
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
- Adjunct Professor of Biochemistry & Molecular Biology
- Adjunct Professor of Biochemistry
- Scientific Director Indiana Liver Research Center (ICLR)
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Education2010 PhD Texas A&M University1990 BS Sul Ross State University
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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.
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PublicationsThe Effects of Taurocholic Acid on Biliary Damage and Liver Fibrosis Are Mediated by Calcitonin-Gene-Related Peptide Signaling.
Mancinelli R; Ceci L; Kennedy L; Francis H; Meadows V; Chen L; Carpino G; Kyritsi K; Wu N; Zhou T; Sato K; Pannarale L; Glaser S; Chakraborty S; Alpini G; Gaudio E; Onori P; Franchitto A; Cells 2022 May 9Indole Supplementation Ameliorates MCD-induced NASH in mice.
Zhu B; Li H; Lu B; Guo X; Wu C; Wang F; Li Q; Xie L; Glaser S; Francis H; Alpini G; Wu C; The Journal of nutritional biochemistry 2022 May 11Suppression of MT1 and Melatonin Treatment Improves Liver Phenotypes in Mdr2<sup>-/-</sup> mice.
Ceci L; Wu N; Carpino G; Chen L; Zhou T; Kennedy L; Kyritsi K; Francis H; Franchitto A; Onori P; Gaudio E; Glaser S; Alpini G; FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2022 MayLipocalin-2 Stimulates Proliferation and a Profibrotic Cholangiocyte Phenotype during Cholestasis.
O'Brien A; Stiles D; White T; Lopez M; Little A; Childs J; Douthitt A; Phan T; Medford A; Chen L; Francis H; Alpini G; Chakraborty S; Glaser S; FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2022 MayMast Cells Contribute to Hepatic Neurokinin1 Receptor Signaling, Subsequent Biliary Damage and Peribiliary Fibrosis Via TGF-ß1 Signaling in MDR2-/- Mouse Model of Primary Scelrosing Cholangitis.
Kundu D; Zhou T; Meadows V; Kennedy L; Ceci L; Kyritsi K; Glaser S; Alpini G; Francis H; FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2022 MayThe protective effects of estrogen on biliary and liver damage are independent of ER-ß signaling in female Mdr2<sup>-/-</sup> mice.
Owen T; Kyritsi K; Chen L; Ceci L; Meadows V; Meyer A; Alpini G; Francis H; Kennedy L; FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2022 MayThe Functional Roles of Immune Cells in Primary Liver Cancer.
Pham L; Kyritsi K; Zhou T; Ceci L; Baiocchi L; Kennedy L; Chakraborty S; Glaser S; Francis H; Alpini G; Sato K; The American journal of pathology 2022 Mar 23Molecular Mechanisms Linking Risk Factors to Cholangiocarcinoma Development.
Ceci L; Zhou T; Lenci I; Meadows V; Kennedy L; Li P; Ekser B; Milana M; Zhang W; Wu C; Sato K; Chakraborty S; Glaser SS; Francis H; Alpini G; Baiocchi L; Cancers 2022 Mar 11FGF1 Signaling Modulates Biliary Injury and Liver Fibrosis in the Mdr2<sup>-/-</sup> Mouse Model of Primary Sclerosing Cholangitis.
O'Brien A; Zhou T; White T; Medford A; Chen L; Kyritsi K; Wu N; Childs J; Stiles D; Ceci L; Chakraborty S; Ekser B; Baiocchi L; Carpino G; Gaudio E; Wu C; Kennedy L; Francis H; Alpini G; Glaser S; Hepatology communications 2022 Mar 10Healthy peribiliary glands are necessary for successful liver transplantation.
Francis H; Kundu D; Baiocchi L; Hepatology (Baltimore, Md.) 2022 Feb 21Macrophage-Specific SCAP Promotes Liver and Adipose Tissue Damage in a Lean NAFLD Model: Lean, Mean, Proinflammatory Machine.
Kennedy L; Francis H; Alpini G; Cellular and molecular gastroenterology and hepatology 2022 Apr 29Organoid Technology: Are Human Cholangiocyte Organoids Immune Protected?
Ekser B; Zhang W; Li P; Francis H; Alpini G; Transplantation 2022 Apr 1Mast Cells Regulate Ductular Reaction and Intestinal Inflammation in Cholestasis Through Farnesoid X Receptor Signaling.
