Regulation of HSC self-renewal by morphogens

描述（由申请人提供）：造血是通过多能造血干细胞（HSC）自我更新和分化的精细调控而发生的。这发生在一个复杂的微环境中，许多因素在造血调节中发挥可能的作用。确定造血干细胞自我更新的调节因子对于临床应用尤其重要，涉及造血干细胞的体内和体外扩增，如造血干细胞移植。这一应用是基于最近对形态因子，特别是Notch家族成员和维生素A受体（RARs）在造血中的作用的新发现。Notchl被很好地描述为HSC自我更新的监管者。我们最近的研究表明，维生素A衍生物全反式维甲酸（ATRA）增强了小鼠造血干细胞的自我更新，而RAR γ信号对这些作用至关重要。我们还发现RAR γ显著影响Notchl的表达，表明这些形态因子之间存在联系。有趣的是，形态因子也调节骨细胞的形成，包括成骨细胞，最近被描述为HSC生态位的关键组成部分；因此，形态因子也可能调节造血干细胞的生态位。本应用旨在进一步探索形态因子在调节HSC自我更新中的相互作用，无论是在孤立的HSC生态位中，还是在与HSC生态位相关的环境中。我们将在这些研究中使用小鼠模型，结合体外细胞和分子生物学技术来确定形态因子之间的相互作用及其对造血干细胞的影响。将进行体内移植研究，以评估这些形态因子对HSC自我更新的影响。因此，该项目的目的是：1)研究已知的独立于HSC生态位调节HSC的形态因子之间的相互作用。2)以上下文依赖的方式确定形态因子对HSC生态位的影响。Lay：近年来，人们一直希望增加能够产生所有血细胞的干细胞的数量，以用于治疗目的，如改善干细胞移植。之前在体外和体内增加这些细胞数量的尝试都不太成功。我们的数据表明，维生素a化合物可能对改善这两种方法都非常有用。

DESCRIPTION (provided by applicant): Hematopoiesis occurs through the fine regulation of self-renewal and differentiation of the pluripotent hematopoietic stem cell (HSC). This occurs in a complex microenvironment, with many factors playing possible roles in the regulation of hematopoiesis. The identification of regulators of HSC self-renewal is especially important for clinical applications involving in vivo and ex vivo expansion of HSCs for purposes such as HSC transplantation. This application is based on recent novel discoveries of the roles of morphogens, in particular members of the Notch family and vitamin A receptors (RARs), in hematopoiesis. Notchl has been well described as being a regulator of HSC self-renewal. We have recently shown that the vitamin A derivative, all-trans retinoic acid (ATRA) enhances the self-renewal of murine HSCs, and that RAR gamma signaling is critical for these effects. We have also shown that RAR gamma significantly impacts on Notchl expression, indicating a link between these morphogens. Interestingly, morphogens also regulate the formation of bone cells, including osteoblasts, which have recently been described as being a key component in the HSC niche; hence morphogens also potentially regulate the HSC niche. This application aims to further explore interactions of morphogens in regulating HSC self-renewal both in isolation of the HSC niche and in a context-dependent manner with respect to the HSC niche. We will use the mouse model in these studies, combining in vitro cellular and molecular biology techniques to determine the interactions between morphogens and their effects on HSCs. In vivo transplant studies will be performed to assess the effects of these morphogens on HSC self-renewal. The aims of this project are therefore to: 1) investigate the interactions between morphogens known to regulate HSCs independent of the HSC niche. 2) determine the impact of morphogens on the HSC niche in a context-dependent manner. Lay: In recent years, there has been a desire to increase the numbers of stem cells that are capable of producing all blood cells for therapeutic purposes such as improving stem cell transplants. Previous attempts to increase the numbers of these cells both outside of and within the body have not been very successful. Our data suggest that a vitamin A compound may be very useful in improving both of these approaches.