Highlights

In brief

As seen in gaps between the muscle cells, selectively killing muscle progenitor cells that express the Lgr5 receptor prevents repair following injury.

© Carly Leung

Unboxing the muscle repair toolkit

20 Sep 2021

Scientists identify a key molecular marker of muscle stem cells, providing novel insights into the mechanisms around muscle regeneration.

Ever pulled a muscle, or felt sore after a workout? That pain is a result of micro tears to the muscle fibers, which can result from everyday physical activities, injury, or certain conditions.

Muscle regeneration is an elaborate process involving a heterogenous population of specialized muscle stem cells that, once activated, divide and fuse with the torn fibers to help restore the muscle’s integrity. Due to a lack of characterization, however, the stem cell-driven mechanisms behind muscle regeneration remain largely unknown, limiting our ability to harness the power of muscle stem cells therapeutically.

A team of researchers led by Nick Barker at A*STAR’s Institute of Molecular and Cell Biology (IMCB) aimed to bridge this gap by studying the diverse molecular landscape of muscle stem cells. They hypothesized that Lgr5—a receptor previously identified as a stem cell marker in various epithelial cells—also delineates a population of skeletal muscle stem cells called muscular progenitor cells (MPCs), and may orchestrate cellular signaling pathways in regeneration and muscle stem cell pool replenishment.

“We have previously shown Lgr5 to be a marker of stem cells contributing to epithelial maintenance of a range of tissues, including the small intestine, colon, skin, pyloric stomach and ovary,” said Barker. “Lgr5 also marks injury-activated stem cells responsible for tissue repair in the corpus stomach and liver.”

The team induced muscle injury in a transgenic mouse model that was genetically modified to enable the researchers to track the activity of Lgr5-expressing cells and their descendants. This technique, known as lineage tracing, follows a cell’s journey through proliferation, differentiation and regeneration.

After an injury, the scientists observed that Lgr5 expression was upregulated, coinciding with stem cell activation and proliferation. They also found that the targeted elimination of Lgr5-expressing cells in injured muscle resulted in a decrease in muscle mass and myofibers, further supporting the hypothesis that Lgr5-expressing progenitor cells are essential for efficient muscle repair.

“In skeletal muscle, Lgr5 was absent in healthy animals, but was quickly upregulated in response to acute damage. We therefore hypothesized that the damage-inducible Lgr5 population could be a reserve stem cell population that helps to quickly repair the muscle,” explained Barker.

Building upon this study, the team plans to explore the signals that regulate the formation of Lgr5-expressing MPCs. “The more we know about the progenitor cells and the underlying mechanisms driving muscle regeneration, the better the chance we have of safely harnessing their regenerative medicine potential in the clinic,” said Barker. “Hopefully, this will eventually lead to improvements in rehabilitation from sports injuries and/or breakthroughs in muscle-wasting disease management.”

The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB).

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References

Barker, N., Leung, C., Ahmad Murad, K.B., Tan, A.L.T., Yada, S., et al. Lgr5 marks adult progenitor cells contributing to skeletal muscle regeneration and sarcoma formation. Cell Reports 33 (12), 108535 (2020) | article

About the Researcher

Nick Barker is currently a Research Director at A*STAR’s Institute of Molecular and Cell Biology (IMCB) and a Visiting Professor at Kanazawa University, Japan. Barker obtained his PhD from Reading University, UK in 1996. Together with Professor Hans Clevers, he identified dysregulated Wnt signaling as the initiating event in colon cancer. In 2001, he joined Semaia Pharmaceuticals to develop colon cancer therapeutics, then returned to Hans Clevers’ group as a Senior Staff Scientist in 2006, where he identified Lgr5 as a marker of various adult stem cell populations and intestinal Lgr5 stem cells as a cell-of-origin of colon cancer. In 2017, he received the prestigious NRF Investigatorship and is recognized as a Web of Science Highly Cited Researcher.

This article was made for A*STAR Research by Wildtype Media Group