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The Forkhead Box F1 Transcription Factor in Disease and Development

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2019, PhD, University of Cincinnati, Medicine: Cancer and Cell Biology.
The forkhead box F1 transcription factor (FOXF1) is a mesenchymal-specific transcription factor and is expressed in mesenchyme-derived cells such as hepatic stellate cells and lung microvascular endothelial cells. FOXF1 functions are critical for transcriptional regulation during development of the liver, lung, and other organs, and has numerous roles in adult diseases. Here, we investigate FOXF1 and its role in hepatic fibrosis and its role in endothelial progenitor cells. Studying FOXF1 throughout different systems will enhance our knowledge base and can be used to develop further studies in a variety of systems. FOXF1 is expressed in the collagen-producing cells of the liver, the hepatic stellate cells (HSC), and HSC activation to myofibroblasts (MFs) requires FOXF1 presence. Therefore, our studies utilize a carbon tetrachloride-induced liver injury model to investigate the role of FOXF1 during liver fibrosis progression. We found that Foxf1 deletion increased collagen depositions and disrupted liver architecture. Timp2 expression was significantly increased in Foxf1-deficient mice while MMP9 activity was reduced. RNA sequencing of purified liver myofibroblasts demonstrated that FOXF1 inhibits expression of pro-fibrotic genes: Col1a2, Col5a2, and Mmp2 in fibrotic livers and binds to active repressors located in promotors and introns of these genes. Overexpression of FOXF1 inhibits Col1a2, Col5a2, and MMP2 in primary murine HSCs in vitro. In summary, we found that FOXF1 prevents aberrant extracellular matrix depositions during hepatic fibrosis by repressing pro-fibrotic gene transcription in HSCs and MFs. FOXF1 is additionally expressed in endothelial cells, which line blood vessels. FOXF1 in an important regulator of vascular formation and has roles in cellular proliferation. Therefore, our studies utilized endothelial colony forming cells (ECFC) to rescue mice with acute lung injury (ALI). We found a 53.8% increase in the survival of mice with ALI, which was associated with a decrease in lung injury; however, further evaluation of the injected ECFCs revealed no fluorescent tracer or FOXF1 expression. We therefore developed a novel embryonic stem cell (ESC) line with GFP:FOXF1 to both trace FOXF1 expression through differentiation to endothelial progenitor cells (EPC) in vitro and to trace the cell in vivo for future studies. Our novel differentiation method yields ~95.2% endothelial cells, 51.5% of which are FOXF1-positive. In summary, we have successfully developed a novel ESC line and a novel EPC differentiation protocol to be used in future studies.
Vladimir Kalinichenko, M.D. Ph.D. (Committee Chair)
Chunying Du, Ph.D. (Committee Member)
David Plas, Ph.D. (Committee Member)
Nikolai Timchenko, Ph.D. (Committee Member)
Chunyue Yin, Ph.D. (Committee Member)
162 p.

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Citations

  • Flood, H. M. (2019). The Forkhead Box F1 Transcription Factor in Disease and Development [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1554213082789579

    APA Style (7th edition)

  • Flood, Hannah. The Forkhead Box F1 Transcription Factor in Disease and Development. 2019. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1554213082789579.

    MLA Style (8th edition)

  • Flood, Hannah. "The Forkhead Box F1 Transcription Factor in Disease and Development." Doctoral dissertation, University of Cincinnati, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1554213082789579

    Chicago Manual of Style (17th edition)