Meadows V; Kennedy L; Ekser B; Kyritsi K; Kundu D; Zhou T; Chen L; Pham L; Wu N; Demieville J; Hargrove L; Glaser S; Alpini G; Francis H; Hepatology (Baltimore, Md.) 2021 Sep 9Melatonin receptor 1A, but not 1B, knockout decreases biliary damage and liver fibrosis during cholestatic liver injury.
Wu N; Carpino G; Ceci L; Baiocchi L; Francis H; Kennedy L; Zhou T; Chen L; Sato K; Kyritsi K; Meadows V; Ekser B; Franchitto A; Mancinelli R; Onori P; Gaudio E; Glaser S; Alpini G; Hepatology (Baltimore, Md.) 2021 Nov 24Adipocyte inducible 6-phosphofructo-2-kinase suppresses adipose tissue inflammation and promotes macrophage anti-inflammatory activation.
Xu H; Zhu B; Li H; Jiang B; Wang Y; Yin Q; Cai J; Glaser S; Francis H; Alpini G; Wu C; The Journal of nutritional biochemistry 2021 May 6Mast Cells Promote Nonalcoholic Fatty Liver Disease Phenotypes and Microvesicular Steatosis in Mice Fed a Western Diet.
Kennedy L; Meadows V; Sybenga A; Demieville J; Chen L; Hargrove L; Ekser B; Dar W; Ceci L; Kundu D; Kyritsi K; Pham L; Zhou T; Glaser S; Meng F; Alpini G; Francis H; Hepatology (Baltimore, Md.) 2021 May 24The Apelin-Apelin Receptor Axis Triggers Cholangiocyte Proliferation and Liver Fibrosis During Mouse Models of Cholestasis.
Chen L; Zhou T; White T; O'Brien A; Chakraborty S; Liangpunsakul S; Yang Z; Kennedy L; Saxena R; Wu C; Meng F; Huang Q; Francis H; Alpini G; Glaser S; Hepatology (Baltimore, Md.) 2021 May 22Organoids and Spheroids as Models for Studying Cholestatic Liver Injury and Cholangiocarcinoma.
Sato K; Zhang W; Safarikia S; Isidan A; Chen AM; Li P; Francis H; Kennedy L; Baiocchi L; Alvaro D; Glaser S; Ekser B; Alpini G; Hepatology (Baltimore, Md.) 2021 Jun 4Methionine- and Choline-Deficient Diet-Induced Nonalcoholic Steatohepatitis Is Associated with Increased Intestinal Inflammation.
Matthews DR; Li H; Zhou J; Li Q; Glaser S; Francis H; Alpini G; Wu C; The American journal of pathology 2021 Jul 7Cyclic AMP Signaling in Biliary Proliferation: A Possible Target for Cholangiocarcinoma Treatment?
Baiocchi L; Lenci I; Milana M; Kennedy L; Sato K; Zhang W; Ekser B; Ceci L; Meadows V; Glaser S; Alpini G; Francis H; Cells 2021 Jul 4Inhibition of Secretin/Secretin Receptor Axis Ameliorates NAFLD Phenotypes.
Chen L; Wu N; Kennedy L; Francis H; Ceci L; Zhou T; Samala N; Kyritsi K; Wu C; Sybenga A; Ekser B; Dar W; Atkins C; Meadows V; Glaser S; Alpini G; Hepatology (Baltimore, Md.) 2021 Jul 29Current Advances in Basic and Translational Research of Cholangiocarcinoma.
Sato K; Baiocchi L; Kennedy L; Zhang W; Ekser B; Glaser S; Francis H; Alpini G; Cancers 2021 Jul 1Adipose tissue inflammation and systemic insulin resistance in mice with diet-induced obesity is possibly associated with disruption of PFKFB3 in hematopoietic cells.
Zhu B; Guo X; Xu H; Jiang B; Li H; Wang Y; Yin Q; Zhou T; Cai JJ; Glaser S; Meng F; Francis H; Alpini G; Wu C; Laboratory investigation; a journal of technical methods and pathology 2021 Jan 18Doublecortin-Like Kinase Protein 1 in Cholangiocarcinoma: Is This the Biomarker and Target We Have Been Looking For?
Meadows V; Francis H; Hepatology (Baltimore, Md.) 2021 JanBiliary Epithelial Senescence in Liver Disease: There Will Be SASP.
Meadows V; Baiocchi L; Kundu D; Sato K; Fuentes Y; Wu C; Chakraborty S; Glaser S; Alpini G; Kennedy L; Francis H; Frontiers in molecular biosciences 2021 Dec 21Centralized Otolaryngology Research Efforts: Stepping-stones to Innovation and Equity in Otolaryngology-Head and Neck Surgery.
