Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.
Department of Cardiology and Department of Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium.
J Am Coll Cardiol. 2019 May 14;73(18):2267-2282. doi: 10.1016/j.jacc.2019.02.049.
Interstitial fibrosis is an important component of diastolic, and systolic, dysfunction in heart failure (HF) and depends on activation and differentiation of fibroblasts into myofibroblasts (MyoFb). Recent clinical evidence suggests that in late-stage HF, fibrosis is not reversible.
The study aims to examine the degree of differentiation of cardiac MyoFb in end-stage HF and the potential for their phenotypic reversibility.
Fibroblasts were isolated from the left ventricle of the explanted hearts of transplant recipients (ischemic and dilated cardiomyopathy), and from nonused donor hearts. Fibroblasts were maintained in culture without passaging for 4 or 8 days (treatment studies). Phenotyping included functional testing, immunostaining, and expression studies for markers of differentiation. These data were complemented with immunohistology and expression studies in tissue samples.
Interstitial fibrosis with cross-linked collagen is prominent in HF hearts, with presence of activated MyoFbs. Tissue levels of transforming growth factor (TGF)-β1, lysyl oxidase, periostin, and osteopontin are elevated. Fibroblastic cells isolated from HF hearts are predominantly MyoFb, proliferative or nonproliferative, with mature α-smooth muscle actin stress fibers. HF MyoFb express high levels of profibrotic cytokines and the TGF-β1 pathway is activated. Inhibition of TGF-β1 receptor kinase in HF MyoFb promotes dedifferentiation of MyoFb with loss of α-smooth muscle actin and depolymerization of stress fibers, and reduces the expression of profibrotic genes and cytokines levels to non-HF levels.
MyoFb in end-stage HF have a variable degree of differentiation and retain the capacity to return to a less activated state, validating the potential for developing antifibrotic therapy targeting MyoFb.
间质纤维化是心力衰竭(HF)舒张和收缩功能障碍的重要组成部分,取决于成纤维细胞向肌成纤维细胞(MyoFb)的激活和分化。最近的临床证据表明,在晚期 HF 中,纤维化是不可逆转的。
本研究旨在检查终末期 HF 中心脏 MyoFb 的分化程度及其表型逆转的可能性。
从移植受者(缺血性和扩张型心肌病)和未使用供体心脏的左心室中分离出成纤维细胞,并进行原代培养。成纤维细胞在无传代的情况下维持培养 4 或 8 天(治疗研究)。表型鉴定包括功能测试、免疫染色和分化标志物的表达研究。这些数据与组织样本的免疫组织化学和表达研究相补充。
HF 心脏中存在交联胶原的间质纤维化,存在激活的 MyoFb。组织中转化生长因子(TGF)-β1、赖氨酰氧化酶、periostin 和骨桥蛋白水平升高。从 HF 心脏分离的成纤维细胞主要是 MyoFb,增殖或非增殖,具有成熟的α-平滑肌肌动蛋白应激纤维。HF MyoFb 表达高水平的促纤维化细胞因子,TGF-β1 通路被激活。在 HF MyoFb 中抑制 TGF-β1 受体激酶可促进 MyoFb 的去分化,导致α-平滑肌肌动蛋白丢失和应力纤维解聚,并降低促纤维化基因和细胞因子水平至非 HF 水平。
终末期 HF 中的 MyoFb 具有不同程度的分化,并保留向较少激活状态逆转的能力,验证了针对 MyoFb 开发抗纤维化治疗的潜力。