Regulation of HSC self-renewal by morphogens

形态发生素对 HSC 自我更新的调节

• 批准号: 7097003
• 负责人: LOUISE E PURTON
• 金额: $ 25.16万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-15 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7097003
• 关键词: all trans retinol; cell communication molecule; cell population study; hematopoiesis; hematopoietic stem cells; laboratory mouse; retinoid binding proteins; tissue /cell culture

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.

描述（申请人提供）：造血是通过多能造血干细胞（HSC）的自我更新和分化的精细调节而发生的。这是在复杂的微环境中发生的，许多因素可能在造血调节中发挥作用。 HSC 自我更新调节因子的鉴定对于涉及 HSC 体内和离体扩增（例如 HSC 移植）的临床应用尤其重要。该应用基于最近关于形态发生素（尤其是 Notch 家族成员和维生素 A 受体 (RAR)）在造血作用中作用的新发现。 Notch1 已被充分描述为 HSC 自我更新的调节剂。我们最近发现，维生素 A 衍生物全反式视黄酸 (ATRA) 可以增强小鼠 HSC 的自我更新，而 RAR 伽马信号传导对于这些作用至关重要。我们还表明 RAR gamma 对 Notch1 表达有显着影响，表明这些形态发生素之间存在联系。有趣的是，形态发生素还调节骨细胞的形成，包括成骨细胞，最近被描述为造血干细胞生态位的关键组成部分。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 自我更新方面的相互作用，无论是在 HSC 生态位的隔离中，还是以与 HSC 生态位相关的环境依赖性方式。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素对 HSC 自我更新的影响。因此，该项目的目标是：1) 研究已知可独立于 HSC 生态位调节 HSC 的形态发生素之间的相互作用。 2) 以上下文相关的方式确定形态发生素对 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数量，用于治疗目的，例如改善干细胞移植。之前尝试增加体内和体外这些细胞的数量并没有取得很大成功。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。