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You are here: Contents > 2004 > Volume 13 Number 5 September 2004 > TISSUE ENGINEERING > Dynamic and Reversible Changes of Interstitial Cell Phenotype During Remodeling of Cardiac Valves

Dynamic and Reversible Changes of Interstitial Cell Phenotype During Remodeling of Cardiac Valves

Elena Rabkin-Aikawa, Mark Farber, Masanori Aikawa, Frederick J. Schoen
Department of Pathology and Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology (HST), Boston, USA

Background and aim of the study: The roles of cardiac valvular interstitial cells (VIC) in extracellular matrix remodeling in fetal development, adaptation and response to injury are largely unknown.
Methods: The phenotype of VIC was studied in health (normal adult human and sheep), development (fetal human and sheep), disease (human mitral valves with myxomatous degeneration), adaptation (clinical pulmonary to aortic valve autografts) and tissue-engineered heart valves matured in vitro and remodeled in vivo. Cell phenotype was assessed using expression of vimentin (V), a-smooth muscle actin (SMA, A), matrix metalloproteinase (MMP)-13/collagenase-3 (M), and SMemb (S).
Results: VIC in normal adult valves were predominantly quiescent fibroblasts immunoreactive to vimentin (89.7 ± 2.5%), but not MMP-13 or SMemb, with only 2.5 ± 0.4% of a-SMA-positive cells (‘normal/quiescent’ phenotype: V+/A-/M-/S-). In contrast, fetal VIC were mostly activated myofibroblasts (‘developing/activated’ phenotype: V+/A+/M+/S+), with 62.1 ± 5.0% of cells staining positive for a-SMA. VIC in myxomatous

valves, short-term autografts and engineered valves in vitro were also activated myofibroblasts with coexpression of vimentin, a-SMA (36.2 ± 3.7%, 19.3 ± 2.4%, and 60.3 ± 9% positive cells, respectively), strong MMP-13 activity indicative of collagen remodeling, and SMemb (‘remodeling/activated’ phenotype: V+/A+/M+/S+). In contrast, VIC in long-term pulmonary autografts and engineered valve explants had a mostly fibroblast-like phenotype, with sparse a-SMA expression (6.0 ± 1% and 5.4 ± 1.0% positive cells) (V+/A-/M-/S-).
Conclusion: Most VIC in normal valves were quiescent with a fibroblast-like phenotype. VIC in developing, diseased, adapting and engineered valves adjust to a dynamic environment through VIC activation and secretion of proteolytic enzymes mediating extracellular matrix remodeling (‘developing/
remodeling/activated’ phenotype), followed by a normalization of phenotype.
The Journal of Heart Valve Disease 2004;13:841-847

Dynamic and Reversible Changes of Interstitial Cell Phenotype During Remodeling of Cardiac Valves

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