MYOCYTE STEM CELLS IN THE MAMMALIAN HEART

描述(改编自申请人的摘要)：本报告的目的 应用程序是为了证明心脏属于 自我更新的器官。假定心肌含有一个亚群 调节心脏生长的心肌细胞：单能的心肌干细胞和 放大细胞。单能的肌细胞干细胞的特征是 端粒酶的存在，而这种酶在扩增细胞中不存在。 来自干细胞的扩增细胞复制迅速，但经历了 专门化结构的渐进性端粒缩短和积累， 达到生长停滞和终末分化。端粒酶活性 在干细胞分裂过程中恢复端粒长度，尽管 这种酶随着年龄的增长而减少，导致端粒的侵蚀和细胞的凋亡 旧心脏的细胞死亡。IGF-1、c-myc和Bcl-2促进端粒酶活性 活动可能会增加干细胞的数量和寿命。IGF-1和 Bcl2通过发挥抗细胞凋亡作用，进一步扩大干细胞池的大小。 相反，转录因子P53和依赖于P53的基因，如Bax 和血管紧张素(Aogen)，对心肌细胞生长有相反的影响。这个 肿瘤抑制因子降低端粒酶活性并被血管紧张素Ⅱ激活， 其合成受到P53诱导的Aogen转录的刺激。这个 P53对端粒酶和细胞生长的负面影响也通过UP促进 Cdk抑制因子p21和促凋亡基因产物bax的调控。这个 癌蛋白p19ARF通过将MDM2隔离在 核仁水平。MDM2是一种p53诱导的基因，具有负反馈 通过产生失活的MDM2-P53复合体对P53产生抑制作用。IGF-1导致转录 从而减弱P53和AngII对心肌细胞内MDM2的影响 端粒酶活性。P16INK4通过增加P53介导的反应 P21的半衰期。此外，p16INK4在其低磷化状态下维持Rb 影响端粒酶活性和细胞生长的形式。这些多个调制器 端粒酶活性和干细胞功能的关系将从胎儿晚期开始分析 在心肌细胞中过表达IGF-1的转基因小鼠发生衰老。 两种性别都将作为年龄和极端条件下的函数进行研究。 心肌梗死引起的生长加速，因为女性心肌细胞 具有较高水平的IGF-1表达，并增强对 凋亡性死亡。雌性小鼠预计会有更多的端粒酶 在生理和生理条件下，有能力的细胞和更大的潜力或肌细胞生长 病理性刺激。

DESCRIPTION (Adapted from Applicant's abstract): The objective of this application is to demonstrate that the heart belongs to the group of self-renewing organs. The myocardium is postulated to contain a subgroup of cardiomyocytes which regulate cardiac growth: unipotent myocyte stem cells and amplifying cells. Unipotent myocyte stem cells are characterized by the presence of telomerase, while this enzyme is absent in amplifying cells. Amplifying cells, which derive from stem cells, replicate rapidly but undergo progressive telomeric shortening and accumulation of specialized structures, reaching growth arrest and terminal differentiation. Telomerase activity restores telomeric length during stem cell division, although the function of this enzyme decreases with age leading to erosion of telomeres and apoptotic cell death in the old heart. IGF-1, c-myc, and Bcl-2 enhance telomerase activity possibly increasing the stem cell number and their lifespan. IGF-1 and Bcl-2 further expand the stem pool size by exerting antiapoptotic effects. Conversely, the transcription factor p53 and p53 dependent genes, such as Bax and angiotensin (Aogen), have opposite consequences on myocyte growth. The tumor suppressor decreases telomerase activity and is activated by Ang II, whose synthesis is stimulated by p53-induced transcription of Aogen. The negative influence of p53 on telomerase and cell growth is also promoted via up regulation of the cdk inhibitorp21 and the proapoptotic gene product Bax. The oncoprotein p19ARF increases p53 stability and quantity by sequestering Mdm2 at the nucleolar level. Mdm2 is a p53-inducible gene that has a negative feedback on p53 by generating inactive Mdm2-p53 complexes. IGF-1 leads to transcription of Mdm2 in myocytes and, thereby, attenuates the impact of p53 and AngII on telomerase activity. P16INK4 favors p53-mediated responses by increasing the half-life of p21. Additionally, p16INK4 maintains RB in its hypophosphorylated form affecting telomerase activity and cell growth. These multiple modulators of telomerase activity and stem cell function will be analyzed from late fetal development to senescence in transgenic mice overexpressing IGF-1 in myocytes. Both genders will be studed as a function of age and under extreme conditions of accelerated growth produced by myocardial infarction, since female myocytes possess higher level of expression of IGF-1 and improved resistance to apoptotic death. Female mice are expected to have a larger number of telomerase competent cells and greater potential or myocyte growth under physiologic and pathologic stimuli.