Growing muscle out of dogmas: all stem cells are not alike for rules

Out-of-the-ordinary activities such as climbing lots of steps or even normal exercise can put significant strain on muscles. Such activities cause tiny tears in the muscle fibers, which the body then repairs on its own. Even when injuries occur, the muscles activate an endogenous regeneration program: a reserve supply of muscle stem cells, known as satellite cells, reside around the muscle fibers and are essential for the repair of damaged muscle cells. Of course, they repair limited damages; it is impossible to regenerate an entire lost muscle, at least with the current scientific knowldge. These satellite cells produce new muscle fibers in a process which results in muscle regeneration. People maintain this ability well into old age. Researchers are particularly interested in these cells, since they could provide targets for new therapeutic approaches for people with muscle diseases, like Duchenne muscular dystrophy. Now scientists have discovered a new subtype of muscle stem cells. These cells have the ability to build and regenerate new muscles, making them interesting targets for the development of gene therapies.

Prof. Simone Spuler, scientist and physician, is a research group leader at the Experimental and Clinical Research Center (ECRC), a joint institution of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and Charité – Universitätsmedizin Berlin, and heads the Myology Group at the MDC. He explained: “Researchers previously assumed that a certain protein – the transcription factor PAX7 – plays a key role in muscle regeneration. Cells from which new muscles arise have enormous potential for developing gene therapies to treat muscle atrophy. And PAX7 is actually onsidered a characteristic property of muscle-building satellite cells. I, by myself, was initially guided by the assumption that the transcription factor was crucial for muscle growth”. The team has now reported in the journal Nature Communications that it’s possible for muscles to grow and regenerate without PAX7. The study characterized a previously unknown subtype of satellite cells that could play an important role in the future development of gene therapies from muscle stem cells.

The research team owes the discovery to a young girl: Lavin has suffered from a genetic form of muscular dystrophy since birth and is the protagonist in the study. Lavin has all the muscles of a healthy person, but each of her muscles is very small. The musculature along her spine is particularly affected by the disease. Lavin’s arms and legs are strong, but she suffers breathing problems and has difficulty bending forward and holding her head up. Gene analysis shows that the gene for PAX7 is damaged in Lavin; her cells can’t produce this protein. The University Hospital Munich discovered this in 2017. Soon thereafter, Dr. Spuler learned of this extremely rare mutation, one that had not been described before. Lavin traveled with her parents to the Berlin-Buch campus, where the scientists took a sample of her muscle tissue. The researchers used a new procedure to filter out Lavin’s satellite cells and then implanted them in mice. They observed that new muscle fibers grew in the mice from Lavin’s cells – despite the absence of PAX7.

Spuler presumes that PAX7 is not equally important for every cell. This would explain why Lavin can walk and climb relatively well, but has hardly any strength in her diaphragm, which causes the breathing problems. But Spuler’s lab is working intensively to figure out how to repair defective genes in muscle cells. For Lavin and her family, this research offers a small glimmer of hope that a suitable therapy will be found. The team collaborated on the study with many colleagues at the MDC and with scientists from institutions abroad. Prof. Nikolaus Rajewsky’s research group at the Berlin Institute for Medical Systems Biology (BIMSB) compared Lavin’s cells with those donated by healthy people. Single-cell analysis, which looks at the activity of each cell individually, revealed a previously unknown cell population. In around 20% of the donors, the majority of the activated satellite cells also don’t produce any PAX7, even though the genetic information is present in the cells. The team instead discovered something else in those cells in which the transcription factor was missing: CLEC14A, a protein that is found in many blood vessel cells. This very protein was highly expressed in Lavin’s muscle stem cells.

Overall, the new study describes a previously unknown subtype of satellite cells. First, the researchers identified these cells in the stem cell niche, which is where the satellite cells reside. Second, master regulator PAX7 is not present in these cells. Third, other characteristic proteins such as CLEC14A are present instead. And fourth, new muscle fibers can be derived from this cell population. Up to now, only cells with PAX7 have been considered as targets for gene therapy research involving satellite cells. The new study shows that the subtype discovered should also play a role in therapeutic development.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Marg A et al., Spuler S. Nat Commun. 2019; 10(1):5776.

Muñoz-Cánoves P, Neves J et al. FEBS J. 2019 Dec 18.

Shimizu K et al., Honda H. J Biosci Bioeng. 2019 Dec 16.

Shelton M et al. PLoS One 2019 Sep 27; 14(9):e0222946.

Incitti T et al. Proc Natl Acad Sci 2019; 116(10):4346–51. 

Mauro A. J Biophys Biochem Cytology 1961; 9:493–495.

Informazioni su Dott. Gianfrancesco Cormaci 1864 Articoli
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry specialty in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Detentore di un brevetto sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of a patent concerning the production of bakery gluten-free products, starting from regular wheat flour). - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica, salute e benessere sui siti web salutesicilia.com e medicomunicare.it