Cardiomyogenesis in the Adult Heart

描述（由申请人提供）：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（hsc）有助于心肌形成。尽管CSCs不对称分裂能够自我更新并形成特化的后代，但该干细胞室是否完全独立于hsc库调节心脏稳态仍然存在争议。为了解决这一生物学问题，我们将采用骨髓移植和异种共生模型来定量地确定造血干细胞和间充质干细胞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，干细胞是否都来自心脏，或者造血干细胞是从骨髓迁移到心肌壁龛，在那里它们获得新的身份，参与这些原始细胞的周转

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.