Cardiac Induction by Small Molecule BMP Inhibitors

小分子 BMP 抑制剂的心脏诱导

• 批准号: 8461665
• 负责人: CHARLES C HONG
• 金额: $ 36.76万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8461665
• 关键词: American; Animals; Blood Vessels; Bone Morphogenetic Proteins; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Lineage; Cell Therapy; Cells; Chemicals; Clinical; Commit; Development; Early treatment; Embryonic Stem Cell Transplantation; Face; Future; Heart; Heart Diseases; Heart failure; Hematopoietic; Hour; In Vitro; Injury; Light; Mesoderm; Mesoderm Cell; Modeling; Molecular Profiling; Multipotent Stem Cells; Mus; Myocardial; Myocardial Infarction; Nature; Organ Transplantation; Pharmaceutical Preparations; Pharmacologic Substance; Phosphotransferases; Pluripotent Stem Cells; Protein Inhibition; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Stem cells; Teratoma; Testing; Therapeutic; Therapeutic Effect; Tissues; Translations; Transplantation; Vascular Endothelial Growth Factor Receptor; base; cardiac repair; cell type; embryonic stem cell; heart cell; improved; in vivo; induced pluripotent stem cell; inhibitor/antagonist; mature animal; mouse model; novel; postnatal; progenitor; public health relevance; regenerative; repaired; small molecule; stem cell differentiation; stem cell therapy; tissue regeneration; tumor

DESCRIPTION (provided by applicant): PROJECT SUMMARY Because the heart has negligible intrinsic capacity to regenerate new tissues to replace those lost to injury, there is currently no definitive heart failure treatment, other than organ transplantation. Recent studies have introduced the prospect of replacing damaged heart tissues with healthy cardiomyocytes derived from pluripotent stem cells. However, realizing the full therapeutic potential of stem cells faces numerous hurdles, including the potential for tumor formation, a low rate of cardiomyocyte formation, and an inadequate mechanistic understanding of cardiomyogenesis. Additionally, translational efforts are hampered by a lack of pharmaceutical agents to boost therapeutic effects of stem cells. Dorsomorphin, the first known small molecule inhibitor of the bone morphogenetic protein (BMP) signaling, is one of the most potent chemical inducers of cardiomyogenesis in mouse embryonic stem (ES) cells. Dorsomorphin treatment during the initial 24 to 48 hours of ES cell differentiation was sufficient for robust cardiomyocyte induction. Strikingly, the massive cardiac induction occurs apparently in the absence of mesoderm induction and at the expense of other mesoderm-derived lineages, including endothelial, smooth muscle and hematopoietic lineages. From these results, we hypothesize that a timely BMP signal inhibition commits the primitive multipotent progenitor cells toward the cardiomyocyte development. The present study takes advantage of this unique and powerful model of cardiac induction to elucidate the mechanism of cardiomyogenic commitment and differentiation. In Aim 1, we examine in detail the effects of small molecule BMP inhibitors on mesoderm, cardiovascular progenitor and cardiomyocyte formation. By comparing the effects of dorsomorphin and an exclusively specific BMP inhibitor DMH1, we will test whether dorsomorphin's known off-target effects against the Flk1 kinase reduces overall mesoderm formation, and whether a pure BMP inhibitor could induce even greater cardiomyocyte formation. In Aim 2, we will examine whether the Flk1+ mesoderm progenitor cells from DMH1-treated ES cells are preferentially committed to become cardiomyocytes. In addition, we will determine the molecular profile of the putative cardiac-committed progenitors induced by the DMH1 treatment. These studies will shed much needed light on the nature of cardiac progenitor cells. In Aim 3, we will take the next logical step to test whether small molecules that robustly induce cardiomyocyte formation in vitro can have a beneficial impact on stem cell therapies to improve cardiac repair in a mouse model of myocardial injury. Utilizing the unique ability of small molecules to block BMP signaling in adult animals, we will explore the potential of in vivo stimulation of cardiomyocyte formation following ES cell transplantation. The present study, which utilizes the small molecule BMP inhibitors to probe the mechanism of cardiomyogenesis, will not only inform future stem cell-based strategies to treat heart disease, but provide valuable pharmaceutical agents to boost the therapeutic effects of stem cells.

描述（由申请人提供）： 项目摘要 由于心脏再生新组织来替代因损伤而失去的组织的内在能力可以忽略不计，因此除了器官移植之外，目前还没有明确的心力衰竭治疗方法。最近的研究提出了用多能干细胞衍生的健康心肌细胞替代受损心脏组织的前景。然而，实现干细胞的全部治疗潜力面临着许多障碍，包括肿瘤形成的潜力、心肌细胞形成率低以及对心肌发生的机制了解不足。此外，由于缺乏增强干细胞治疗效果的药剂，转化努力受到阻碍。 Dorsomorphin 是第一个已知的骨形态发生蛋白 (BMP) 信号传导小分子抑制剂，是小鼠胚胎干 (ES) 细胞心肌生成最有效的化学诱导剂之一。在 ES 细胞分化的最初 24 至 48 小时内，Dorsomorphin 处理足以诱导心肌细胞的强健。引人注目的是，大量的心脏诱导显然是在没有中胚层诱导的情况下发生的，并且以其他中胚层衍生谱系为代价，包括内皮、平滑肌和造血谱系。根据这些结果，我们假设及时的 BMP 信号抑制使原始多能祖细胞向心肌细胞发育方向发展。本研究利用这种独特而强大的心脏诱导模型来阐明心肌生成和分化的机制。在目标 1 中，我们详细研究了小分子 BMP 抑制剂对中胚层、心血管祖细胞和心肌细胞形成的影响。通过比较dorsomorphin和专门特异性BMP抑制剂DMH1的作用，我们将测试dorsomorphin已知的针对Flk1激酶的脱靶作用是否会减少整体中胚层形成，以及纯BMP抑制剂是否可以诱导更大的心肌细胞形成。在目标 2 中，我们将检查 DMH1 处理的 ES 细胞中的 Flk1+ 中胚层祖细胞是否优先分化为心肌细胞。此外，我们将确定 DMH1 治疗诱导的假定的心脏定向祖细胞的分子谱。这些研究将为心脏祖细胞的性质提供急需的线索。在目标 3 中，我们将采取下一个合乎逻辑的步骤来测试在体外强力诱导心肌细胞形成的小分子是否可以对干细胞疗法产生有益影响，以改善心肌损伤小鼠模型的心脏修复。利用小分子阻断成年动物 BMP 信号传导的独特能力，我们将探索 ES 细胞移植后体内刺激心肌细胞形成的潜力。本研究利用小分子 BMP 抑制剂来探索心肌生成机制，不仅将为未来基于干细胞的心脏病治疗策略提供信息，而且为增强干细胞的治疗效果提供有价值的药物制剂。