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Mouse teeth give insight into tissue regeneration

Researchers hope to one day use stem cells to heal burns, patch damaged heart tissue, even grow kidneys and other transplantable organs from scratch. This dream edges closer to reality every year — and now, basic research has information from the front teeth of mice that helps.

One of the enduring puzzles for stem cell researchers is how remarkable stem cells know when it's time to expand in number and transform into mature, adult cells able to renew injured or aging tissue.

What is highly observable in mice are their constantly growing incisors. The defining feature of all rodents as mice, too, rely on sharp, chisel-like gnashers to burrow, defend, and gnaw food. Inside the jaw bone, an incisor looks more like a walrus tusk or the teeth of a saber-toothed tiger. Only the sharpened tips show through the gums at the front of the mouse mouth.

As the front of the tooth wears down, a pool of stem cells deep inside the jaw, the innermost part of the tooth, constantly rebuilds each incisor by pushing new growth forward. Imagine the lead in a mechanical pencil being renewed.

"As we grow older our teeth start to wear out. In nature, once you don't have your teeth anymore, you die. As a result, mice and many other animals - from elephants to some primates - grow their teeth continuously. Our lab's objective is to learn the rules that let mouse incisors grow continuously — to help us one day grow teeth in the lab. Also, to identify general principles that could enable us to understand processes of tissue renewal more broadly."

Ophir Klein MD, PhD, Professor, Orofacial Sciences in University of California San Francisco, Department of Pediatrics and Institute for Human Genetics, School of Dentistry and Pediatrics in the School of Medicine, San Francisco, California, USA.

In the study published online April 27, 2017, in Cell Stem Cell, Jimmy Hu, PhD, a postdoctoral researcher in the Klein laboratory, reports that signals sent by surrounding tissues trigger dental stem cells to come out of a dormant state and hop on the conveyor belt of tooth regrowth, beginning the process of transforming from stem cells into mature tooth tissue.

"We usually think of stem cells responding to chemical signals to start proliferating and differentiating, but here there's an exciting interaction between the physical environment surrounding the cells that prompts them to meet the demands of a growing tooth."

Jimmy Kuang-Hsien Hu PhD, postdoctoral candidate, Department of Orofacial Sciences, Program in Craniofacial Biology, University of California, San Francisco, San Francisco, California, USA

Hu and colleagues also found that integrins — the proteins that sit in cell membranes and link a cell's internal skeleton to the larger protein scaffolding of surrounding tissue — trigger a newly described signaling cascade within stem cells causing them to begin rapidly multiplying or "proliferating." Although it's not exactly clear what are these external signals, the authors propose cells could simply be detecting they are in a new region. The back of the tooth needs to actively produce more cells responding to changes in local tissue stiffness and/or physical forces pulling and pushing on the cells.

"Our data clearly show that as stem cells move into their designated proliferating space, they ramp up integrin production. These integrins allow the cells to interact with extracellular molecules and trigger expansion in stem cell number before eventually producing a large pool of mature dental cells."

Jimmy Kuang-Hsien Hu PhD

Of additional interest to the researchers is that both integrins and YAP — a molecule involved in the newly discovered integrin-triggered signaling cascade — have been implicated in the growth of certain types of tumors, which are thought to share some features with stem cell biology. This finding gives more evidence, among cancer researchers, that interactions between cancer cells and surrounding tissue may be a key step in triggering tumor growth.

Klein adds: "Integrins and YAP had been implicated in cancer before, but our work connects the two in an organ as opposed to a Petri dish. Wouldn't it be nice if the same insights that let us learn to grow new tissues in the lab also lead to improved therapies to prevent the growth of tumors in patients?"

• The YAP/TAZ transcriptional cofactors are required for incisor maintenance
• YAP/TAZ prevent premature differentiation of transit-amplifying (TA) cells
• YAP/TAZ activate mTOR signaling to promote TA cell proliferation
• Integrin α3 and FAK regulate YAP nuclear localization via CDC42 and PP1A

Tissue homeostasis requires the production of newly differentiated cells from resident adult stem cells. Central to this process is the expansion of undifferentiated intermediates known as transit-amplifying (TA) cells, but how stem cells are triggered to enter this proliferative TA state remains an important open question. Using the continuously growing mouse incisor as a model of stem cell-based tissue renewal, we found that the transcriptional cofactors YAP and TAZ are required both to maintain TA cell proliferation and to inhibit differentiation. Specifically, we identified a pathway involving activation of integrin α3 in TA cells that signals through an LATS-independent FAK/CDC42/PP1A cascade to control YAP-S397 phosphorylation and nuclear localization. This leads to Rheb expression and potentiates mTOR signaling to drive the proliferation of TA cells. These findings thus reveal a YAP/TAZ signaling mechanism that coordinates stem cell expansion and differentiation during organ renewal.

Additional authors on the study were Wei Du, PhD, of UCSF and Sichuan University in China; Samuel J. Shelton, PhD, and Michael C. Oldham, PhD, of UCSF; and C. Michael DiPersio, PhD, of Albany Medical College in New York. The work was funded by the National Institutes Dental and Craniofacial Research of the National Institutes of Health (R01-DE024988, R35-DE026602, F32-DE023705, K99-DE025874).

About UCSF: UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises three top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children's Hospitals in San Francisco and Oakland, and other partner and affiliated hospitals and healthcare providers throughout the Bay Area. Please visit http://www.ucsf.edu/news.
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Apr 28, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   

A 'cervical loop' (TOP RIGHT) at the back of the mouse incisor is where dental stem cells live and generate new tooth tissue. Klein and lab caused cells to randomly produce different-colored fluorescent proteins, making it easier to tell neighbor cells apart, while they tracked regeneration microscopically.
Image Credit:
Klein Lab / UCSF


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