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My laboratory has pursued studies on the cell and molecular mechanisms of heart development that utilized in vivo dynamic labeling studies to demonstrate that heart development is progressive, irreversible and occurs by the addition of new segments including ones derived from extracardiac sources. Three dimensional culture assays were also developed that faithfully recapitulated in vivo morphogenetic processes which permitted identification of: (1) a novel heart forming field that gave origin to the outflow track at the arterial pole of the heart (, (2) specific growth factors of the TGFß supergene as inducers of the outflow track and the transformation of specific populations of endothelial cells into multiple progenitor cells of internal partitions that divide the heart into right and left sides a and their respective valves and (3) specific matricellular proteins (periostin and CCN1,2) as ligands that activate integrin-linked, nodal intracellular kinase pathways in valvuloseptal progenitor cells that promote their differentiation into fibroblasts and regulate cytoskeletal changes that promote their remodeling into sculpted leaflets. Modifications of the culture system have also permitted the functional assessment of the viscoelastic properties of developing valves and the role of biomechanical signaling in cardiac cell and matrix differentiation.
Current studies focus on using patient based, gene discoveries for developing remedial etiologies and therapies for congenital heart malformations and developmentally-linked, adult heart valve diseases. We are also exploring the use of bone marrow derived, hematopoietic stem cells as carriers of genetic “payloads” to normalize or restore the function of degenerative heart valve diseases or to re-engineer cardiac fibrotic tissues like infarct scars to benefit patient health following cardiac injury. Lastly, we are applying and integrating bioprinting technology and principles of developmental biology to engineer complex micro-organs for use as personalized tissue replacements or to study mechanisms of human diseases. Our spheroidal approach to bioprinting tissues is shown in the figure below. Spheroids called “bioink” are formulated from stem cells and hydrogels containing inductive signals and linkers - are robotically positioned and assembled into 3D structures such as the tubular (vascular-like) structure shown. Details of the process are described in a video paper Grace et al. 2015
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Markwald, Roger