Cardiovascular Developmental Bioengineering Lab

Research

Developmental Redux of Adult Valve Disease

Adult valve disease is characterized by acute or chronic deterioration of leaflet tissue matrix resulting in stenosis and/or regurgitation. Some etiologies result in the formation of calcific, sometimes bone-like nodules resulting in brittle fracture of the leaflets. Others result in a conversion from a fibrous collagenous matrix to proteoglycan rich matrix, simultaneously swelling and weakening the tissue. These progressive matrix transitions are mediated by changes in resident cell behavior that is incompletely understood, but is thought to be related to changes in the local mechanical environment. We and others have shown that the endothelial and interstitial cells that populate these tissues are mechanosensitive in unique ways not mimicked by other cells. These two cell types are derivatives of the same endocardial precursor cell in embryonic development. Several studies by us and others have shown that these embryonic cells are pluripotent, capable of forming bone, cartilage, and muscle cells, yet generally form fibroblastic cells in the valve. The developmental evolution of embryonic valves involves the remodeling of a thick proteoglycan rich matrix into thin fibrous tissue with a highly organized collagen lattice network. Let’s consider the embryonic process as a conveyor belt along which the precursor cells advance. At defined points along the belt, these cells are subjected to specific biological and mechanical stimuli, each one changing the phenotype of the cells. At the end of the process, quiescent adult phenotypes in organized mature matrix results. It may therefore be possible that some adult diseases can be explained as a reversal of this conveyor belt, or a recapitulation of embryonic phenotypes.

The second thrust seeks to understand how perturbations in mechanical signaling in adult valve diseases results in changes in cell behavior, specifically towards a reversion to embryonic phenotypes. We have developed 3D engineered tissue co-culture models of adult valves that can be stimulated via mechanical forces and/or bioactive ligands to induce physiological or pathological cell differentiation. Our current focus is on two proteins, periostin and cadherin-11, whose proper embryonic and adult expression is important for postnatal valvular homeostasis. The overall goal is to develop targeted strategies to induce in vivo cellular repair of adult valve diseases at a stage prior to tissue failure to remove the need for replacement altogether.

Related Publications:
- [PDF] Porcine Aortic Valve Interstitial Cells in Three-Dimensional Culture: Comparison of Phenotype with Aortic Smooth Muscle Cells (external link), Jonathan T. Butcher and Robert M. Nerem from Journal of Heart Valve Disease (2004)

- [PDF] The Next Frontier in Cardiovascular Developmental Biology - An Integrated Approach to Adult Disease? (external link), Roger R. Markwald and Jonathan T. Butcher from Nature Clinical Practice - Cardiovascular Medicine (2007)

- [PDF] Valvular Endothelial Cells and the Mechanoregulation of Valvular Pathology (external link), Jonathan T. Butcher and Robert M. Nerem from Philosophical Transactions of the Royal Society B - Biological Sciences (2007)

- Neonatal and Adult Cardiovascular Pathophysiological Remodeling and Repair, Russel A. Norris, Thomas K. Borg, Jonathan T. Butcher, and Roger R. Markwald from Annals of the New York Academy of Sciences (2008)