The endoplasmic reticulum as a determinant of hematopoietic niche homeostasis

内质网作为造血生态位稳态的决定因素

• 批准号: 507292932
• 负责人: Professor Dr. Robert A.J. Oostendorp
• 金额: --
• 依托单位: Klinik und Poliklinik für Innere Medizin III: Hämatologie und Onkologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/507292932?language=en
• 关键词: endoplasmic; reticulum; determinant; hematopoietic; niche

Hematopoietic stem cells (HSCs) produce all blood cell lineages in response to stressors. The bone marrow (BM) microenvironment (also called: the BM niche) maintains this multilineage repopulation (LTR) ability of HSCs for the life time of the organism. It is known that in chronic stress (infections or inflammation) and in aging, the LTR ability (LTR) of HSCs is strongly reduced. However, it remains largely unclear how outside signals from the BM niche trigger and maintain LTR ability and self-renewal of HSCs. We have established mouse models in which specific primary changes in the BM niche cause secondary reduction of LTRA in HSCs. In the mouse strain we will be using, we deleted the Sfrp1 gene in Osterix-expressing osteoprogenitor cells (OS1Del/Del mice). In this project, we will study how the changes in BM niche cells from these mice change their communication with HSCs and their ability to maintain the LTRA of these cells.Our preliminary data from the transcriptome of OS1Del/Del mice shows deregulation of endoplasmic proteostasis in sorted osteoprogenitors. Further validation studies confirmed downregulation of proteostatic factors at the protein level, and a strong reduction of protein degradation in BM niche cells from OS1Del/Del mice. Proteostasis is a critical cellular maintenance process, not only for removing misfolded proteins, but also for sorting of proteins for secretion to the extracellular space. As such, endoplasmic proteostasis would be a determining factor in regulating communication between BM niche cells and HSCs. In this project we will further investigate endoplasmic proteostasis in BM niche cells, as well as identify critical mediators in both the endoplasmic proteostatic process and in the secretome. Furthermore, we will treat OS1Del/Del mice with the aim to restore endoplasmic proteostasis in the BM niche and to improve the LTR ability of HSCs. A long-term goal of these experiments is to identify niche-directed strategies to prevent exhaustion of HSCs with LTR ability in chronic stress (infections or inflammation) and in aging.

造血干细胞（HSC）产生所有的血细胞谱系响应压力。骨髓（BM）微环境（也称为：BM生态位）在生物体的生命周期内维持HSC的这种多谱系再增殖（LTR）能力。已知在慢性应激（感染或炎症）和衰老中，HSC的LTR能力（LTR）强烈降低。然而，目前尚不清楚来自骨髓小生境的外部信号如何触发和维持HSC的LTR能力和自我更新。我们已经建立了小鼠模型，其中BM生态位的特定原发性变化导致HSC中LTRA的继发性减少。在我们将使用的小鼠品系中，我们删除了表达Osterix的骨祖细胞（OS 1Del/Del小鼠）中的Sfrp 1基因。在这个项目中，我们将研究这些小鼠的BM龛细胞的变化如何改变它们与HSC的通讯以及它们维持这些细胞的LTRA的能力。我们来自OS 1Del/Del小鼠的转录组的初步数据显示，在分选的骨祖细胞中，内质网蛋白稳态失调。进一步的验证研究证实了蛋白质水平的蛋白质抑制因子下调，以及来自OS 1Del/Del小鼠的BM小生境细胞中蛋白质降解的强烈减少。蛋白质稳态是关键的细胞维持过程，不仅用于去除错误折叠的蛋白质，而且用于分选蛋白质以分泌到细胞外空间。因此，内质网蛋白质稳态将是调节BM龛细胞和HSC之间通讯的决定因素。在这个项目中，我们将进一步研究在BM龛细胞的内质网蛋白质稳态，以及确定在内质网蛋白质稳态过程和分泌组的关键介质。此外，我们将治疗OS 1Del/Del小鼠，目的是恢复BM龛中的内质网蛋白质稳态，并提高HSC的LTR能力。这些实验的长期目标是确定利基导向的策略，以防止在慢性应激（感染或炎症）和衰老中具有LTR能力的HSC耗尽。