Dr. Lester. F. Lau
- PhD, Cornell University
- Postdoctoral Fellow, Johns Hopkins University School of Medicine
Extracellular Matrix Signaling in Wound Healing, Inflammation, and Cancer
The extracellular matrix plays critical roles in regulating diverse biological and pathological processes, including developmental morphogenesis, wound healing and tissue repair, inflammation and host defense, and progression of diseases including cancer. Our laboratory is interested in the biological functions of CCNs, a family of cysteine-rich, dynamically expressed matricellular proteins that regulates a broad spectrum of cellular activities through direct binding to integrin receptors. Whereas CCN1 is required for cardiovascular development during embryogenesis, in adulthood it plays critical roles in wound healing, inflammation, and tissue regeneration. Aberrant expression of Ccn1 is associated with pathologies related to chronic inflammation and injury repair. We are elucidating the functions of CCN1 using mouse models that are genetically altered in Ccn1 by targeted and conditional knockouts, allelic replacements, and transgenic expression.
Wound healing and tissue regeneration
In the liver, CCN1 is essential for the regeneration of bile ducts as a result of cholestastic injury through its activation of Notch signaling in cholangiocytes and hepatic progenitor cells, leading to progenitor cell differentiation into cholangiocytes and proliferation of cholangiocytes. In the intestine, CCN1 promotes mucosal healing and restitution after damage from colitis, in part through the activation of IL-6. After regeneration of parenchymal tissue in wound repair, CCN1 directly induces cellular senescence in myofibroblasts, thereby triggering the expression of an anti-fibrotic genetic program to dampen and restrict extracellular matrix deposition, thus limiting fibrosis. These findings indicate that CCN1 regulates multiple aspects of wound healing in various tissues, suggesting a potential therapeutic value in tissue repair. Our current work focuses on how CCN1 directs tissue regeneration in the liver, intestine, and skin.
Inflammation and cancer
Our recent studies have shown that CCN1 is an opsonin that promotes the phagocytic clearance of apoptotic neutrophils by macrophages in cutaneous wound healing. Since CCN1 promotes wound repair and regulates the resolution of inflammation, it is not surprising that through these activities CCN1 is also able to reduce the risk of inflammation-related tumorigenesis. Indeed, CCN1 suppresses carcinogen-induced liver cancer. We are currently examining the mechanism of CCN1 action in tumor suppression in multiple models of carcinogenesis.
Aleksandar M. Babic, M.D., Ph.D., St. Louis Cord Blood Bank
Ian J. Davis, M.D. Ph.D., University of North Carolina at Chapel Hill
Carrie Franzen, Ph.D., Loyola University Medical Center
Tatiana M. Grzeszkiewicz, M.D., Ph.D.,Palo Alto Medical Foundation
Thomas H. Hazel, Ph.D., Neuralstem, Inc.
Vladislava Juric, Ph.D., Gilead Sciences
Maria L. Kireeva, Ph.D., National Cancer Institute
Branko V. Latinkic, Ph.D., Cardiff University, UK.
Shr-Jeng Leu, Ph.D., Yang Ming University, Taiwan
Fan-E Mo, Ph.D., National Cheng Kung University, Taiwan
Ricardo I. Monzon, Ph.D., Saint Xavier University
Dimitri G. Pestov, Ph.D., University of Medicine and Dentistry of New Jersey
Zaklina Strezoska, Ph.D., GE Health Care
Viktor Todorović, Ph.D., AbbVie
Gregg T. Williams, Ph.D., Abbott Laboratories Diagnostics Division
Mayme Wong, Ph.D., Eli Lilly and Company
George P. Yang, M.D., Ph.D., Stanford University
Jeong Kyo Yoon, Ph.D, Maine Medical Center Research Institute
Jennifer Young, Ph.D., University of Rochester
Jun, J-I., Kim, K.H., and Lau, L.F. (2015) The matricellular protein CCN1 mediates neutrophil efferocytosis in cutaneous wound healing. Nat. Commun., 6:7386 doi: 10.1038/ncomms8386.
Kim, K.H., Chen, C.-C., Alpini, G. and Lau, L.F. (2015) CCN1 induces hepatic ductular reaction through integrin αvβ5-mediated activation of NFκB. J. Clin. Invest. 125:1886-1900.
Jun, J.I. and Lau, L.F. (2011) Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets. Nat. Rev. Drug Discov. 10:945-963.
Jun, J.I. and Lau, L.F. (2010) The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat. Cell Biol. 12: 676-685