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University of Rochester

1. Hoffman, Corey M. The Bone Marrow Microenvironment in the Setting of Acute Injury and Aging.

Degree: PhD, 2020, University of Rochester

Hematopoietic stem cells (HSCs) are positioned at the apex of hematopoiesis and are regulated by their bone marrow microenvironment or niche. Due to this, HSCs are used clinically as a curative therapy for hematopoietic diseases. Recent work has aimed to activate the niche as a means to therapeutically enhance the outcome of bone marrow transplants, but also to stimulate endogenous hematopoiesis as an alternative. Activation of the niche with increased support for HSC function could mitigate damage from radiation injury or promote hematopoiesis in older individuals who are not candidates for bone marrow transplants. While hematopoietic injury is a major cause of morbidity and mortality following radiation, the role of the HSC niche in hematopoietic and HSC recovery after radiation is poorly understood. We sought to investigate niche engagement at acute time points (24 and 48 hours) after sub-lethal (6.5Gy) total body irradiation (TBI). This assessment included characterizing the endogenous response of the niche to ionizing radiation, and the niche in response to both injury and a mitigating agent. We used the mitigating agent 16, 16-dimethyl Prostaglandin E2 (dmPGE2), 24 hours after injury and subsequently quantified changes in the niche 48 post 6.5Gy injury. Previous work has shown pharmacologic treatment with dmPGE2 in mice accelerates hematopoietic recovery and survival after radiation injury. After injury, multiple niche populations including osteoblasts, mesenchymal stem cells, and endothelial are still present in the marrow. dmPGE2 appears to preferentially act on the bone marrow vasculature in the setting of injury, as only irradiated and treated animals had expanded sinusoidal endothelial cells. This work suggests that dmPGE2 acts on endothelial cells and may promote survival by maintaining vascular integrity. The aging process represents its own challenge in the hematopoietic system resulting from continuous proliferation of HSCs over the duration of an organism’s lifetime, rather than rapid proliferation in a short period of time following TBI. Aging can result in bone marrow failure, anemia, infection, and pathological hematopoiesis. Another hallmark of an aged marrow is myeloid skewing, with lesser support towards lymphopoiesis. In aged animals we find that macrophages are expanded, and appear to contribute to aging of the hematopoietic system through an inflammatory phenotype. Aged macrophages have increased expression of the inflammatory cytokine Interleukin-1β, which negatively regulate normal hematopoiesis. Functionally, aged macrophages have reduced capacity to clear dead/dying cells, which in turn contributes another source of inflammation to the aged marrow. We believe these changes lead to a functionally aged marrow which favors an expanded phenotypic stem-cell pool and myeloid skewing; two hallmarks of the aged hematopoietic system. Overall, these studies highlight the critical role of specific niche populations in the setting of recovery from injury and aging. Since HSCs are therapeutically…

Subjects/Keywords: HSC; Aging; Efferocytosis; PGE2

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Hoffman, C. M. (2020). The Bone Marrow Microenvironment in the Setting of Acute Injury and Aging. (Doctoral Dissertation). University of Rochester. Retrieved from http://hdl.handle.net/1802/35491

Chicago Manual of Style (16th Edition):

Hoffman, Corey M. “The Bone Marrow Microenvironment in the Setting of Acute Injury and Aging.” 2020. Doctoral Dissertation, University of Rochester. Accessed April 09, 2020. http://hdl.handle.net/1802/35491.

MLA Handbook (7th Edition):

Hoffman, Corey M. “The Bone Marrow Microenvironment in the Setting of Acute Injury and Aging.” 2020. Web. 09 Apr 2020.

Vancouver:

Hoffman CM. The Bone Marrow Microenvironment in the Setting of Acute Injury and Aging. [Internet] [Doctoral dissertation]. University of Rochester; 2020. [cited 2020 Apr 09]. Available from: http://hdl.handle.net/1802/35491.

Council of Science Editors:

Hoffman CM. The Bone Marrow Microenvironment in the Setting of Acute Injury and Aging. [Doctoral Dissertation]. University of Rochester; 2020. Available from: http://hdl.handle.net/1802/35491

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