Modulation of aged hematopoietic stem cell niches

描述（由申请人提供）：造血系统的老化导致发生细胞减少、骨髓增生异常综合征（MDS）、骨髓增生性疾病和白血病的风险增加。Calvi实验室和其他人已经证明了成骨细胞谱系在正常造血干细胞和祖细胞（HSPC）调节中的核心作用，成骨细胞谱系是骨髓微环境的关键组成部分。衰老改变了小鼠模型和人类的HSPCs，减少了它们的静止性和重建骨髓的能力，并且被认为对整个造血系统的衰老起重要作用。数据开始支持老化微环境对HSPC老化的作用。然而，这在人类中还没有被描述过，并且尚不清楚刺激生态位是否会逆转或减轻衰老的影响。我们最近证明了两种刺激骨髓微环境的药物（甲状旁腺激素和前列腺素E2）迅速增加HSPC的静止并刺激体内HSC生态位。基于这些结果，我们假设生态位的老化有助于HSPC功能障碍，这些变化可以通过生态位刺激来修复。在本应用中，我们提出了一种高度整合和转化的方法，我们将使用年轻和老年人类样本和小鼠实验以及2种MDS小鼠模型来验证我们的中心假设，并确定使用先前证明通过微环境刺激增加hsc的治疗方法是否可以修复生态位和/或HSPCs的年龄依赖性变化。在这个项目中，我们将确定1)HSPCs是否会在衰老环境中由于衰老生态位而变得功能失调，以及2)生态位细胞在以下情况下的靶向调节

DESCRIPTION (provided by applicant): Aging of the hematopoietic system results in an increased risk of developing cytopenias, Myelodysplastic syndromes (MDS), myeloproliferative disorders and leukemias. The Calvi laboratory and others have demonstrated the central role of osteoblastic lineage cells, a critical component of the marrow microenvironment, in normal hematopoietic stem and progenitor cell (HSPC) regulation. Aging changes HSPCs in both murine models and humans, decreasing their quiescence and their ability to reconstitute the marrow, and is thought to contribute importantly to aging of the whole hematopoietic system. Data are beginning to emerge supporting a role of the aging microenvironment on HSPC aging. However, this has not been described in humans, and it is unknown whether stimulation of the niche will reverse or mitigate the effects of aging. We have recently demonstrated that 2 pharmacologic agents which stimulate the marrow microenvironment (Parathyroid hormone and Prostaglandin E2) rapidly increase HSPC quiescence and stimulate the HSC niche in vivo. Based on these results, we hypothesize that aging of the niche contributes to HSPC dysfunction and that these changes can be remediated by niche stimulation. In this application, we propose a highly integrated and translational approach in which we will use young and aged human samples and murine experiments as well as 2 murine models of MDS to verify our central hypothesis and determine if use of treatments previously demonstrated to increase HSCs through microenvironmental stimulation can remediate age-dependent changes in the niche and /or in HSPCs. In this project we will determine if 1) HSPCs become dysfunctional in the setting of aging as a result of the aging niche and 2) targeted modulation of niche cells in the context of aging can improve HSPC support and prevent progression to MDS-related bone marrow failure. Completion of these aims will elucidate a novel therapeutic strategy to reverse marrow failure and susceptibility to leukemia in older adults.