Adult Stem Cell Therapy For Cardiac Failure

成体干细胞治疗心力衰竭

• 批准号: 7594420
• 负责人: NEAL DAVID EPSTEIN
• 金额: $ 172.09万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7594420
• 关键词: Adipose tissue; Adult; Antibodies; Antigens; Binding; Brain; Breast; Cancer cell line; Cancerous; Cardiac; Cardiac Myocytes; Cardiac Output; Cell Differentiation process; Cell Nucleus; Cell surface; Cells; Chronic; Commit; Condition; Cultured Cells; Embryo; Expressed Sequence Tags; Fibroblast Growth Factor; Frequencies; Golgi Apparatus; Growth Factor; Harvest; Heart; Heart failure; Home environment; Human; Hypertrophy; Immune; Immunoprecipitation; Laboratories; Learning; Life; Malignant Neoplasms; Malignant neoplasm of kidney; Mass Spectrum Analysis; Membrane Proteins; Monoclonal Antibodies; Mus; Myoblasts; Myocardial Ischemia; Myofibroblast; Neurons; Nuclear; Numbers; Other Agency or Organization; Pathway interactions; Peptides; Physiological; Play; Population; Process; Recovery; Renal carcinoma; Role; Sarcomeres; Skeletal Muscle; Staging; Standards of Weights and Measures; Stem cells; Structure; Surface; Surface Antigens; Time; Tissues; Toxin; Transplantation; Veins; Yeasts; adult stem cell; antigen binding; cancer cell; cancer stem cell; day; design; embryo/fetus antigen; embryonic antigen; human tissue; injured; novel; pressure; satellite cell; stem cell therapy; tissue culture

Heart failure may occur from a variety of causes including ischemic heart disease, toxins, pressure or volume overload. Recovery of cardiac function is hindered by a long known observation that cardiac myocytes do not divide in appreciable numbers during adult life. Physiologic demands for increased cardiac output are met by hypertrophy of existing cardiac myocytes through the formation of additional sarcomeres (the unitary contractile apparatus) within these cells. At the present time, the only remedy for end stage heart failure is cardiac transplant, which is limited by the supply of matched hearts and complicated by the need to suppress immune rejection. We have discovered a previously unknown subpopulation of stem cells in adult murine skeletal muscle that can be transformed into beating cardiomyocytes under primary tissue culture conditions. These cells are not satellite cells, myofibroblasts or myoblasts. A portion of the freshly isolated stem cells, injected into the vein of a mouse with chronic heart failure, will home to the heart and progress along a pathway to cardiac cell differentiation. More recently, we have raised a monoclonal antibody to a cell surface antigen unique to another subset of these stem cells. This novel monoclonal in combination with another antibody (Sca 1), defines 3 populations from adult skeletal muscle, which, at the time of isolation are already committed to become either: (1) adipose, (2) neuronal, or (3) cardiac cells, when grown in culture under the same standard conditions. The novel antibody defines an antigen that is present on neuronal stem cells across species and which first appears in the mouse embryo on day 12.5, the first day that neurons can be observed. When the antibody is used to harvest cells from total day 12.5 mouse embryos, the harvested cells grow into neurons in cell culture containing only FGF as a growth factor. Thus, the antigen recognized by the monoclonal is an embryonic antigen present on neuronal stem cells across species. Immunoprecipitation and Mass-Spectroscopy have been used to to identify the antigen detected by the monoclonal antibody. The result has been corroborated through the use of the antibody against a panel of 17,000 human ESTs from human brain. We hope to obtain a peptide that binds the antigen which could be tagged for mouse and perhaps human nuclear studies. Recently, prompted by the frequency of inappropriate expression of fetal antigens in injured or cancerous tissue, we have determined that this antigen appears in a subset of brain, breast and kidney cancer. We have identified a cancer cell line that expresses the identified antigen on its surface and many lines in which the antigen is trapped within the cell in an internal structure called an "exocyst" This perinuclear structure is mostly unknown to cell biologists with the exception of those who study yeast. The exocyst sits next to Golgi bodies outside the nucleus and is responsible for processing proteins and membrane delived to the cell surface. We intend to explore its role in both stem cells and cancer over the next year.

心力衰竭可能来自多种原因，包括缺血性心脏病，毒素，压力或体积超负荷。悠久的观察结果阻碍了心脏功能的恢复，即心肌细胞在成人生活中不会有明显的数量分裂。通过在这些细胞中形成其他肉瘤（单一的收缩仪），现有心肌细胞的肥大来满足心脏输出增加的生理需求。目前，终末期心力衰竭的唯一补救措施是心脏移植，这受到匹配心脏的供应的限制，并因抑制免疫排斥的需要而变得复杂。我们已经发现了成年鼠骨骼肌中干细胞的先前未知的亚群，可以转化为在原发性组织培养条件下跳动的心肌细胞。这些细胞不是卫星细胞，肌纤维细胞或成肌细胞。新鲜分离的干细胞的一部分，注射到具有慢性心力衰竭的小鼠静脉中，将回到心脏，并沿着心脏细胞分化的途径进展。 最近，我们将单克隆抗体提高到了这些干细胞另一个子集特有的细胞表面抗原。 这种新型的单克隆与另一种抗体（SCA 1）结合使用，定义了成人骨骼肌的3个群体，在隔离时，该肌肉已经承诺​​成为：（1）脂肪，（2）神经元或（3）心脏细胞，在培养在相同的标准条件下在培养中生长。 新型抗体定义了一种跨物种神经元干细胞上存在的抗原，该抗体在第12.5天（可以观察到神经元的第一天）首次出现在小鼠胚胎中。 当使用抗体从总12.5小鼠胚胎中收获细胞时，收获的细胞在仅包含FGF作为生长因子的细胞培养中生长成神经元。 因此，单克隆识别的抗原是跨物种神经元干细胞上存在的胚胎抗原。 免疫沉淀和质谱镜检查已用于鉴定单克隆抗体检测到的抗原。 通过使用抗体对人类脑的17,000人EST的抗体使用，结果得到了证实。 我们希望获得一种结合抗原的肽，该抗原可以标记为小鼠甚至人类的核研究。 最近，是由于受伤或癌组织中胎儿抗原表达不当的频率，我们确定该抗原出现在大脑，乳腺癌和肾癌的一部分中。我们已经确定了一条癌细胞系在其表面上表达鉴定的抗原的癌细胞系，其中许多抗原被困在细胞内的线，以一种称为“胞外囊”的内部结构，这种核细胞结构在细胞生物学家中大多是未知的，除了研究酵母菌的那些人以外。 外囊肿位于核外的高尔基体旁边，负责处理细胞表面的蛋白质和膜。 我们打算在明年探索其在干细胞和癌症中的作用。