Regulation of HSC self-renewal by morphogens

描述(申请人提供)：造血通过对多能造血干细胞(HSC)自我更新和分化的精细调节而发生。这发生在一个复杂的微环境中，许多因素可能在造血调控中发挥作用。HSC自我更新调节因子的识别对于HSC体内和体外扩增的临床应用尤其重要，例如HSC移植。这一应用是基于最近对形态原，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自我更新的调节者。我们最近发现维生素A的衍生物全反式维甲酸(ATRA)可以促进小鼠HSCs的自我更新，而RAR伽马信号在这些作用中起关键作用。我们还表明，RAR伽马显著影响Notchl的表达，表明这些形态原之间存在联系。有趣的是，形态原还调节骨细胞的形成，包括成骨细胞，成骨细胞最近被描述为HSC生态位的关键组成部分；因此，形态原也潜在地调节HSC生态位。这项应用旨在进一步探索形态因子在调节HSC自我更新方面的相互作用，既独立于HSC生态位，又以与HSC生态位相关的上下文依赖的方式。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HSCs的影响。将进行体内移植研究，以评估这些形态原对HSC自我更新的影响。因此，该项目的目的是：1)研究已知的调控HSC的形态原之间的相互作用，而不依赖于HSC的生态位。2)以上下文相关的方式确定形态因素对HSC生态位的影响。Lay：近年来，人们一直希望增加干细胞的数量，这些干细胞能够产生所有的血细胞，用于治疗目的，如改善干细胞移植。以前增加体内和体外这些细胞数量的尝试都不是很成功。我们的数据表明，维生素A化合物在改善这两种方法方面可能非常有用。

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.