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.
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发表时间：
2004-09
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通讯作者：
Elena Rabkin-Aikawa;M. Farber;M. Aikawa;F. Schoen
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作者：
Elena Rabkin-Aikawa;M. Farber;M. Aikawa;F. Schoen
背景与目的心脏瓣膜间质细胞（维克）在胎儿发育、适应和损伤反应中细胞外基质重塑中的作用尚不清楚。方法研究健康人和羊、胎儿人和羊、疾病人二尖瓣粘液瘤样变性、适应性人肺动脉瓣-主动脉瓣移植物和体外成熟和体内重构的组织工程心脏瓣膜中维克的表型。使用波形蛋白（V）、α-平滑肌肌动蛋白（SMA，A）、基质金属蛋白酶（MMP）-13/胶原酶-3（M）和SMemb（S）的表达评估细胞表型。结果正常成人瓣膜中的维克主要是对波形蛋白免疫反应的静止成纤维细胞（89.7 +/- 2.5%），而不是MMP-13或SMemb，只有2.5 +/- 0.4%的α-SMA阳性细胞（“正常/静止”表型：V+/A-/M-/S-）。相比之下，胎儿维克主要是活化的肌成纤维细胞（“发育/活化”表型：V+/A+/M+/S+），62.1 +/- 5.0%的细胞α-SMA染色阳性。粘液瘤瓣膜、短期自体移植物和体外工程瓣膜中的维克也是活化的肌成纤维细胞，其共表达波形蛋白、α-SMA（分别为36.2 +/-3.7%、19.3 +/-2.4%和60.3 +/- 9%阳性细胞），强MMP-13活性指示胶原重塑，SMemb（“重塑/活化”表型：V+/A+/M+/S+）。相比之下，长期肺自体移植物和工程瓣膜取出物中的维克主要具有成纤维细胞样表型，α-SMA表达稀疏（6.0 +/- 1%和5.4 +/- 1.0%阳性细胞）（V+/A-/M-/S-）。结论正常人瓣膜维克样细胞多呈静止状态，具有成纤维细胞样表型。发育、患病、适应和工程化瓣膜中的维克通过维克激活和分泌介导细胞外基质重塑（“发育/重塑/激活”表型）的蛋白水解酶来调节动态环境，随后表型正常化。
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), 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-). 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.