Norris Russell A, Borg Thomas K, Butcher Jonathan T, Baudino Troy A, Banerjee Indroneal, Markwald Roger R
Cardiovascular Developmental Biology Center, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA.
Ann N Y Acad Sci. 2008 Mar;1123:30-40. doi: 10.1196/annals.1420.005.
The neonatal heart undergoes normal hypertrophy or compensation to complete development and adapt to increased systolic pressures. Hypertrophy and increased neonatal wall stiffness are associated with a doubling of the number of fibroblasts and de novo formation of collagen. Normal postnatal remodeling is completed within 3-4 weeks after birth but can be rekindled in adult life in response to environmental signals that lead to pathological hypertrophy, fibrosis, and heart failure. The signals that trigger fibroblast and collagen formation (fibrosis) as well as the origin and differentiation of the cardiac fibroblast lineage are not well understood. Using mice studies and a single-cell engraftment model, we have shown that cardiac fibroblasts are derived from two extracardiac sources: the embryonic proepicardial organ and the recruitment of circulating bone marrow cells of hematopoietic stem cell origin. Periostin, a matricellular protein, is normally expressed in differentiating fibroblasts but its expression is elevated several fold in pathological remodeling and heart failure. Our hypothesis that periostin is profibrogenic (i.e., it promotes differentiation of progenitor mesenchymal cells into fibroblasts and their secretion and compaction of collagen) was tested using isolated and cultured embryonic, neonatal, and adult wild-type and periostin-null, nonmyocyte populations. Our findings indicate that abrogation of periostin by targeted gene deletion inhibits differentiation of nonmyocyte progenitor cells or permits misdirection into a cardiomyocyte lineage. However, if cultured with periostin or forced to express periostin, they became fibroblasts. Periostin plays a significant role in promoting fibrogenesis residual stress, and tensile testings indicated that periostin played an essential regulatory role in maintaining the biomechanical properties of the adult myocardium. These findings indicate that periostin is a profibrogenic matricellular protein that promotes collagen fibrogenesis, inhibits differentiation of progenitor cells into cardiomyocytes, and is essential for maintaining the biomechanical properties of the adult myocardium.
新生儿心脏会经历正常的肥大或代偿过程以完成发育并适应升高的收缩压。肥大和新生儿心脏壁硬度增加与成纤维细胞数量翻倍以及胶原蛋白的重新形成有关。正常的出生后重塑在出生后3 - 4周内完成，但在成年期可因导致病理性肥大、纤维化和心力衰竭的环境信号而再次激活。触发成纤维细胞和胶原蛋白形成（纤维化）的信号以及心脏成纤维细胞谱系的起源和分化尚未完全明确。通过小鼠研究和单细胞移植模型，我们发现心脏成纤维细胞来源于两个心外来源：胚胎的心外膜器官以及造血干细胞来源的循环骨髓细胞的募集。骨膜蛋白是一种基质细胞蛋白，通常在分化的成纤维细胞中表达，但其表达在病理性重塑和心力衰竭中会升高数倍。我们关于骨膜蛋白具有促纤维化作用（即它促进祖间充质细胞分化为成纤维细胞以及它们分泌和压实胶原蛋白）的假设，通过分离和培养胚胎、新生儿及成年野生型和骨膜蛋白缺失的非心肌细胞群体进行了验证。我们的研究结果表明，通过靶向基因缺失消除骨膜蛋白会抑制非心肌祖细胞的分化或导致其错误分化为心肌细胞谱系。然而，如果与骨膜蛋白一起培养或被迫表达骨膜蛋白，它们就会变成成纤维细胞。骨膜蛋白在促进纤维化、残余应力方面发挥重要作用，拉伸测试表明骨膜蛋白在维持成年心肌的生物力学特性方面起着至关重要的调节作用。这些研究结果表明，骨膜蛋白是一种促纤维化的基质细胞蛋白，它促进胶原蛋白纤维化，抑制祖细胞分化为心肌细胞，并且对于维持成年心肌的生物力学特性至关重要。
