Research

Current research projects include:
  1. Molecular regulatory mechanisms of cranial neural crest cell fate determination:

One of the key features of craniofacial development is the formation of the cranial neural crest (CNC) cells.  The specification, migration, proliferation, survival and ultimate fate determination of the CNC cells play important roles in regulating craniofacial development.  Unlike the trunk neural crest, CNC cells give rise to an array of cell types during embryonic development.  For example, CNC cells form most of the hard tissues of the head, such as bone, cartilage and teeth, whereas hard tissues in the rest of the body are formed from mesoderm cells.  Genetic disorders, environmental insults or the combination of both can alter the fate determination of CNC cells and result in craniofacial malformations.  We have established multiple clinically relevant transgenic animal models which have fundamentally changed the way we study CNC cells in development and diseases (Chai et al., 2000; Yuan et al., 2020). Our research, in conjunction with the work of others, has significantly advanced the understanding of how this important population of pluripotent cells is initially established in the early embryo and the molecular mechanisms that mediate neural crest cell lineage segregation, differentiation and final contribution to a particular tissue type.

  1.  Molecular regulation of CNC-derived mesenchymal stem cells and craniofacial tissue regeneration:

The in vivo identity of mesenchymal stem cells (MSCs) and the niche that regulates MSCs are poorly understood. We have recently identified CNC-derived MSCs in adult jawbones. These MSCs have stem cell properties and can give rise to different cell types in craniofacial tissue regeneration. In parallel, using a mouse incisor model, we discovered that the neurovascular bundle (NVB) acts as an MSC niche and sensory nerves provide Shh protein, activating Gli1 expression in periarterial cells that contribute to all mesenchymal derivatives. These periarterial cells do not express classical MSC markers used to define MSCs in vitro.  NG2+ pericytes represent a MSC subpopulation derived from Gli1+ cells; they contribute little to homeostasis but are actively involved in injury repair (Zhao et al., 2014).  In parallel, we recently discovered that craniosynostosis results from diminished MSCs in cranial sutures and manipulation of MSCs can generate a new biological suture for animal models with craniosynostosis (Zhao et al., 2015). Collectively, these discoveries position us to translate our basic research into patient care and will provide long lasting benefits for our patients.

  1. Molecular and cellular regulatory mechanism of palatogenesis:

Cleft palate is one of the most common congenital birth defects and adversely affects the quality of life. Although many mutant animal models with cleft palate have been generated, many of them do not correlate with palatal defects seen in humans. Significantly, my research program has been focusing on TGF-β signaling mechanisms in regulating tissue-tissue interactions to control craniofacial development and how abnormal TGF-β signaling causes congenital malformations. We have generated important animal models that closely mimic the cleft palate condition in humans. Our work has provided crucial evidence that mutation in Tgfb causes cleft palate in mice and humans.  Most importantly, we have made significant progress in identifying the molecular signaling mechanisms that are responsible for causing cellular defects and cleft palate (Iwata et al., 2012). Furthermore, we have identified a novel TGF-β signaling mechanism that regulates embryonic development. We have applied this information and prevented cleft palate in Tgfb mutant mice. Our study will help to develop important diagnostic biomarkers and drug targets for the prevention and treatment of patients with congenital malformations.

  1. Cranial suture MSCs and craniosynostosis:

Craniosynostosis results from premature fusion of the cranial suture(s), which contain mesenchymal stem cells (MSCs) that are crucial for calvarial expansion in coordination with brain growth. Infants with craniosynostosis have skull dysmorphology, increased intracranial pressure, and complications such as neurocognitive impairment that compromise quality of life. Animal models recapitulating these phenotypes are lacking, hampering the development of urgently needed innovative therapies. Our recent studies have shown that Twist1+/- mice with craniosynostosis have increased intracranial pressure and neurocognitive behavioral abnormalities, recapitulating features of human Saethre-Chotzen syndrome. Using a biodegradable material combined with MSCs, we have successfully regenerated a functional cranial suture that corrects skull deformity, normalizes intracranial pressure and rescues neurocognitive behavior deficits. MSC-based cranial suture regeneration offers a paradigm shift in treatment to reverse skull and neurocognitive abnormalities in this devastating disease. Our current study continues to address how suture MSCs interact with the dura and lymphatic system inside the cranium to control suture patency and coordinate brain development and function.

  1. Regulatory mechanism of tooth root development:

The investigation of the regulatory mechanism of tooth development offers an important opportunity to test how tissue-tissue interactions control organogenesis. To date, most studies have focused on early stages of tooth development. We have very limited information on the molecular regulatory mechanism of tooth root development despite the fact that dental roots are crucial for the physiological function of our dentition and oral health. Furthermore, dental root defects resulting from developmental malformations, pathological conditions and dental treatments are common and significantly compromise quality of life. Using different mutant models, we have shown that Bmp/Tgf-β, Shh, Fgf, and Nfic are involved in regulating root development. With our recent publications, we have provided a better understanding of how the Bmp/Tgf-β signaling cascade regulates the interaction between the dental epithelium and mesenchyme during tooth root development and how signaling pathway disruption can lead to craniofacial malformations. The knowledge gained from this study will serve as the foundation for stem cell-mediated tooth regeneration.

  1. FaceBase Consortium:

Our group has been  intimately involved in the design and operation of the FaceBase Consortium from its inception, and I served as the Chair of the Steering Committee in FaceBase 1 and 2. We have contributed a total of over 460 datasets to FaceBase to date through our  spoke projects on palate and jaw development in FaceBase 1 and 2, respectively, as well as our ongoing efforts in FaceBase 3. Along with Carl Kesselman of USC’s Information Sciences Institute (ISI), I serve as Co-PI of the FaceBase Hub. Our team works in close concert with ISI scientists to identify, recruit, and curate datasets; develop innovative new features; and conduct outreach and training activities for FaceBase users and contributors. We continue to build FaceBase as an important and comprehensive data resource for the research community.

  1. C-DOCTOR:

The Center for Dental, Oral, and Craniofacial Tissue and Organ Regeneration (C-DOCTOR) is one of two resource centers that comprise the Dental, Oral, and Craniofacial Tissue Regeneration Consortium (DOCTRC), which was established in March 2017 through cooperative agreements from NIDCR. DOCTRC’s objective is to develop resources and strategies to regenerate damaged or injured dental, oral, and craniofacial tissues. The DOCTRC initiative was designed to shepherd new therapies through pre-clinical studies and into human clinical trials, commercialization, and broad clinical adoption. Along with Jeffrey Lotz, PhD of the University of California, San Francisco, I serve on the C-DOCTOR Internal Leadership Council as a co-PI. In addition to this administrative role, I lead the Interdisciplinary Translational Project titled “Calvarial Bone Regeneration Using 3D-Printed Scaffold and Bone Marrow Aspirate.” Our group has been completing preclinical activities to prepare for submission of an Investigational Device Exemption (IDE) package to the FDA to enable a Phase I clinical trial in humans. These preclinical activities include completion of safety and efficacy studies in small and large animal models (e.g., mice, rabbits, and swine); medical device packaging design and validation; sterilization validation; stability testing; and biocompatibility testing. We are committed to translating research from bench to bedside and making an impact on the lives of patients around the world.