Cardiomyogenesis in the Adult Heart

描述(申请人提供)：一个需要解决的重要问题是，成人心脏中的心肌细胞再生是否完全由常驻的c-kit阳性心脏干细胞(CSCs)的激活和承诺控制，还是来自骨髓的循环造血干细胞(HSCs)有助于心肌生成。尽管CSCs可以不对称地分裂，能够自我更新并形成一个专门的后代，但这个干细胞室是否在调节心脏内稳态方面完全独立于HSCs池仍然存在争议。为了解决这一生物学问题，我们将利用骨髓移植和异种共生模型来定量地确定HSCs和CSCs在成年期心肌细胞更新和缺血性心肌损伤后组织再生中的相对作用。另一个补充问题是，壁龛中的干细胞是否都来自心脏，或者造血干细胞从骨髓迁移到心肌壁龛，在那里它们获得了新的身份，参与了这些原始细胞的更替。 细胞在其微环境中。如果是这样的话，造血干细胞将参与保存心脏中的干细胞库，这构成了整个生命过程中心肌的生长储备。一个共同的机制涉及细胞内钙离子振荡，细胞周期进入，不对称分裂，以及心肌细胞转录因子NKX2.5的核穿梭，被认为调节CSCs和HSCs向心肌细胞的谱系特征。最终，将确定HSC转分化的分子机制，并仔细定义骨髓在心肌发生中的参与。

DESCRIPTION (provided by applicant): An important issue in need of resolution concerns whether myocyte regeneration in the adult heart is controlled exclusively by activation and commitment of resident c-kit-positive cardiac stem cells (CSCs), or circulating hematopoietic stem cells (HSCs) from the bone marrow contribute to cardiomyogenesis. Although CSCs divide asymmetrically being able to self-renew and form a specialized progeny, whether this stem cell compartment is fully independent from the pool of HSCs in regulating cardiac homeostasis remains controversial. In an attempt to resolve this biological problem, bone marrow transplantation and a model of parabiosis will be employed to establish quantitatively the relative role of HSCs and CSCs in myocyte renewal in adulthood and in tissue regeneration following ischemic myocardial injury. An additional complementary question is whether stem cells in the niches are all of cardiac origin or HSCs migrate from the bone marrow to the myocardial niches where they attain a new identity participating in the turnover of these primitive cells in their microenvironment. If this were the case, HSCs would be involved in the preservation of the stem cell pool in the heart, which constitutes the growth reserve of the myocardium throughout the course of life. A common mechanism involving oscillations in intracellular Ca2+, cell cycle entry, asymmetric division, and nuclear shuttling of the myocyte transcription factor Nkx2.5 is postulated to regulate the lineage specification of CSCs and HSCs into cardiomyocytes. Ultimately, the molecular mechanisms of HSC transdifferentiation will be identified and the involvement of the bone marrow in cardiomyogenesis carefully defined.