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展为细胞减少症、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实验室和其他实验室已经证明了成骨细胞系细胞在正常的造血干细胞和祖细胞(HSPC)调节中的中心作用，成骨细胞系细胞是骨髓微环境的关键组成部分。衰老改变了小鼠和人类模型中的HSPC，减少了它们的静止状态和重建骨髓的能力，并被认为对整个造血系统的衰老起着重要作用。开始出现的数据支持老化微环境在HSPC老化中的作用。然而，这在人类中还没有得到描述，也不知道刺激利基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E_2)在体内迅速增加HSPC的静止和刺激HSC的生态位。基于这些结果，我们假设生态位的老化有助于HSPC功能障碍，并且这些变化可以通过生态位刺激来补救。在这一应用中，我们提出了一种高度整合和翻译的方法，其中我们将使用年轻和老年人类样本和小鼠实验以及2个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补救利基和/或HSPC中与年龄相关的变化。在这个项目中，我们将确定1)HSPC是否由于老化的生态位而在衰老的环境中变得功能失调，以及2)在 衰老可以改善HSPC的支持，防止进展为MDS相关的骨髓衰竭。完成这些目标将阐明一种新的治疗策略，以逆转老年人的骨髓衰竭和白血病易感性。

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.