Muscle and fiber stem cells can be grown in the laboratory from reprogrammed connective tissue cells (microscope image). Credit: ETH Zurich Laboratory / Bar-Nur
Professor Ori Bar-Nur and colleagues at ETH Zurich pioneered the cultivation of muscle cells in the laboratory, currently using mouse cells as their primary model. While their current study is centered on mouse cells, the team is also interested in exploring the potential of human and bovine cells. The implications of their research are manifold: laboratory-cultured human muscle tissue could serve surgical needs, while human muscle stem cells might offer a therapeutic solution for those with muscle diseases. On the other hand, cultivating beef muscle tissue in the laboratory could transform the meat industry by eliminating the need to slaughter animals.
However, for now, the ETH team’s research is focused on optimizing muscle stem cell generation and making it safer. They have now succeeded in doing so through a new approach.
Reprogrammed cells
Like other researchers in the field, scientists at ETH Zurich used a different type of cell that is easier to grow as a starting material for producing muscle cells: connective tissue cells. Using a mixture of small molecules and proteins, they molecularly “reprogram” these cells, turning them into muscle stem cells, which then multiply rapidly and produce muscle fibers.
“This approach allows us to produce large amounts of muscle cells,” explained Xhem Qabrati, a doctoral student in Bar-Nur’s group and one of the two lead authors of the study. “Although muscle cells can also be cultured directly from a muscle biopsy, the cells tend to lose their function once isolated, making it difficult to produce cells in large numbers.”
An important component of the spent cocktail – and a key catalyst for cell transformation – is the MyoD protein. It is a transcription factor that regulates the activity of certain muscle genes in the cell nucleus. MyoD is normally absent in connective tissue cells. Before these cells can turn into muscle cells, scientists must induce them to produce MyoD in their nucleus over a period of several days.
No genetic engineering
Until recently, researchers turned to genetic engineering for this process: They used virus particles to carry the virus DNA blueprint for the MyoD protein into the cell nucleus. There, the virus incorporates these building instructions into the genome, enabling the cell to produce the MyoD protein.
However, this approach carries a security risk: scientists cannot control exactly where the virus genome inserts these instructions. Sometimes viruses integrate into the middle of vital genes, damaging them, or this insertion process can cause changes that can trigger the formation of cancer cells.
This time, Bar-Nur and his colleagues used a different approach to deliver MyoD to connective tissue cells, inspired by an mRNA vaccine to COVID-19: instead of using viruses to insert the DNA blueprint of the MyoD gene, they insert the mRNA transcript of this gene into the cell.
Since this leaves the cell’s genome unchanged, it avoids the negative consequences associated with such changes. The mRNA still allows connective tissue cells to produce MyoD protein, so that – along with other components of the cocktail optimized by the ETH researchers – they can turn into muscle and fiber stem cells.
The researchers recently published their new approach in the journal NPJ Regenerative Medicine. They were the first to reprogram connective tissue cells into muscle stem cells without genetic engineering.
Help with muscular dystrophy
Muscle cells produced in this way are also fully functional, as the researchers demonstrated in experiments with mice suffering from Duchenne muscular dystrophy. In humans, this rare hereditary disease deprives sufferers of the protein necessary for muscle stability, meaning they experience progressive muscle wasting and paralysis.
ETH Zurich scientists injected unblemished muscle stem cells into the muscles of Duchenne muscular dystrophy mice that carry this defect. They were able to show that healthy stem cells form the repaired muscle fibers within the muscles.
“This kind of muscle stem cell transplant could be of great help to patients with advanced Duchenne, who are already severely affected by muscle atrophy,” explained Inseon Kim, another doctoral student in Bar-Nur’s group and one of the lead authors of the study. .
This method is suitable for producing the large quantities of muscle stem cells required for this purpose. What’s more, the fact that it does so without genetic engineering and the associated risks makes it attractive for potential therapeutic use in humans in the future.
Alternative meat production
However, researchers have yet to adapt their approach to human cells; this is their next step. “In addition, we wanted to investigate whether it is also possible to convert connective tissue cells into muscle cells directly in the body by injecting MyoD mRNA and other cocktail components into mice affected by muscle disease,” said Bar-Nur. This approach, too, could one day help human patients.
Lastly, Bar-Nur and his team wanted to incorporate their new findings into their ongoing work with bovine cells – another research stream in the lab. They hope this method will aid current efforts to cultivate animal muscle stem cells for the production of cultured meat, an alternative method of producing meat for consumption.
Reference: “direct conversion of transgene-free murine fibroblasts into functional muscle stem cells” by Xhem Qabrati, Inseon Kim, Adhideb Ghosh, Nicola Bundschuh, Falko Noé, Andrew S. Palmer and Ori Bar-Nur, 8 Aug 2023, npj Regenerative Medicine.
DOI: 10.1038/s41536-023-00317-z
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