Bone Marrow and Cardiac Progenitor Cells in Cardiac Repair

描述(申请人提供)：尽管几个实验室已经鉴定出心脏前体细胞，但关于成人心脏中心肌细胞再生的争议还没有解决。同样，骨髓来源的祖细胞的可塑性及其获得心肌细胞谱系和再生死亡心肌的能力也受到了挑战。因此，这一应用的主要目的之一是通过一种包括遗传标记和克隆标记的新方法来确定c-kit阳性的BMPC和CPC是否获得心脏表型并产生大量心肌细胞承诺的后代。这两类祖细胞对急性和慢性缺血性心力衰竭的治疗效果取决于它们(A)在受损心脏的恶劣环境中存活的能力，(B)移植到心肌内的能力，以及(C)生长和分化的能力。骨髓基质细胞可能具有生长潜力，优于干细胞，但转分化可能影响这一特性，干细胞可能构成一种更有效的心脏修复治疗形式。转分化的过程可能会改变BMPC的生长行为，可能会通过端粒-端粒酶系统的改变、细胞过早衰老和细胞凋亡来部分丧失其分裂能力。类似地，来源于骨髓基质细胞的肌细胞在获得成体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也可能保持比代表受损心脏最合适细胞的CPC更强的再生能力。对于骨髓基质细胞，新形成的心肌细胞似乎具有胎儿-新生儿的特性，可能无法达到成体表型，这一问题可能不会影响CPC的承诺。1交界处和梗死区的相对低氧可能会调节Notch通路，而持续的Notch激活可能会抑制NKX2.5的下调，从而抑制从早期到晚期的心肌细胞分化。Notch可能抑制GATA4的转录，这可能是不可逆转的心肌细胞承诺的关键。这一行为符合分化延迟模型，在该模型中，Notch的持久性与成熟的进程相反。最终，这项拟议的工作解决了以下问题：在缺血性心力衰竭中，在心肌细胞和冠状动脉再生方面，骨髓基质细胞是否优于、等于或低于细胞。

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.