MYOCYTE STEM CELLS IN THE MAMMALIAN HEART

描述（改编自申请人的摘要）：本申请的目的 应用是为了证明心脏属于 自我更新的器官心肌被假定包含一个亚组， 调节心脏生长的心肌细胞：单能肌细胞干细胞和 放大细胞单能肌细胞干细胞的特征在于： 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， 进行性端粒缩短和特化结构的积累， 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凋亡。 衰老心脏中的细胞死亡IGF-1、c-myc和Bcl-2增强端粒酶活性 活性可能增加干细胞数量和它们的寿命。IGF-1和 Bcl-2通过发挥抗凋亡作用进一步扩大干细胞池的大小。 相反，转录因子p53和p53依赖性基因，如Bax， 和血管紧张素（Aogen）对肌细胞生长具有相反的结果。的 肿瘤抑制因子降低端粒酶活性并被Ang II激活， 其合成受到p53诱导的Aogen转录的刺激。的 p53对端粒酶和细胞生长的负面影响也通过up-regulated 调节cdk受体p21和促凋亡基因产物Bax。的 癌蛋白p19 ARF通过在一定浓度下隔离Mdm 2而增加p53的稳定性和数量。 核仁水平。mdm 2是一个p53诱导的基因，具有负反馈作用， 通过产生无活性的Mdm 2-p53复合物来抑制p53。IGF-1导致转录 Mdm 2在心肌细胞中的表达，从而减弱p53和AngII对 端粒酶活性P16 INK 4通过增加细胞内的蛋白质水平而有利于p53介导的应答。 P21的半衰期。此外，p16 INK 4维持RB的低磷酸化， 影响端粒酶活性和细胞生长。这些多个调制器 端粒酶活性和干细胞功能的分析将从晚期胎儿 在肌细胞中过表达IGF-1的转基因小鼠中发育至衰老。 两性都将作为年龄和极端条件下的函数进行研究 心肌梗死引起的加速生长，因为女性心肌细胞 具有更高水平的IGF-1表达和改善的对 凋亡性死亡预计雌性小鼠的端粒酶数量更多 在生理和生理条件下， 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.