Myofibroblast Phenotype and Reversibility of Fibrosis in Patients With End-Stage Heart Failure
Myofibroblast Phenotype and Reversibility of Fibrosis in Patients With End-Stage Heart Failure
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DOI：
10.1016/j.jacc.2019.02.049
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发表时间：
2019-05-14
影响因子：
24
通讯作者：
Sipido, Karin R.
中科院分区：
文献类型：
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作者：
Nagaraju, Chandan K.;Robinson, Emma L.;Sipido, Karin R.
背景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，并且依赖于成纤维细胞活化和分化为肌成纤维细胞（MyoFb）。最近的临床证据表明，在晚期心力衰竭中，纤维化是不可逆的。 目的 本研究旨在检查终末期心力衰竭中心脏 MyoFb 的分化程度及其表型可逆性的潜力。 方法 从移植受者（缺血性和扩张型心肌病）的外植心脏的左心室和未使用的供体心脏中分离成纤维细胞。成纤维细胞在不传代的情况下维持培养4或8天（治疗研究）。表型分析包括功能测试、免疫染色和分化标记的表达研究。这些数据得到了免疫组织学和组织样本表达研究的补充。 结果 心力衰竭心脏中，交联胶原间质纤维化很明显，并存在活化的 MyoFb。转化生长因子 (TGF)-β1、赖氨酰氧化酶、骨膜素和骨桥蛋白的组织水平升高。从心力衰竭心脏中分离的成纤维细胞主要是 MyoFb，增殖性或非增殖性，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，并且 TGF-β 1 途径被激活。抑制 HF MyoFb 中的 TGF-β 1 受体激酶可促进 MyoFb 去分化，导致 α-平滑肌肌动蛋白丢失和应力纤维解聚，并将促纤维化基因的表达和细胞因子水平降低至非 HF 水平。 结论 终末期 HF 中的 MyoFb 具有不同程度的分化，并保留返回到较低激活状态的能力，验证了开发针对 MyoFb 的抗纤维化治疗的潜力。 (C) 2019 年作者。由爱思唯尔代表美国心脏病学会基金会出版。
BACKGROUND 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.OBJECTIVES The study aims to examine the degree of differentiation of cardiac MyoFb in end-stage HF and the potential for their phenotypic reversibility.METHODS 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.RESULTS Interstitial fibrosis with cross-linked collagen is prominent in HF hearts, with presence of activated MyoFbs. Tissue levels of transforming growth factor (TGF)-beta 1, lysyl oxidase, periostin, and osteopontin are elevated. Fibroblastic cells isolated from HF hearts are predominantly MyoFb, proliferative or nonproliferative, with mature alpha-smooth muscle actin stress fibers. HF MyoFb express high levels of profibrotic cytokines and the TGF-beta 1 pathway is activated. Inhibition of TGF-beta 1 receptor kinase in HF MyoFb promotes dedifferentiation of MyoFb with loss of alpha-smooth muscle actin and depolymerization of stress fibers, and reduces the expression of profibrotic genes and cytokines levels to non-HF levels.CONCLUSION 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. (C) 2019 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.