It has been suggested that bone repair following craniofacial injury could be supported by a stem cell niche in the sutures. A new paper in Development identifies a key role for neural crest-derived progenitors in skull repair and suggests that injuries close to the sutures heal more efficiently, possibly due to better access to these progenitors. To learn more about the story behind the paper, we caught up with first author, Daniel Doro, and corresponding authors Sachiko Iseki, Professor at Tokyo Medical and Dental University, Japan, and Karen J. Liu, Professor of Genetics and Development at King's College London, UK.
Left to right: Daniel Doro, Karen Liu and Sachiko Iseki
Sachiko and Karen, can you give us your scientific biography and the questions your labs are trying to answer?
KJL: My group works on neural crest development, and I had been following Professor Iseki's career for many years. In fact, her work on embryonic origins of cranial bones, begun during her postdoctoral training in Professor Gillian Morriss-Kay's lab, was the basis and inspiration for this work. Sending Daniel to Tokyo, after his PhD in my group at King's College London, was a great opportunity for our teams to work closely together and to examine neural crest contributions in repair.
SI: As mentioned above, I worked with Gillian Morriss-Kay as a postdoc, and we started research on skull development in association with craniosynostosis, defined as early obliteration of one or more cranial sutures. This was at the beginning, when people began to find the genes responsible for this condition, so it was clear we needed to understand the underlying developmental biology. Since I've had my own independent lab, we have been lucky to continue working on craniofacial development and regeneration with good collaborators, including Karen and Daniel.
Daniel, how did you come to work in the lab and what drives your research today?
DD: After I finished my Masters in Genetics back in Brazil, I was very keen to do a PhD in an area where I could apply all the molecular biology tools that I had acquired and also work with mouse models. Professor Karen Liu very kindly gave me the opportunity to join a project on craniofacial development that later evolved into a more regenerative/stem cell biology study. My current interest has shifted towards bone cancer research, where the bone biology that I learned during my PhD has been very useful.
Tell us about the background of the field that inspired your work
KJL, SI & DD: Both teams were interested in the embryonic origins of the calvarial bone and the implications for congenital anomalies, such as craniosynostosis or premature closure of the cranial sutures, which can be a serious problem in babies. In 2015, a number of groups described the existence of a calvarial stem cell niche, inspiring us to consider the interplay between the neural crest lineage and craniofacial stem cells, and what these cells might do later in life.
Can you give us the key results of the paper in a paragraph?
KJL, SI & DD: First, we provided unique fluorescent visualization of the neural crest/mesoderm boundary at the cranial sutures in adults. This gives us finer resolution and updates our understanding of initial observations made in the early 2000s. Then, we combined wounding experiments to show that suture proximity is an important factor in cranial healing, and that all the sutures harbour stem cell populations. Importantly, the neural crest contribution to repair is detectable in every cranial defect, irrespective of the embryonic origin of the bone and adjacent suture.
Importantly, the neural crest contribution to repair is detectable in every cranial defect, irrespective of the embryonic origin of the bone and adjacent suture
When doing the research, did you have any particular result or eureka moment that has stuck with you?
DD: I remember often seeing the odd distribution of the neural crest suture mesenchyme in the neural crest-lineage traced mouse heads and finding it somewhat different from the schematics in the literature. One day I felt like I needed to have a conclusive view of the neural crest-mesoderm boundary in those specimens. I decided to scan the region of interest with high resolution microscopy; this was a long, laborious and costly procedure, but it paid off. When I saw the very clear boundary in the midline, I instantly felt like the literature needed some updating.
Wnt1::cre (left) and Mesp1::cre (right) drivers reveal neural crest and mesoderm lineages in cranial sutures in adult mice. Membrane green fluorescent protein (green) labels cre-expressing tissues, while membrane tomato (red) labels cre-negative cells.
And what about the flipside: any moments of frustration or despair?
DD: Those were always present. What most people outside science do not realise is that very often our work feels painfully slow and unrewarding. This work was started years ago, during my PhD! We spend so much time troubleshooting, or life gets in the way, so there is never enough time to properly explore. But the few eureka moments make it worth the effort.
Why did you choose to submit this paper to Development?
KJL, SI & DD: We felt that the major findings of this study would interest developmental biologists working on cranial development and that they illustrate the importance of development in regeneration. As such, Development felt like a very fitting vehicle to update the scientific community.
What is next for you after this paper?
KJL, SI & DD: We have more exciting work coming up regarding suture contributions for repair in the context of craniosynostosis syndromes, which also highlight the ontological differences of osteoprogenitors derived from different embryonic layers.
Where will this story take your labs next?
KJL: The neural crest lineage has fascinating cell behaviours and we would love to follow these cells live in the embryo, when they are migratory, and later in life, when they reactivate. This is still challenging, so we also use 3D-explant cultures, which help us understand cell-environment interactions.
Finally, let's move outside the lab – what do you like to do in your spare time?
DD: I am a confessed ‘wanderluster’. I'm always looking for opportunities to travel and experience different places, peoples, cultures, etc.
KJL & SI: As you can see, we are an international team (UK-based Brazilian and American with Japanese)! We all love to travel and try new foods!
D.D. & K.J.L.: Centre for Craniofacial & Regenerative Biology, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London SE1 9RT, UK.
D.D. & S.I.: Department of Molecular Craniofacial Embryology and Oral Histology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan.
E-mail: [email protected]; [email protected]; [email protected]