Dynamic and reversible changes of interstitial cell phenotype during remodeling of cardiac valves.
OBJECTIVE
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), alpha-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 alpha-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 alpha-SMA. VIC in myxomatous valves, short-term autografts and engineered valves in vitro were also activated myofibroblasts with coexpression of vimentin, alpha-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 alpha-SMA expression (6.0 +/- 1% and 5.4 +/- 1.0% positive cells) (V+/A-/M-/S-).


CONCLUSIONS
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.
Rabkin-Aikawa
Elena
E
Department of Pathology, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA.
Farber
Mark
M
Aikawa
Masanori
M
Schoen
Frederick J
FJ
D000199:Actins / Q000096:biosynthesis; D000328:Adult; D000818:Animals; D017364:Collagenases / Q000096:biosynthesis; D005314:Embryonic and Fetal Development / Q000502:physiology; D005347:Fibroblasts / Q000502:physiology*; D006349:Heart Valve Diseases / Q000503:physiopathology*; D006350:Heart Valve Prosthesis; D006351:Heart Valves / Q000166:cytology / Q000196:embryology / Q000502:physiology* / Q000503:physiopathology; D006801:Humans; D053509:Matrix Metalloproteinase 13; D009130:Muscle, Smooth / Q000378:metabolism; D009218:Myosins / Q000096:biosynthesis; D010641:Phenotype; D012756:Sheep; D023822:Tissue Engineering; D014746:Vimentin / Q000096:biosynthesis
D000199:Actins; D014746:Vimentin; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D009218:Myosins