Understanding Craniofacial Development

No region of our anatomy more powerfully conveys our moods and emotions than the face, nor elicits more profound reactions when a disease or genetic disorder leaves behind a disfigurement. In recent years, remarkable strides have been made toward elucidating the molecular mechanisms that regulate craniofacial morphology. Key to those insights is a deeper understanding of the cranial neural crest, an embryonic cell population with nearly unparalleled pluripotency. What factors drive cranial neural crest cell migration, proliferation and differentiation has been under intense investigation for nearly 150 years, yet we are still gaining insights into this regulation through the use of experimental and genetic manipulations in mice, birds, and fish.

The most basic features of the face go back to the dawn of vertebrate development and the master sculptor of the face is evolution. Following in the footsteps of Darwin (whose interest in beak morphology was piqued by studying domesticated pigeons), investigators continue to unravel how variations in facial form arise. These discoveries are not only applicable to the bird beaks: Nature appears to have developed a common blueprint for the face, the same molecular mechanisms that control growth and patterning in a bird beak also regulate facial development in mammals.

Beyond understanding the genetic, molecular, and cellular processes that regulate normal craniofacial development we must also remember how differences in facial anatomy deeply affect an individuals’ self-perception and their acceptance in our beauty-conscious society. Poets and scientists alike recognize that the face is an elemental part of our makeup. We must constantly remember how “looking different” can impact all aspects of a person's life, far beyond the physical limitations that may be imposed by a deformity. 

Biomechanics and Implant Biology

Biomechanical conditions dictate how tissues heal. If sub-optimal mechanical boundary conditions prevail, then even the most potent stem cell-inducing factors and cell therapies are ineffective. Consequently, our laboratory has focused on the simple question of how skeletal stem cells, residing within a bone injury site, actually respond to mechanical stimuli. In this proposal our goal is to understand how skeletal stem cells that surround an implant respond to the mechanical stimulus of implant loading. We have, for the first time, the ability to precisely control and quantify the mechanical stimulus and then to directly test how that mechanical stimulus affects cell behavior. 

In this proposal our goal is to understand how skeletal stem cells, residing within a bone injury site, actually respond to mechanical stimuli.

Using novel, genetically engineered mice we can detect the type of physical stimulus required to transcriptionally activate the Wnt signaling pathway; we can then follow cells that respond to this mechanically-induced Wnt signal and determine their ultimate fate in an in vivo environment.Never before have we had the ability to so precisely regulate the molecular signals and mechanical stimuli that shape the skeleton Our long-term goal is to leverage this knowledge, and our understanding of mechanically-coupled Wnt signaling, to optimize bone regeneration in a variety of contexts including implant osseointegration.

Aging and the skeleton 

Our skeletons become progressively more fragile as we age and this fragility translates into poor bone healing potential. Why does this happen? And can the effects be reversed? Stem cells in the bone marrow cavity are partly responsible: instead of becoming bone-producers, these stem cells become fat-producers. Understanding when and how human stem cells degenerate may explain why some conditions, such as delayed bone healing, increase with age and also why bone grafts from elderly people tend to fail. 

Our research focuses on mesenchymal stem cells (MSCs) that reside in the marrow cavity. We know that MSCs from healthy people over age 65 make less bone compared to MSCs from healthy people under age 35, irrespective of their sex. We set out to understand why MSCs lose this bone-forming capacity and have found that bone marrow from healthy, aged animals has significantly reduced levels of the stem cell factor, Wnt3a compared to bone marrow from healthy young animals. Treating bone marrow from aged animals with Wnt3a restores their bone-forming ability back to levels seen in bone marrow from young animals. We are working on moving these kinds of laboratory discoveries into clinical applications. As the 78 million-member baby boom generation enters their seventh and eighth decades of life they are living longer and expecting to enjoy better fitness and health than previous generations. We hope that these findings will translate into “regenerative medicine” strategies that have the potential to transform musculoskeletal health in the elderly. 

Building a tooth

William Blake famously penned, “To see the world in a grain of sand and to see Heaven in a wildflower…” (W. Blake, 1803): which is an unlikely- but fitting- metaphor for the study of the dentition. By unraveling the tissue interactions that control the development and patterning of teeth, we are gaining new insights  into how this unique craniofacial organ is generated. One day, soon, these same factors may be harnessed to regenerate a diseased dentition. For example, research in our group has focused on regenerating the dental pulp.

Our goal of regenerative dental medicine is to stimulate from stem/progenitor cells residing in the pulp cavity the generation of dentin and in doing so, preserve the vitality and function of teeth.

Most toothaches are the result of chronic bacterial infections that cause inflammation of the connective, vascular, lymphatic and nervous tissues occupying a chamber in the center of the tooth. When these tissues, collectively referred to as the pulp, become chronically inflamed they must be removed in a procedure known as a root canal treatment. In an effort to treat these conditions, a century’s old procedure called pulp capping is often employed. When the inflammatory insult is acute, and the extent of trauma is mild, then the pulp itself can sometimes mount a repair response. Our goal of regenerative dental medicine is to stimulate from stem/progenitor cells residing in the pulp cavity the generation of dentin and in doing so, preserve the vitality and function of teeth. We are testing whether WNT proteins can stimulate stem cells in the adult pulp, which would result in a superior repair repair response. Our data is encouraging: rodent pulp cavities treated with WNT show significantly more dentin formation, suggesting that a therapeutic strategy involving a WNT protein may one day obviate the need for root canals.

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