Regulation of HSC self-renewal by morphogens

描述（由申请人提供）：造血通过多能造血干细胞（HSC）自我更新和分化的精细调节发生。这发生在复杂的微环境中，许多因素在造血的调节中发挥可能的作用。鉴定HSC自我更新的调节剂对于涉及HSC的体内和离体扩增的临床应用尤其重要，所述HSC的体内和离体扩增用于诸如HSC移植的目的。本申请基于最近对形态发生素，特别是Notch家族成员和维生素A受体（RAR）在造血中的作用的新发现。Notchl被很好地描述为HSC自我更新的调节剂。我们最近发现，维生素A衍生物，全反式维甲酸（ATRA）增强了小鼠HSC的自我更新，RAR γ信号传导对这些作用至关重要。我们还表明RAR γ显著影响Notchl表达，表明这些形态发生剂之间的联系。有趣的是，形态发生素也调节骨细胞的形成，包括成骨细胞，其最近被描述为HSC生态位中的关键组分;因此形态发生素也可能调节HSC生态位。本申请旨在进一步探索形态发生素在调节HSC自我更新中的相互作用，既在HSC生态位的隔离中，又在HSC生态位的背景依赖性方式中。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发生素之间的相互作用及其对HSC的影响。将进行体内移植研究以评估这些形态发生剂对HSC自我更新的影响。因此，本项目的目的是：1）研究已知独立于HSC生态位调节HSC的形态发生素之间的相互作用。2)以上下文依赖的方式确定形态发生素对HSC生态位的影响。铺设：近年来，人们希望增加能够产生用于治疗目的的所有血细胞的干细胞的数量，例如改善干细胞移植。以前试图增加这些细胞在体外和体内的数量的尝试都不是很成功。我们的数据表明，维生素A化合物可能对改善这两种方法非常有用。

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.