Cardiac Fibroblasts in Postnatal Development and Adult Injury Response

摘要 心脏成纤维细胞及其转化为肌成纤维细胞以产生细胞外基质(ECM)的能力， 心室重构和纤维化反应一直是一个重要的医学研究领域 关联性。在此，发育心脏生物学家提出了双PI更新重新提交申请 和以成人疾病为基础的心脏生物学家研究出生后心脏如何在成年后成熟，然后 通过直接旁分泌串扰和ECM转换回具有疾病刺激的类似胎儿的程序 反馈。在该奖项的上一个资金周期中，我们确定了存在的关键监管关系 在发育和患病的成人心脏中的肌细胞和成纤维细胞之间，ECM和 转化生长因子-β(转化生长因子-β)作为这两种细胞之间的整合平台。我们有 还观察到成纤维细胞表达GDF10和表皮生长因子(EGF)家族成员 多发性营养素(PTN)介导成纤维细胞和心肌细胞之间的临界串扰。在这里，我们将调查 假设转化生长因子β是一种肌细胞选择性成熟因子，控制成纤维细胞的活性，在产生 出生后心脏内有效的ECM，也是成人疾病的基础，PTN和GDF10平行 信号串扰进一步调节成纤维细胞增殖并促进心肌细胞肥大 发展和疾病。双PI续签申请有3个具体目标：1)检查如何 心肌细胞产生转化生长因子β1/2/3及其向心脏成纤维细胞的信号转导是细胞外基质新生儿的基础 成熟与成人心室重塑，2)研究心脏成纤维细胞如何产生ECM调节 发育心肌细胞成熟与成人心脏重塑部分通过转化生长因子β1/2/3 隔离/释放，以及3)检测心脏成纤维细胞分泌的生长因子PTN和 GDF10在出生后心脏发育和成人损伤中的作用总而言之，这些具体的目标将揭示小说 在出生后心脏成熟的信号机制，并决定这些机制是如何 在疾病中重新部署。因此，该计划的影响将是确定新的信号机制 以及可在治疗上靶向治疗人类心脏病以积极影响心脏重构的效应器 和长期的纤维化，增加了对治疗先天性畸形和发育的影响 发育异常。

Abstract The cardiac fibroblast and its ability to convert into a myofibroblast for extracellular matrix (ECM) production, ventricular remodeling and the fibrotic response has been an area of recent investigation with important medical relevance. Here, a dual-PI renewal resubmission application is proposed by a developmental cardiac biologist and adult disease-based cardiac biologist to address how the postnatal heart matures in adulthood and then transitions back to a fetal-like program with disease stimulation through direct paracrine crosstalk and ECM feedback. During the past funding cycle of this award, we identified key regulatory relationships that exist between myocytes and fibroblasts in both the developing and diseased adult heart, whereby the ECM and transforming growth factor-β (TGFβ) served as an integrating platform between these 2 cell-types. We have also observed that fibroblast-expressed GDF10 and the epidermal growth factor (EGF) family member pleiotrophin (Ptn) mediate critical crosstalk between fibroblasts and myocytes. Here, we will investigate the hypothesis that TGFβ is a myocyte selective maturation factor that controls fibroblast activity in generating an effective ECM within the postnatal heart that also underlies adult disease, and that parallel Ptn and GDF10 signaling crosstalk further regulates fibroblast proliferation and promotes cardiomyocyte hypertrophy in development and disease. The dual-PI renewal application has 3 specific aims: 1) To examine how cardiomyocyte generated TGFβ1/2/3 and its subsequent signaling to cardiac fibroblasts underlie ECM neonatal maturation and adult ventricular remodeling, 2) To examine how cardiac fibroblast generated ECM regulates developmental cardiomyocyte maturation and adult heart remodeling, in part through TGFβ1/2/3 sequestration/release, and 3) To examine the function of the cardiac fibroblast-secreted growth factors Ptn and GDF10 in postnatal heart development and adult injury. Collectively, these specific aims will uncover novel signaling mechanisms that underlie heart maturation just after birth and determine how these mechanisms are redeployed in disease. Thus, the impact of this program will be the identification of novel signaling mechanisms and effectors that can be therapeutically targeted in human heart disease to positively effect cardiac remodeling and longstanding fibrosis, with added implications for treating congenital malformations and developmental growth abnormalities.