Michele Pritchard, PhD
Associate Director, Interdisciplinary Graduate Program in Biomedical Sciences
Pharmacology, Toxicology & Therapeutics
PhD, University of New York at Buffalo
Postdoctoral, Case Western Reserve University
Postdoctoral, Cleveland Clinic
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 the 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.