Tufts Scientists Develop New Model of Stem Cell Behavior

BOSTON — When the integrity of human skin is interrupted, either by injury or surgery, an intricately orchestrated process of wound repair and regeneration ensues. Knowledge of the factors and signals involved in this process has been greatly advanced by the in vitro study of three-dimensional models of human skin, called human skin equivalents (HSEs). At the forefront of this research is a team of scientists in the Division of Cancer Biology and Tissue Engineering at Tufts University School of Dental Medicine (TUSDM). Led by Division Director Jonathan A. Garlick, DDS, PhD, the team recently developed a novel type of HSE and, with more precision than was previously possible, identified a specific structural component of human skin that may be essential for normal stem cell behavior in tissue repair and maturation.

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“Before this study, we knew that intact basement membrane niche provides signals that control the late epidermal stem cells,” says Garlick, the study’s corresponding author. “Yet, tissue culture studies have been limited by the fact that most HSEs have not demonstrated recognizable basement membranes.” He explains, “The basement membrane is a complex of proteins that support the epidermis (the outermost layer of skin), separating it from and attaching it to the underlying dermis.”

In the first study of its kind to investigate how purified basement membrane components direct tissue growth in HSEs, Garlick and colleagues fabricated human three-dimensional tissues by coating polycarbonate membranes with individual basement membrane components and non-basement membrane proteins. They examined the different influences of each of these factors on the growth and development of normal human epidermal cells in tissue culture. “What we learned,” says Garlick, “is that by adapting HSEs to engineer tissues on specific basement matrix proteins coated with Type IV collagen, we can fabricate artificial tissues in which stem cells behave more like they do in living skin.”

“In our models, the presence of the basement membrane Type IV collagen enabled the development of normal tissue structure, supported stem cell proliferation and survival, and improved maturation and organization of the basement membrane zone,” says Garlick, who is a professor in the Department of Oral and Maxillofacial Pathology at TUSDM. He adds, “In the absence of Type IV collagen, these processes did not occur in a manner consistent with what is observed in normal human skin.”

“Our results may have implications for the therapeutic use of artificial skin-like tissues,” says Garlick. “If we are going to successfully replace living tissues with their artificial counterparts, we must capture the regenerative potential of stem cells. The more closely we replicate living human tissue in the laboratory, the closer we get to this goal.”

As director of the Center for Integrated Tissue Engineering (CITE) at TUSDM, Garlick is dedicated to furthering the understanding of human disease through the investigation of three-dimensional tissue models. He believes that future studies utilizing the novel HSEs he and his colleagues have developed may help clarify how specific proteins in the basement membrane microenvironment interact with epithelial stem cells to control their development of a well-organized epithelium, which has important implications for regenerative medicine. CITE is now using HSEs as human, “pre-clinical” or “surrogate” tissues that act as a translational modality to provide more meaningful correlations between in vitro screening assays for toxicity and efficacy and in vivo tissue outcomes in human clinical trials.

This work was supported by a grant from the U.S. Army Medical Research and Materiel Command.

Segal N, Andriani F, Pfeiffer L, Kamath P, Lin N, Satyamurthy K, Egles C, Garlick JA. Matrix Biology. 2008 April;27(3):163-70.”The basement membrane microenvironment directs the normalization and survival of bioengineered human skin equivalents.”  

About Tufts University School of Dental Medicine

Founded in 1868, Tufts University School of Dental Medicine (TUSDM) is committed to leadership in education, patient care, research and community service. Students obtain an interdisciplinary education, integrated with medicine, with access to training in dental specialties. Clinics managed at TUSDM provide quality comprehensive care to more than 18,000 diverse individuals annually, including those with special needs. Nationally and internationally, the School promotes health and educational programs and researches new procedures, materials and technologies to improve oral health.



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