New Delhi: Researchers have identified a gene expressed during regeneration critical for muscle repair. The key human skeletal muscle gene was also found in a subset of muscle fibres that could support human muscle stem cells after transplantation.
Although skeletal muscle is one of the most regenerative organ systems, there exists a need to improve regeneration for the more than 400 chronic muscle disorders and injuries that present clinically, including rotator cuff injuries and certain muscle disorders like Duchenne Muscular Dystrophy (DMD) or congenital muscular dystrophy.
The study was published in the journal Nature Cell Biology. Michael H. Hicks, assistant professor in the Department of Physiology and Biophysics at the University of California, Irvine School of Medicine, is the co-corresponding author of the study, along with April D. Pyle, professor in the department of microbiology, immunology, and molecular genetics at UCLA
"With our discovery, the development of 'muscle in a dish' is one step closer to reality," says Hicks. "We've been researching this for years, and its implications for treating disease, muscle disorders, and tears are immense."
When confronted with an injury, our muscles naturally do a good job at repairing themselves. However, the muscle cannot meet the demands of regenerating new tissues in severe injuries and genetic muscular diseases. Researchers say one solution is to take the cells from a dish and replicate how a healthy human body repairs muscle, as newly generated muscle made in a lab can support stem cells better than the exhausted muscle tissue.
One disorder the Hicks lab hopes to treat with their lab-grown muscle progenitors is tearing to the rotator cuff muscles, which affects up to 30 per cent of people over the age of 65.
Damage to the rotator cuff muscles and tendon results in loss of mobility, prolonged hospitalization, and increased dependency on health care providers. Even after surgical attachment of the rotator cuff tendon to the bone, the muscle often fails to regenerate or incompletely regenerates, leading to decreased function.
Stem cell niches
Hicks has funding from the UCI Anti-Cancer Challenge to use his approach for muscle reconstruction after radiation therapy for cancer survivors.
"Muscle stem cells are exposed to significant doses of radiation during radiotherapeutic management of cancer," says Hicks. "The use of ionizing radiation has the potential to damage muscle stem cells and limit the recovery of muscle mass following disuse or over with age."
Muscle stem cells are supported within anatomically defined specialized compartments, termed niches, that regulate their balance of self-renewal and differentiation over a person's lifetime. Establishing new stem cell niches is essential for long-term cell therapies, in which transplanted muscle stem cells must balance the formation of new muscle fibres and maintain the stem cell pool to respond to future injuries.
Researchers demonstrated the formation of regenerating human myofibers following transplantation is a key source of niche emergence from transplanted human cells, which has previously been overlooked.
"This subset of regenerating muscle fibres resulted in a 50-fold better ability to support transplanted muscle progenitor cells," said Pyle. "It would be interesting to determine whether myofibers in homeostasis or in disease settings could be stimulated to make the skeletal muscle more regenerative and less susceptible to a broad range of diseases."
Using a new technology called spatial RNA sequencing, the researchers further characterized the interaction of transplanted muscle progenitor cells with the subset of muscle fibres, a unique gene called ACTC1. The equipment recently obtained by the UCI Genomics Research and Technology Hub has a powerful ability to perform segmentation of cell types directly adjacent to one another and to obtain RNA information from those cell types.
"We tailored a high-dimensional spatial analysis platform to identify how transplanted human progenitor cells and myofibers in a mouse were communicating," says Ben Clock, a graduate student involved in the study.
In the future, the team plans to dive deeper into restored muscle function, including assessing the ability of the newly formed human muscles to connect with the motor neurons to restore motor control to the transplanted cells.
The Hicks lab at the UCI School of Medicine is pursuing both basic and translational avenues as their next steps. The ability to generate these muscle stem cells in the lab is currently under patent review by the US, Europe, and Japan. Hicks and Pyle also have plans to start a company to translate muscle stem cells for patients.
In a previous study from 2017, Hicks and Pyle made strides to create and repair skeletal muscle, termed progenitor cells, in the lab with gene editing. Yet, to date, retention of human muscle progenitors after transplantation from cells grown in the lab has proven challenging.
Results from this study have identified several vital receptors and ligand candidates on the muscle progenitor cells that could allow them to interact with the myofibers, but these candidates will need to be validated before they can be used as therapeutic targets to improve muscle regeneration.