David Sassoon is the Director of the U787-Myology Group (INSERM-UPMC-Association Institut de Myologie) at the Institute of Myology. His research focuses on stem cell regulators. In March he will publish an article* on a new population of muscle resident interstitial cells that have very promising properties for cell therapy. Two teams from the group led the research: one directed by Giovanna Marazzi & David Sassoon, the other by Edgar Gomes. How did you discover PICs?
Immunofluorescence staining was used to label the transcription factor, Pax7 and regulatory factor, PW1 on muscle sections. We were thus able to identify a novel small subpopulation of interstitial cells (PW1+/ Pax7-) that we called PICs (for PW1 + Insterstitial Cells) that are distinct from satellite cells (SAT) (PW1+/ Pax7+). On a muscle section, we observe as many PICs SAT cells. (photo)
Until now SAT cells have been considered “the” muscle stem cells, thus responsible in particular for regeneration and growth. However, we have observed that they do not divide easily and therapies with these cells do not work very well (except for the treatment of very small muscles such as the eye muscles). They do not include all of the qualities of stem cells from other tissues. What are the characteristics of these cells?
The fate of PICs is variable; they therefore represent a population of true stem cells. Their pluripotency allows them to both differentiate into several cell types and to replicate in significant proportions.
For example, in vivo, if freshly isolated PICs are injected into a muscle, some differentiate into SAT cells, many into muscle fibres and many replicate into PICs. When PICs are grown in vitro, a majority becomes smooth muscle and no longer expresses PW1, and the minority that remain PW1+ begins to express all of the genes involved in myogenesis to become skeletal muscle fibres. Henceforth, the PICs lose their plasticity. We are therefore investigating which local in vivo signals stimulate PICs replication.
In addition, we have observed that there are many PICs at birth and that their number decreases with age, unlike SAT cells whose number remains stable. In the article you state that PICs do not come from the same cell lineage as SAT cells. What are the consequences?
This upsets the “dogma” that the muscle lineage is well established in the embryo. Here we show that half of the population of myogenic cells, until now ignored although it has the most robust and richest stem cell potential, does not come from this lineage! We will now investigate the potential of these cells that are extremely interesting for therapy. But as I said earlier, we must identify the signals that allow their replication. Does this discovery open new perspectives for cell therapy?
We have demonstrated that PICs trigger positive signals for muscle. Furthermore, we have shown that the number of PICs is very important for healthy muscle tissue, that the communication PICs/SAT cell is essential for the SAT cell. This is all very promising to improve cell therapy. What are the next steps?
For the time being, we have just begun a 5-year project supported by the European Community (EC-FP7). Three trials are planned concerning the mobilization of stem cells in muscle and blood vessels. The idea is for 15 teams and 3 companies to work together; clinical researchers, researchers working to find a therapy and researchers with a more fundamental focus, keeping in mind the importance of this translational research. As project coordinator, I managed to steer the course of the project in order not to conduct it linearly, following the “bench to bedside” direction but rather to start based on the results of research that is already well advanced. Which will then allow us the time to ask i) why it did not work, or ii) why it did not work as well as expected, or iii) why it worked better than expected. This is a more circular than linear functioning!
Finally regarding regenerative medicine, transplantation of PICs is a possible approach but presently extremely expensive and complicated, even so, it is interesting to continue research in this direction. One can imagine correcting one’s own cells and reinjecting them, but there is still a low risk (increasingly better controlled) related to the use of viruses. In the end, what appears to be the easiest to achieve is the search for existing pharmaceutical molecules, targeted to stimulate stem cells or to improve the tissue environment. This appears to be achievable the most rapidly.
* Mitchell KJ, Pannérec A, Cadot B, Parlakian A, Besson V, Gomes ER, Marazzi G, Sassoon DA. Identification and characterization of a non-satellite cell muscle resident progenitor during postnatal development. Nat Cell Biol. 2010 Jan 31. [Epub ahead of print] February 2010Interview by Anne Berthomier, translation by Racquel N. Cooper