Brenner MJ; Nelson RF; Valdez TA; Moody-Antonio SA; Nathan CO; St John MA; Francis HW; Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery 2021 Dec 14Mast cells in liver disease progression: An update on current studies and implications.
Pham L; Kennedy L; Baiocchi L; Meadows V; Ekser B; Kundu D; Zhou T; Sato K; Glaser S; Ceci L; Alpini G; Francis H; Hepatology (Baltimore, Md.) 2021 Dec 12Social Networks and Cognitive Function: An Evaluation of Social Bridging and Bonding Mechanisms.
Perry BL; McConnell WR; Peng S; Roth A; Coleman M; Manchella M; Roessler M; Francis H; Sheean H; Apostolova L; The Gerontologist 2021 Aug 2Heterogeneity of Hepatic Stellate Cells in Fibrogenesis of the Liver: Insights from Single-Cell Transcriptomic Analysis in Liver Injury.
Zhang W; Conway SJ; Liu Y; Snider P; Chen H; Gao H; Liu Y; Isidan K; Lopez KJ; Campana G; Li P; Ekser B; Francis H; Shou W; Kubal C; Cells 2021 Aug 19Feedback Signaling between Cholangiopathies, Ductular Reaction, and Non-Alcoholic Fatty Liver Disease.
Zhou T; Kundu D; Robles-Linares J; Meadows V; Sato K; Baiocchi L; Ekser B; Glaser S; Alpini G; Francis H; Kennedy L; Cells 2021 Aug 12Impact of Aging on Liver Cells and Liver Disease: Focus on the Biliary and Vascular Compartments.
Baiocchi L; Glaser S; Francis H; Kennedy L; Felli E; Alpini G; Gracia-Sancho J; Hepatology communications 2021 Apr 10Circadian Rhythm and Melatonin in Liver Carcinogenesis: Updates on Current Findings.
Han Y; Chen L; Baiocchi L; Ceci L; Glaser S; Francis H; Alpini G; Kennedy L; Critical reviews in oncogenesis 2021Kupffer Cells: Inflammation Pathways and Cell-Cell Interactions in Alcohol-Associated Liver Disease.
Slevin E; Baiocchi L; Wu N; Ekser B; Sato K; Lin E; Ceci L; Chen L; Lorenzo SR; Xu W; Kyritsi K; Meadows V; Zhou T; Kundu D; Han Y; Kennedy L; Glaser S; Francis H; Alpini G; Meng F; 2020 Sep 11An exploratory test of a couples-based condom-use intervention designed to promote pleasurable and safer penile-vaginal sex among university students.
Gesselman AN; Ryan R; Yarber WL; Vanterpool KB; Beavers KA; Francis H; Grant BT; Wood K; Graham CA; Milhausen R; Sanders SA; Crosby RA; Journal of American college health : J of ACH 2020 Nov 5The interplay between mast cells, pineal gland, and circadian rhythm: Links between histamine, melatonin, and inflammatory mediators.
Pham L; Baiocchi L; Kennedy L; Sato K; Meadows V; Meng F; Huang CK; Kundu D; Zhou T; Chen L; Alpini G; Francis H; Journal of pineal research 2020 Nov 29Bile Acid Receptor Therapeutics Effects on Chronic Liver Diseases.
Meadows V; Kennedy L; Kundu D; Alpini G; Francis H; Frontiers in medicine 2020 Jan 29Neuroendocrine 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 13Cholangiocarcinoma: bridging the translational gap from preclinical to clinical development and implications for future therapy.
Baiocchi L; Sato K; Ekser B; Kennedy L; Francis H; Ceci L; Lenci I; Alvaro D; Franchitto A; Onori P; Gaudio E; Wu C; Chakraborty S; Glaser S; Alpini G; Expert opinion on investigational drugs 2020 Dec 8Downregulation 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 13Knockdown 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 12Possible 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 11Intercellular 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 2Pinealectomy 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 16Secretin/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 28Modulation 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 25Knockout 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 30Hepatocyte-specific and extra-hepatocyte actions of perilipin-2 during fatty liver disease: benefits of being extra.
Kennedy L; Francis H; Alpini G; The Journal of physiology 2019 Jan 29Preclinical 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 22Dual 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 16Amelioration 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 -
AwardsOrg: 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