43330-Francis, Heather
Faculty

Heather Francis, PhD

Professor of Medicine

Bio

Dr. Heather Francis joined the Division of Gastroenterology and Hepatology in January, 2019 as the Scientific Director of the Indiana Center for Liver Research (ICLR) and a Professor of Medicine. Dr. Francis recently was an Associate Professor of Medical Physiology at Texas A&M College of Medicine.

Education and Post-Graduate Training

PhD, 2010, Texas A&M University Health Sciences College

BS, Biology, 1990, Sul Ross State University

Titles & Appointments

  • Professor of Medicine
  • Adjunct Professor of Anatomy, Cell Biology & Physiology
  • Education
    2010 PhD Texas A & M University
    1990 BS Sul Ross State University
  • Research

    Research Interests

    The main focus and goal of my basic science research program is to understand and identify target therapies for chronic and often fatal liver diseases. Cholangiopathies are diseases that target cholangiocytes and include diseases like Primary Biliary Cholangitis (PBC), Primary Sclerosing Cholangitis (PSC) and Cholangiocarcinoma (CCA). For these diseases there are no "true" therapeutic options that can eradicate the disease in patients. Thus far, liver resection or transplantation is the primary mode of action in terms of treatment. Further, the rise in obesity rates have induced a dramatic increase in non-alcoholic fatty liver disease (NAFLD), which when left untreated can often lead to cirrhosis, fibrosis and liver failure. As of 2015, over 17,000 people were awaiting liver transplantations and more than 1,500 people will die waiting for available organs or live donor liver transplantation. Therefore, identification of targets for early diagnosis and potential therapies are critical to improve patient outcome. My laboratory strives to produce high quality, reproducible data generated from cell lines, in vivo rodent models and human liver samples. I am currently funded by both the NIH (R01) and a VA Merit. My past funding includes a VA Career Development Award and funding from PSC Partners Seeking a Cure.

    Novelty of research:

    My research team has dedicated the past several years developing a program to better understand the paracrine role that mast cells play in chronic liver diseases. While cholangiocytes are the targets of cholangiopathies and the key cell type involved in these diseases, the paracrine action of other resident and non-resident cell types cannot be overlooked. Mast cells are inflammatory cells that were once thought to only be important in allergic reactions; however, studies are demonstrating that mast cells play critical roles in a number of diseases including cholangiopathies. Our data has demonstrated that mast cells migrate into the liver following liver damage and their number increases upon injury creating an inflammatory microenvironment.

    Important findings to date:

    We have specifically identified the following:

