Zoltan Hajdu, MD
Assistant Professor for Anatomical Sciences
Edward Via College of Osteopathic Medicine
Hematopoietic-derived cell – endocardium crosstalk in mitral valve homeostasis
Valve interstitial cells (VICs) together with the overlying valve endocardial cells (VECs) are responsible for proper maintenance of the extracellular matrix, and thus the homeostatic form and function of the entire heart valves. VICs are a heterogeneous cell population that have been described as phenotypically quiescent, activated, osteoblastic and progenitor cells. In addition to these previously described VIC populations, we have recently described VICs of bone marrow hematopoietic origin evidenced by their expression of CD45 and other markers. Based on theirimmunological phenotype, the proximally located hematopoietic-derived VICs can be divided into two distinct populations: a superficially positioned CD45+/CD133+ VICs (a progenitor cell population) and a more deeply positioned CD45+/CD133- VICs that exhibit a synthetic phenotype (based on Hsp47 and periostin expression). During our investigation of the role of these hematopoietic-derived VICs in valve homeostasis, we made a striking observation that systemic lipopolysaccharide (LPS) exposure leads to a rapid and marked reduction in the population of CD45+/CD133+ progenitor cells within the valve interstitium with concomitant epithelial-to-mesenchymal transition (EMT) by the overlying valvular endocardium. While post-natal EMT in the valve endocardium is associated with pathological remodeling of the leaflets, the signaling mechanisms that initiate post-natal EMT are poorly understood. These observations, combined with our preliminary findings of coordinate expression of TLR4 and Notch1 by progenitor VICs and VECs, lead us to hypothesize that molecular signaling between this novel population of CD45+ progenitor VICs and overlying VECs is essential for homeostatic maintenance of form and biomechanical function of the valve leaflets. Therefore, the main focus of this project will be to identify key effectors of the signaling pathway between VECs and hematopoietic-derived VICs in maintenance of mitral valve homeostasis.