Michele Pritchard, PhD
Associate Director, Interdisciplinary Graduate Program in Biomedical Sciences
Ph.D. State University of New York at Buffalo, Roswell Park Graduate Division, 2003
Postdoctoral Fellow, Case Western Reserve University, 2006
Postdoctoral Fellow, Cleveland Clinic, 2008
Research Associate, Cleveland Clinic, 2009
Project Scientist, Cleveland Clinic, 2011
Assistant Professor, Case Western Reserve University, 2012
Hyaluronan, regeneration, inflammation, wound-healing response, fibrosis, hepatic stellate cells, macrophages, congenital hepatic fibrosis/ARPKD, alcohol, liver, ovary
Overview. I am fascinated by the regenerative capacity of the liver. I am not alone in this fascination. Indeed, the Greeks were so intrigued by the liver's ability to repair itself that they documented their observations in the myth of Prometheus. If we could harness the power of organ regeneration, we could cure many diseases and attenuate organ functional decline which accompanies aging.
The liver is exquisite at regenerative wound repair after acute liver injury. However, this incredible capacity for regeneration fails in the context of chronic liver injury. My laboratory's research is focused on understanding the role of the extracellular matrix (ECM) in regenerative vs scar-forming (fibrotic) wound repair. Specifically, we focus our attention on an ECM carbohydrate called hyaluronan (HA) and a series of HA-related molecules. Together, these molecules form what we call ‘The HA Network'. The HA-related molecules in the HA network consist of HA synthesizing and degrading enzymes, HA binding proteins which organize HA matrices in the ECM, and the receptors through which HA signals in various cells. We got interested in hyaluronan due to the large literature which describes an important role HA in scarless (non-fibrotic) wound healing in fetal tissues and hypothesize that by targeting the HA network, we can ‘fetalize' tissue to attenuate organ fibrosis. Half of our research is focused on the liver as it is an organ capable of regenerative and scar forming repair allowing us to compare the HA network between these two injury repair states. The other half of our research investigates the HA network in models used to explore normal or premature aging in liver as well as in the ovary. Descriptions of these two research areas are found below.
1. Role for the hyaluronan network in liver wound repair
Hyaluronan (HA), an extracellular matrix glycosaminoglycan, is increased in the plasma of patients with liver disease; HA plasma concentration directly correlates with liver disease severity. HA has different biological functions based on molecular mass; low molecular mass HA promotes inflammation and angiogenesis while high molecular mass HA promotes tissue homeostasis. While much research is devoted to understanding the roles of HA in inflammation and fibrosis in the skin, lung and intestine, little is known about the role of HA in the liver.
We are currently investigating how HA contributes to hepatic inflammation, fibrosis, and fibrosis resolution in response to injury induced by various hepatotoxicants, and in a genetic disease called congenital hepatic fibrosis found in patients with autosomal recessive polycystic kidney disease (CHF/ARPKD). We hypothesize that the HA network modulates the hepatic microenvironment during health and disease and that perturbations in the tightly-regulated, HA network precipitate fibrosis. Currently, we are carefully characterizing the HA network in livers from various animal models of human liver disease, liver regeneration, and in human-derived material. Moreover, we are utilizing pharmacologic and genetic strategies to modulate the HA network in mice and rats to improve hepatic wound repair, or prevent/reverse liver fibrosis. Finally, we have recently established some new techniques to interrogate hyaluronan biology in isolated macrophages and hepatic stellate cells and are exploring the use of organoid systems to model liver regeneration, in vitro.
2. Impact of alterations in the hyaluronan network in ovarian aging
Recently, we have broadened our interest in fibrosis to include two new ‘pathologies': physiologic aging and premature aging induced by iatrogenic insults. This new interest was fostered by the development of a collaboration with Dr. Francesca E. Duncan (Northwestern University), a reproductive biologist interested in understanding the mechanisms behind the decline in fertility with advanced maternal age. In June of 2016, our first collaborative study was published. This study demonstrated the robust development and progression of ovarian fibrosis concomitant with chronic inflammation in mice by 22 months of age. The findings of this study suggest that alterations in the ovarian stroma may contribute to loss of fertility associated with advanced maternal age. Current work is exploring how changes in the HA network drive chronic inflammation and fibrosis in ovaries over an aging continuum in mice, naked mole rats, and in humans. We received an NIH R01 from the NICHD in Feb 2018 to study hyaluronan biology in ovarian aging for the next 5 years.
In summary, the long-term goal of our research is to identify ways to prevent organ fibrosis and subsequent functional decline by targeting the HA network.
Selected Publications (from last 5 years):
(* indicates manuscripts for which I am corresponding author.)
