that MSC-CM stimulates migration of resident CASCs. PDGF-AA is an important paracrine factor in this process, although the synergic role of other growth factors has to be further investigated. These findings contribute to the development of future therapies in which paracrine agents can be utilized to activate the endogenous repair system of the heart.