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.
Hematopoietic stem cells, HSCs, are at the apex of the hematopoietic hierarchy and their ability to maintain blood cell production is in part regulated through interactions with the surrounding bone marrow microenvironment, BME, or niche. Hematopoietic aging is manifested in impaired blood cell production, increased risk of infection, bleeding and the need for transfusions and it also results in increased risk of leukemia. In this application we propose to study how aging changes the interactions of the niche with HSCs. We have previously defined component of the niche which we can stimulate with therapies already available for the treatments of bone disorders in aged patients. Therefore we plan to also determine if these therapies will decrease the effects of hematopoietic aging and alter the risk of progression to MDS-related bone marrow failure. These studies will be performed in both human samples as well as mouse models of MDS, making our effort readily translatable to the clinic.
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