Bone Marrow and Cardiac Progenitor Cells in Cardiac Repair

描述（由申请人提供）：尽管几个实验室已经鉴定出心脏祖细胞（CPC），但关于成人心脏中肌细胞再生的争议尚未解决。同样，骨髓源祖细胞（BMPC）的可塑性及其获得肌细胞谱系和再生死亡心肌的能力也受到了挑战。因此，本申请的主要目的之一是通过涉及遗传标记和克隆标记的新方法来确定c-kit阳性BMPC和CPC是否获得心脏表型并产生大量肌细胞定向子代。这两类祖细胞对急性和慢性缺血性心力衰竭的治疗功效取决于它们的能力（a）在受损心脏的不利环境中存活，（B）在心肌内移植，和（c）生长和分化。BMPC可能具有上级于CPC的生长潜力，但转分化可能影响这一特性，CPC可能构成心脏修复的更强大的治疗形式。转分化过程可能改变BMPC的生长行为，其可能通过端粒-端粒酶系统的改变、细胞过早衰老和凋亡而部分丧失其分裂能力。类似地，来自BMPC的肌细胞在获得成人表型方面可能具有固有的局限性。相反的情况也可能是正确的，即使在转分化后，BMPC也可能保留比代表受损心脏最合适细胞的CPC更强的再生能力。对于BMPC，新形成的肌细胞似乎具有胎儿-新生儿特性，可能无法达到成人表型，这是一个可能不会影响CPC定型的问题。在1边缘和梗死的相对缺氧可以调节Notch通路，延长的Notch激活可以抑制Nkx2.5的下调，从而抑制从早期到晚期的心肌细胞分化的过渡。Notch可能抑制GATA 4的转录，这可能是不可逆的心肌细胞承诺的关键。这种行为符合分化延迟的模型，其中Notch的持续存在反对成熟的进展。最终，所提出的工作解决的问题是否BMPC是上级，平等，或低于CPC的心肌细胞和冠状动脉血管再生缺血性心力衰竭。

DESCRIPTION (provided by applicant): Although several laboratories have identified cardiac progenitor cells (CPCs), the controversy concerning myocyte regeneration in the adult heart has not been resolved. Similarly, the plasticity of bone marrow derived progenitor cells (BMPCs) and their ability to acquire the myocyte lineage and regenerate dead myocardium has been challenged. Therefore, one of the major objectives of this application is to determine by a novel approach that involves genetic tagging and clonal marking, whether c-kit-positive BMPCs and CPCs acquire a cardiac phenotype and give rise to a large number of myocyte-committed progeny. The therapeutic efficacy of these two classes of progenitor cells for acute and chronic ischemic heart failure depends on their ability (a) to survive in the hostile milieu of the damaged heart, (b) to engraft within the myocardium, and (c) to grow and differentiate. BMPCs may have a growth potential, which is superior to CPCs but transdifferentiation could affect this characteristic and CPCs may constitute a more powerful form of therapy for cardiac repair. The process of transdifferentiation may alter the growth behavior of BMPCs, which may lose in part their capability of dividing through alterations of the telomere-telomerase system, premature cellular senescence, and apoptosis. Similarly, myocytes derived from BMPCs may possess inherent limitations in the acquisition of the adult phenotype. The opposite may also be true and BMPCs may retain even after transdifferentiation a stronger regenerative capacity than CPCs representing the most appropriate cells for the damaged heart. With BMPCs, the newly formed myocytes appear to have fetal- neonatal properties and may not reach the adult phenotype, a problem that may not affect the commitment of CPCs. Relative hypoxia at the1 border and infarct may modulate the Notch pathway, and prolonged Notch activation may inhibit downregulation of Nkx2.5 and, thereby, the transition from early to late myocyte differentiation. Notch may repress transcription of GATA4, which could be critical for irreversible myocyte commitment. This behavior conforms to a model of differentiation delay in which the persistence of Notch opposes the progression of maturation. Ultimately, the proposed work addresses the question whether BMPCs are superior, equal, or inferior to CPCs for the regeneration of cardiomyocytes and coronary vessels in ischemic heart failure.