    • In both rodent and human models, we have found that mast cells play a critical role in not only the initial repair of the liver, but also in the progression of liver damage and disease.
    • Mast cells migrate in close proximity to damaged bile ducts during PSC and CCA and release inflammatory mediators like histamine. Blocking both mast cell migration and the release of mast cell-derived histamine using an FDA approved drug, cromolyn sodium, improves hepatic damage and fibrosis in both human and rodent models of PSC and CCA.
    • We have developed a novel technique to isolate mature hepatic mast cells from rats.
    • Bile acids like ursodeoxycholate (UDCA) can inhibit mast cell release of histamine and improve liver function and ameliorate damage and fibrosis in PSC mice.
    • Complete loss of mast cells using mast cell deficient mice reveals that, when subjected to injury, the lack of mast cells decreases the degree of damage and fibrosis seen in typical cholangiopathies.
    • Reintroduction of mast cells into deficient mice or wild-type mice (that have low mast cell numbers) increases liver damage and hepatic fibrosis demonstrating that these inflammatory cells play a key role in the regulation of biliary disorders.
    • By using over-the-counter drugs that block H1 and H2 histamine receptors, we have been able to decrease biliary damage and hepatic fibrosis via the loss of mast cell function in these models.
    • In mice lacking histidine decarboxylase (HDC, the enzyme that promotes histamine synthesis) fed a high fat, high sugar water diet there is increased weight gain and fatty liver damage, but decreased fibrosis and biliary damage. Further, the histamine-leptin signaling pathway is disrupted in these mice fed high fat, high sugar water diets, which is a potential area that could be targeted in NAFLD.
    • Loss of HDC impairs proper liver regeneration following 70% partial hepatectomy.
  • Publications
    Bile Acid Receptor Therapeutics Effects on Chronic Liver Diseases.
    Meadows V; Kennedy L; Kundu D; Alpini G; Francis H; Frontiers in medicine 2020 Jan 29
    Neuroendocrine Changes in Cholangiocarcinoma Growth.
    Sato K; Francis H; Zhou T; Meng F; Kennedy L; Ekser B; Baiocchi L; Onori P; Mancinelli R; Gaudio E; Franchitto A; Glaser S; Alpini G; Cells 2020 Feb 13
    Downregulation of hepatic stem cell factor by Vivo-Morpholino treatment inhibits mast cell migration and decreases biliary damage/senescence and liver fibrosis in Mdr2<sup>-/-</sup> mice.
    Meadows V; Kennedy L; Hargrove L; Demieville J; Meng F; Virani S; Reinhart E; Kyritsi K; Invernizzi P; Yang Z; Wu N; Liangpunsakul S; Alpini G; Francis H; Biochimica et biophysica acta. Molecular basis of disease 2019 Sep 13
    Knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes in the Mdr2<sup>-/-</sup> mouse model of primary sclerosing cholangitis (PSC).
    Zhou T; Kyritsi K; Wu N; Francis H; Yang Z; Chen L; O'Brien A; Kennedy L; Ceci L; Meadows V; Kusumanchi P; Wu C; Baiocchi L; Skill NJ; Saxena R; Sybenga A; Xie L; Liangpunsakul S; Meng F; Alpini G; Glaser S; EBioMedicine 2019 Sep 12
    Possible application of melatonin treatment in human diseases of the biliary tract.
    Baiocchi L; Zhou T; Liangpunsakul S; Ilaria L; Milana M; Meng F; Kennedy L; Kusumanchi P; Yang Z; Ceci L; Glaser S; Francis H; Alpini G; American journal of physiology. Gastrointestinal and liver physiology 2019 Sep 11
    Intercellular Communication between Hepatic Cells in Liver Diseases.
    Sato K; Kennedy L; Liangpunsakul S; Kusumanchi P; Yang Z; Meng F; Glaser S; Francis H; Alpini G; International journal of molecular sciences 2019 May 2
    Pinealectomy or light exposure exacerbates biliary damage and liver fibrosis in cholestatic rats through decreased melatonin synthesis.
    Chen L; Zhou T; Wu N; O'Brien A; Venter J; Ceci L; Kyritsi K; Onori P; Gaudio E; Sybenga A; Xie L; Wu C; Fabris L; Invernizzi P; Zawieja D; Liangpunsakul S; Meng F; Francis H; Alpini G; Huang Q; Glaser S; Biochimica et biophysica acta. Molecular basis of disease 2019 Mar 16
    Secretin/secretin receptor signaling mediates biliary damage and liver fibrosis in early-stage primary biliary cholangitis.
    Kennedy L; Francis H; Invernizzi P; Venter J; Wu N; Carbone M; Gershwin ME; Bernuzzi F; Franchitto A; Alvaro D; Marzioni M; Onori P; Gaudio E; Sybenga A; Fabris L; Meng F; Glaser S; Alpini G; FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2019 Jun 28
    Modulation of the Tryptophan Hydroxylase 1/Monoamine Oxidase-A/5-Hydroxytryptamine/5-Hydroxytryptamine Receptor 2A/2B/2C Axis Regulates Biliary Proliferation and Liver Fibrosis During Cholestasis.
    Kyritsi K; Chen L; O'Brien A; Francis H; Hein TW; Venter J; Wu N; Ceci L; Zhou T; Zawieja D; Gashev AA; Meng F; Invernizzi P; Fabris L; Wu C; Skill NJ; Saxena R; Liangpunsakul S; Alpini G; Glaser SS; Hepatology (Baltimore, Md.) 2019 Jul 25
    Knockout of a-calcitonin gene-related peptide attenuates cholestatic liver injury by differentially regulating cellular senescence of hepatic stellate cells and cholangiocytes.
    Wan Y; Ceci L; Wu N; Zhou T; Chen L; Venter J; Francis H; Bernuzzi F; Invernizzi P; Kyritsi K; Baker P; Huang Q; Wu C; Sybenga A; Alpini G; Meng F; Glaser S; Laboratory investigation; a journal of technical methods and pathology 2019 Jan 30
    Preclinical insights into cholangiopathies: disease modeling and emerging therapeutic targets.
    Sato K; Glaser S; Kennedy L; Liangpunsakul S; Meng F; Francis H; Alpini G; Expert opinion on therapeutic targets 2019 Apr 22
    Dual Role of Bile Acids on the Biliary Epithelium: Friend or Foe?
    Baiocchi L; Zhou T; Liangpunsakul S; Lenci I; Santopaolo F; Meng F; Kennedy L; Glaser S; Francis H; Alpini G; International journal of molecular sciences 2019 Apr 16
    Amelioration of Ductular Reaction by Stem Cell Derived Extracellular Vesicles in MDR2 Knockout Mice via Lethal-7 microRNA.
    McDaniel K; Wu N; Zhou T; Huang L; Sato K; Venter J; Ceci L; Chen D; Ramos-Lorenzo S; Invernizzi P; Bernuzzi F; Wu C; Francis H; Glaser S; Alpini G; Meng F; Hepatology (Baltimore, Md.) 2019 Apr 12
  • Awards
    Org: Sul Ross State University
    Desc: Distinguished Alumni
    Scope: University
    Date: 2018-03-23
    Org: American Physiological Society/GI & Liver
    Desc: New Investigator of the Year
    Scope: National
    Date: 2016-04-01
    Org: American Association for Cancer Research
    Desc: Scholar-in-Training Award
    Scope: National
    Date: 2008-05-02

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