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Increased TGF-beta Signaling Drives Different Hematopoietic Disease Outcomes following Stress Hematopoiesis

Javier, Jose Emmanuel F
http://orcid.org/0000-0001-6618-9190
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1617109578665394

Abstract Details

2021, PhD, University of Cincinnati, Medicine: Cancer and Cell Biology.
Hematopoietic stem cells (HSCs) regenerate the hematopoietic tissue during stress hematopoiesis, requiring that HSCs come out of quiescence and re-fill the depleted pool, as well as self-renew to maintain a healthy HSC pool. Injuries associated with stress hematopoiesis include myeloablative chemotherapy, infection/inflammation and allogeneic bone marrow transplantation. However, self-renewal and differentiation must be tightly controlled. Too much differentiation results in an exhaustion of the HSC pool and bone marrow failure, while too much self-renewal can lead to leukemogenesis. The transforming growth factor ß (TGFß) signaling pathway has been well-studied to regulate HSCs during steady state hematopoiesis. However, very little is known about its role in regulating HSCs during stress hematopoiesis. Moreover, its role in HSC regulation is both context-dependent and concentration dependent. Using a mouse model to conditionally overexpress an active form of the main TGFß ligand, aTGFß1, we found that increased aTGFß1 caused very little impact in the hematopoietic system during steady state hematopoiesis, driving a very mild neutropenia and bone marrow dysplasia during aging. However, aTGFß1 overexpression prevented the murine hematopoietic system from recovering to normal levels of peripheral blood leukocyte and platelet levels after chemotherapeutic stress using 5-fluorouracil. Moreover, during the recovery phase aTGFß1-overexpressing mice had increased HSC cell cycling and DNA double strand breaks compared to controls. Separately, acute inflammation-driven stress caused by polyinosinic:polycytidilic acid (pIC) drove pancytopenia, bone marrow dysplasia and splenomegaly, but expanded the hematopoietic stem and progenitor (HSPC) pool long after the short-term effects of pIC had resolved, phenotypes similar to the human bone marrow failure myelodysplasia. Mechanistically, we found that aTGFß1 overexpression altered the HSC transcriptome after pIC-driven stress, up-regulating genes related to mitochondrial biogenesis and the respiratory transport chain. Functional analysis showed that aTGFß1-overexpressing HSCs had increased mitochondrial content relative to controls, and maintained a higher mitochondrial membrane potential, suggesting that aTGFß1-overexpressing HSCs had more mitochondria that were active long-term after pIC stress. Additionally, we found that aTGFß1-overexpressing pIC-stressed HSCs had higher levels of reactive oxygen species. We also found that aTGFß1-overexpressing pIC-stressed HSCs had elevated levels of active caspase 1, an enzyme canonically known to drive a pro-inflammatory form of cell death but recently has been shown to also regulate cellular metabolism. We also found evidence that the mitochondrial anti-viral signaling protein (MAVS) may be chronically active in aTGFß1-overexpressing pIC-stressed HSCs. Surprisingly, we also found that transplanting aTGFß1-overexpressing pIC-stressed HSCs during the recovery phase of inflammation drove the development of acute pre-B cell acute lymphoblastic leukemia that was transplantable. Increased TGFß signaling has never before been implicated in lymphoid leukemogenesis, with the expectation that a combination of inflammation followed by transplant stress would accelerate bone marrow failure in aTGFß1-overexpressing bone marrow recipients. Altogether, our data suggests that increased TGFß signaling modulates hematopoietic response to different stressors to drive very different disease outcomes, and suggests a role for TGFß signaling as a therapeutic target for various bone marrow diseases.
Marie-Dominique Filippi, Ph.D. (Committee Chair)
Paul Andreassen, Ph.D. (Committee Member)
Jose Cancelas-Perez, M.D. (Committee Member)
H. Leighton Grimes, Ph.D. (Committee Member)
Gang Huang, Ph.D. (Committee Member)
Damien Reynaud (Committee Member)
93 p.
Health Sciences
Transforming growth factor beta; hematopoiesis; bone marrow failure; myelodysplasia; chemotherapy; leukemia

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Citations

  • Javier, J. E. F. (2021). Increased TGF-beta Signaling Drives Different Hematopoietic Disease Outcomes following Stress Hematopoiesis [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1617109578665394

    APA Style (7th edition)

  • Javier, Jose Emmanuel. Increased TGF-beta Signaling Drives Different Hematopoietic Disease Outcomes following Stress Hematopoiesis. 2021. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1617109578665394.

    MLA Style (8th edition)

  • Javier, Jose Emmanuel. "Increased TGF-beta Signaling Drives Different Hematopoietic Disease Outcomes following Stress Hematopoiesis." Doctoral dissertation, University of Cincinnati, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1617109578665394

    Chicago Manual of Style (17th edition)

ucin1617109578665394
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This open access ETD is published by University of Cincinnati and OhioLINK.
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