Jiang L, Fang P, Septer S, Apte U, *Pritchard MT. Inhibition of mast cell degranulation with cromolyn sodium exhibits organ-specific effects in polycystic kidney (PCK) rats. 2018. International Journal of Toxicology. 37(4):308-326. PubMed PMID: 29862868.
McCullough RL, McMullen MR, Sheehan MM, Poulsen KL, Roychowdhury S, Chiang DJ, Pritchard MT, Caballeria J, Bataller R, Nagy LE. 2018. Complement Factor D protects mice from ethanol-induced inflammation and liver injury. American Journal of Physiology, Gastrointestinal and Liver Physiology. 315(1):G66-G79. PubMed PMID:29597356.
Jiang L, Sun L, Edwards G, Manley Jr. M, Wallace DP, Septer S, Manohar C, Pritchard MT and Apte U. 2017. Increased YAP activation is associated with hepatic cyst epithelial cell proliferation in ARPDK/CHF. Gene Expression: The Journal of Basic Liver Research. 17(4):313-326. PubMed PMID: 28915934.
Fausther M, Pritchard MT, Popov YV, Bridle K. Contribution of liver non-parenchymal cells to hepatic fibrosis: Interactions with the local microenvironment (Editorial). 2017. BioMed Research International. Article ID 6824762. PubMed PMID: 28299331.
McCracken JM, Chalise P, Briley S, Dennis K, Jiang L, Duncan FE, *Pritchard MT. 2017. C57BL/6 substrains exhibit different responses to acute carbon tetrachloride exposure: Implications for work involving transgenic mice. Gene Expression: The Journal of Basic Liver Research. 17(3):187-205. PubMed PMID: 28234577.
Jiang L, Fang P, Weemhoff JL, Apte U, *Pritchard MT. 2016. Evidence for a "Pathogenic Triumvirate" in Congenital Hepatic Fibrosis in Autosomal Recessive Polycystic Kidney Disease. Biomed Research International. 2016:4918798. PubMed PMID: 27891514.
Briley SM, Jasti S, McCracken JM, Hornick JE, Fegley B, Pritchard MT, Duncan FE. 2016 Reproductive age-associated fibrosis in the stroma of the mammalian ovary. Reproduction. 152(3):245-60. PubMed PMID: 27491879. **This work was featured on the cover (September-December 2016), and was also highlighted by Bioscientifica, the Faculty of 1000, and BBC radio (The Naked Scientists)**
McCracken JM, Jiang L, Deshpande KT, O'Neil MF, *Pritchard MT. 2016. Differential effects of hyaluronan synthase 3 deficiency after acute vs chronic liver injury in mice. Fibrogenesis and Tissue Repair. 9:4. PubMed PMID: 27042213.
Deshpande KT, Liu S, McCracken JM, Jiang L, Gaw TE, Kaydo LN, Richard ZC, O'Neil MF, *Pritchard MT. 2016. Moderate (2%, v/v) Ethanol Feeding Alters Hepatic Wound Healing after Acute Carbon Tetrachloride Exposure in Mice. Biomolecules. 6(1):5. PubMed PMID: 26751492.
*Pritchard MT, McCracken JM. 2015. Identifying Novel Targets for Treatment of Liver Fibrosis: What Can We Learn from Injured Tissues which Heal Without a Scar? Current Drug Targets. 16(12): 1332-1346. PubMed PMID: 26302807.
Pritchard MT, Apte U. 2015. Animal models to study liver regeneration in Liver Regeneration: Basic Mechanisms, Relevant Models and Clinical Applications. 1st Edition, Elsevier, p.15 - 40.
DeSantis DA, Lee P, Doerner SK, Ko CW, Kawasoe JH, Hill-Baskin AE, Ernest SR, Bhargava P, Hur KY, Cresci GA, Pritchard MT, Lee CH, Nagy LE, Nadeau JH, Croniger CM. 2013. Genetic resistance to liver fibrosis on A/J mouse chromosome 17. Alcoholism: Clinical and Experimental Research. 37(10):1668-79. PubMed PMID: 23763294.
Chiang DJ, Roychowdhury S, Bush K, McMullen MR, Pisano S, Niese K, Olman MA, Pritchard MT, Nagy LE. 2013. Adenosine 2A receptor antagonist prevented and reversed liver fibrosis in a mouse model of ethanol-exacerbated liver fibrosis. PLoS One. 8(7):e69114. PubMed PMID: 23874883. *TOP 25%
MOST CITED PLOS ONE ARTICLES (as of June 2017)*
Dixon LJ, Barnes M, Tang H, Pritchard MT, Nagy LE. 2013. Kupffer cells in the liver. Comprehensive Physiology. 3(2):785-97. PubMed PMID: 23720329.