Adhesion of muscle stem cells to their niche provides stable anchorage, and biochemical and biomechanical signals required for quiescence. In their work, Robert Krauss and colleagues reveal the role of catenin/cadherin-based adhesion interactions in maintaining niche localization. To find out more about their work, we spoke to the first author, Margaret Hung, and the corresponding author, Robert Krauss, Professor in Cell, Developmental and Regenerative Biology at the Icahn School of Medicine, Mount Sinai.
Margaret Hung (left) and Robert Krauss (right)
Robert, can you give us your scientific biography and the questions your lab is trying to answer?
RK: I was originally trained as a cancer biologist, but the natural direction of discoveries made in my lab moved us first into developmental biology and subsequently into stem cell biology (which is of course a branch of developmental biology). As a student and postdoc, I followed the research that led to the discovery of MyoD by Andrew Lassar and Hal Weintraub, and when the opportunity arose to work in skeletal myogenesis, I jumped in eagerly. The overarching question driving our current work is, how do quiescent stem cells detect tissue damage to initiate the quiescence-activation transition required for successful regeneration? Muscle stem cells (MuSCs) usually do not detect the agents of injury themselves; rather, they detect that myofibers have been injured. Yet the transition out of quiescence begins just seconds after muscle is damaged. We therefore hypothesize that very rapid changes to the niche are sensed by MuSCs. Niche adhesion molecules will certainly play an important role in this process, and our paper in Development addresses roles of classical cadherins as niche factors.
Margaret, how did you come to work in the lab and what drives your research today?
MH: After finishing my MS in cancer biology, I was looking to shift my focus towards stem cells and regenerative biology. I had no background in muscle biology, but I was fascinated by the regenerative capacity of skeletal muscle and the open questions Rob was trying to answer for the field. Another significant aspect of my decision to join the lab was the exceptional mentorship from Rob, which I felt would set a great foundation for my professional future. Currently, I am continuing research in muscle biology at Regeneron Pharmaceuticals, New York, to drive therapeutic development for genetic muscle diseases and metabolic disorders.
Tell us about the background of the field that inspired your work
MH and RK: There was previously an understanding that apical, cadherin-based adhesion was important for maintenance of MuSC quiescence. Although a previous study from our lab offered strong support for this conclusion, MuSCs that lacked two major cadherins, N- and M-cadherin, were still able to maintain apical adhesion, remain in the niche and mount a regenerative response. We sought to determine what happens when cadherin-based junctions were completely ablated in MuSCs.
Can you give us the key results of the paper in a paragraph?
MH and RK: When either pair of compensatory cadherin-binding partners (αE-/αT-catenin or β-/γ-catenin) is genetically removed from MuSCs, the cells are gradually lost. We demonstrated in vivo that MuSC attrition is due to inappropriate activation, precocious differentiation and eventual fusion into the adjacent myofiber. Additionally, cadherin-based adhesion is necessary for MuSCs to return to the niche after acute injury and regeneration.
When doing the research, did you have any particular result or eureka moment that has stuck with you?
MH: One of the great joys of science is being the only person to know a scientific result, even if only for a moment. One evening, I was at the microscope when I saw a MuSC outside its niche, and then another. On top of that, some were activated. It was the perfect piece of data to kick off characterizing the in vivo phenotype and I was ecstatic!
Transverse section through mouse hindlimb skeletal muscle, with an α-catenin-deficient MuSC actively cycling. The MuSC is labelled for Pax7 (magenta) and Ki67 (grey); myofibers are encircled by wheat germ agglutinin (green) and nuclei are marked with DAPI (blue).
And what about the flipside: any moments of frustration or despair?
MH: Looking back, I remember how much time each of those data points required and how much troubleshooting went into them. While most of the work was exciting and stimulating, sometimes it felt extremely slow, with rewards few and far between. Seeing it all together and sharing it with the scientific community has made it worth the wait!
Why did you choose to submit this paper to Development?
RK: First, we both admire Development and its rigorous but fair review process. Each issue has many papers we find interesting and the overall layout, including front section matter like this, is excellent. Second, The Company of Biologists is a great institution, and we like to support it. We're both huge supporters of sustainability and biodiversity initiatives. When The Company of Biologists announced their Forest of Biologists initiative in partnership with the Woodland Trust last year, it was heartening to see a tangible investment in conservation. And now we're lucky enough to have contributed to it! Most importantly, we felt that this story was a natural fit for the journal. One of our colleagues who read a draft of the paper made the same suggestion without our mentioning which journals we were considering, and that sealed it!
When The Company of Biologists announced their Forest of Biologists initiative in partnership with the Woodland Trust last year, it was heartening to see a tangible investment in conservation
What is next for you after this paper?
MH: I've recently moved into the biotech sector and am happily still involved in the muscle biology field. I think muscle diseases are an underserved area of clinical development and am eager to contribute to new therapeutic research.
Where will this story take your lab next?
RK: We are eager to identify additional niche factors that promote MuSC quiescence and understand how their functions must be overridden by injury-induced changes to the niche. The signalling mechanisms that underlie these processes are largely obscure and challenging to study. Our recent work argues that the MuSC cytoskeleton is dynamic, even during quiescence, and that changes in those dynamics underlie the transition to the activated state. We hope to identify and understand these processes.
Finally, let's move outside the lab – what do you like to do in your spare time?
MH: I love spending time with my dog, and reading and traveling. The east coast is so beautiful in the autumn, so I enjoy heading out of New York City and hiking too.
RK: I enjoy traveling, reading, music (favourites are The Beatles and Miles Davis), movies and tennis – both watching the professionals and playing (though not often enough).
M.H. & R.K: Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
R.K.: Bioinformatics for Next Generation Sequencing Core, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
E-mail: [email protected]
