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Title: | Characterization of cellular dynamics during bone marrow regeneration in normal and leukemic states |
Authors: | Zhao, Xueli |
Advisor: | Bhatia, Mick |
Department: | Biochemistry and Biomedical Sciences |
Publication Date: | 2023 |
Abstract: | Bone marrow (BM) regeneration is needed to overcome myelosuppression during cancer therapy-induced injury to maximize the dose and effectiveness of tumor targeting therapy. Damage to the BM includes radiation and chemotherapy in the clinical setting, as well as transformation of the hematopoietic tissue to cancerous states such as acute myeloid leukemia (AML). Here studies of the hematopoietic cells of the BM were initiated using single cell RNA sequencing resolution and revealed that the endurance and maintenance of BM macrophages correlated to regeneration of healthy BM and in vivo recovery post injury induced by whole body irradiation or chemotherapy similar to that in the treatment of AML patients. Based on this correlation to regeneration, detailed cellular characterization of these BM macrophages demonstrated that their involvement in hematopoietic regeneration was associated by iron cycling through erythrophagocytosis and BM erythroblastic island development. However, in contrast to healthy BM regeneration, in the presence of AML disease, macrophages were repressed during chemotherapy, leading to reduced cycled iron and hematopoiesis. Using single cell level visualization of BM cells via multiplex ion beam imaging for several features and hallmarks of BM regeneration, we observed that dysregulation of iron in AML was accompanied by defects in adipocyte regeneration post chemotherapy not seen in normal BM tissue. The involvement of adipocyte reduction to AML disease included a regulatory feedback loop back in iron regulation controlled by macrophages. Transfusion of macrophages in patient-derived AML xenografts restored their ability to support regeneration following BM-damaging radiation treatment; measured by iron availability, adipocyte development and hematopoietic regeneration that extended overall survival of mice with human leukemic disease. In contrast, depletion of BM macrophages using a knockout mouse model of macrophage deletion compromised the BM niche and hematopoietic tissue recovery after radiation injury, suggesting macrophages have a direct role in supporting BM regeneration. Given these observations were seen in AML patient BM, and reproduced in xenograft models, we investigated the generalizable role of macrophage in regeneration using non-mammalian models. Regenerating signatures of macrophage were found to be evolutionarily conserved and upregulated in both limb and fin regeneration of axolotl and polypterus. Collectively, these studies define and characterize a previously unappreciated association and dynamic nature of BM macrophages, adipocytes and iron exchange in BM regeneration. These findings have implications to tissue regeneration, specifically to BM damaging modalities in current AML therapy that targets leukemic cells at the expense of healthy BM niche of patients. |
URI: | http://hdl.handle.net/11375/29333 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Zhao_Xueli_2023.12_PhD.pdf | 7.34 MB | Adobe PDF | View/Open |
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