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, liver, ovary, wound repair, aging, iatrogenic insult, fibrosis, regeneration, inflammation, macrophage, hepatic stellate cells, Rhamm, alcohol-associated liver disease, congenital hepatic fibrosis/ARPKD
We view the extracellular matrix as the final frontier of wound healing and aging research. Investigations over decades have identified cells and signaling pathways important for parenchymal cell injury and functional decline. Unfortunately, these advances have not led to improvements in wound repair (i.e. regenerative repair and/or prevention of fibrosis). What lags behind this research is a clear understanding of how the extracellular matrix, the structural elements which help tissues perform their critical biological functions, is involved in these processes. My laboratory strives to fill this knowledge deficit and focuses our research on understanding how biology of the extracellular matrix glycosaminoglycan, hyaluronan, can be leveraged to improve regenerative wound repair and prevent fibrosis that occurs in the context of tissue injury or aging.
Currently, we have 3 ongoing projects exploring hyaluronan biology in fibrosis, and regeneration and are briefly described below.
1. Impact of hyaluronan fragmentation in reproductive aging
Physiologic aging and premature aging induced by iatrogenic insults profoundly affect fertility. Moreover, in physiologic aging, the ovaries age before any other organ and can lead to problems in conceiving a child given the trend in delaying childbearing in Western countries. While most reproductive aging research has focused on the oocyte, our recently published study was the first to demonstrate that the ovarian stroma changes with advanced reproductive age – it becomes fibrotic and inflamed. We have also observed a striking loss of ovarian hyaluronan with age leading us to hypothesize that hyaluronan is involved in age-associated ovarian stromal changes. Current work is testing this hypothesis using sophisticated in vitro systems and in mice, naked mole rats, and in humans. This work is in collaboration with Drs. Francesca Duncan (Northwestern University), Ned Place (Cornell University), and Melissa Holmes (University of Toronto).
2. Hyaluronan-mediated acceleration of alcohol-induced liver injury
Alcohol-associated liver disease (ALD) is incurable using pharmacological agents. Unfortunately, liver transplant remains the only life-preserving strategy for patients with advanced ALD. Many pathological mechanisms driving ALD are known, but none has led to FDA approved therapeutic agents. Moreover, identifying early ALD intervention points will help prevent disease progression, limiting the morbidity and mortality associated with advanced liver disease. Our lab recently discovered a unique accumulation of hyaluronan in livers from donors who consumed alcohol compared to livers from donors who did not consume alcohol. In both cases, the donor livers were steatotic – an early form of liver disease characterized by fat accumulation in hepatocytes. Moreover, the livers with more hyaluronan also exhibited more collagen accumulation suggesting a pathogenic tie between alcohol, hyaluronan, and early fibrogenic chances. Our current studies are testing the hypothesis that alcohol consumption uniquely induces hepatic hyaluronan production and accelerates alcohol-associated fibrogenesis using a novel mouse model of ALD. In addition, because hepatic stellate cells are responsible for hepatic hyaluronan synthesis, we are testing the hypothesis that acetaldehyde, a reactive ethanol metabolite, is required for ethanol-enhanced hyaluronan production.
3. Role for hyaluronan in liver regeneration
Hyaluronan is well-known for its roles in tissue pathology. However, hyaluronan is also an important mediator of development and of ‘scarless’ wound repair (i.e. regeneration). Recent observations from our group have shown, for the first time, that liver regeneration is associated with a robust hyaluronan accumulation. If we inhibit hyaluronan synthesis, liver regeneration is delayed. Moreover, if we look for hepatic hyaluronan in an animal model where liver injury is so severe that livers cannot regenerate, hyaluronan is not produced. Collectively, these data suggest a critical role for hyaluronan in liver regeneration and further suggest that hyaluronan could be used to improve liver regeneration, or even be used as a biomarker to indicate ongoing liver regeneration. Currently, we are focused on three-interrelated areas: 1) identifying the signaling pathways required for regeneration-associated hyaluronan production; 2) exploring the role hyaluronan has on repair-associated macrophage function; 3) interrogating the role of hyaluronan-mediated tissue micromechanics in hepatic stellate cell activation during liver regeneration.
In summary, the long-term goal of our research is to identify ways to prevent organ fibrosis and to improve wound repair by targeting hyaluronan.
Selected Publications accepted or recently reviewed with favorable outcome (from last 6 years):
(* indicates manuscripts for which I am corresponding author.)
Rowley JE, Rubinstein GE, Manuel SL, Surgnier J, Kapitsinou PP, Duncan FE, *Pritchard MT. Tissue-specific fixation methods are required for optimal in situ visualization of hyaluronan in the ovary, kidney, and liver. Journal of Histochemistry and Cytochemistry. Revision submitted, September 1st, 2019.
Quan N, Harris LR, Halder R, Trinidad C, Johnson BW, Horton S, Kimler BF, Pritchard MT, Duncan FE. Differential sensitivity of inbred mouse strains to ovarian damage in response to low dose total body irradiation. Biology of Reproduction. Published August 22nd, 2019.
Dipali SS, Ferreira CR, Zhou, LT, Pritchard MT, Duncan FE. 2019. Histologic analysis and lipid profiling reveal reproductive age-associated changes in peri-ovarian adipose tissue. Reproductive Biology and Endocrinology. 12;17(1):46. PubMed PMID: 31189477.
Jiang L, Fang P, Septer S, Apte U, *Pritchard MT. 2018. Inhibition of mast cell degranulation with cromolyn sodium exhibits organ-specific effects in polycystic kidney (PCK) rats. 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. 2017. Contribution of liver non-parenchymal cells to hepatic fibrosis: Interactions with the local microenvironment (Editorial). 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 of Reproduction (September-December 2016), and was also highlighted by Bioscientifica, the Faculty of 1000, and BBC radio (The Naked Scientists), and has been cited 29 time since it was published in September 2016.
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.
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)*