Cardiomyogenesis in the Adult Heart

描述（由申请人提供）：需要解决的一个重要问题涉及成人心脏中的肌细胞再生是否仅由驻留的c-kit阳性心脏干细胞（CSC）的激活和定型控制，或者来自骨髓的循环造血干细胞（HSC）是否有助于心肌发生。虽然CSC不对称分裂能够自我更新并形成特化后代，但这种干细胞区室在调节心脏稳态方面是否完全独立于HSC库仍然存在争议。为了解决这一生物学问题，将采用骨髓移植和联体共生模型来定量地建立HSC和CSC在成年期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，小生境中的干细胞是否都是心脏起源的，或者HSC是否从骨髓迁移到心肌小生境，在那里它们获得新的身份，参与这些原始细胞的周转。 微环境中的细胞。如果是这种情况，HSC将参与心脏干细胞库的保存，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Ca 2+的振荡，细胞周期的进入，不对称分裂，和核穿梭的心肌细胞转录因子Nkx2.5被假定为调节的CSC和HSC的谱系特化为心肌细胞。最终，HSC转分化的分子机制将被确定，骨髓在心肌发生中的参与将被仔细定义。

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.