Human Skeletal Muscle Atlas Developed

Researchers at the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at UCLA have developed a roadmap of how human skeletal muscle develops. Their work was published yesterday in Cell Stem Cell.

The roadmap will be useful for researchers who aim to develop muscle stem cells in the lab that can be used in regenerative cell therapies for muscle diseases, including muscular dystrophies, and sarcopenia. "Muscle loss due to aging or disease is often the result of dysfunctional muscle stem cells," said April Pyle, senior author of the paper. "This map identifies the precise gene networks present in muscle progenitor and stem cells across development, which is essential to developing methods to generate these cells in a dish to treat muscle disorders."

Researchers already have the capacity to generate skeletal muscle cells from human pluripotent stem cells. However, until now, they had no way of determining where these cells fall on the continuum of human development. "We knew that the muscle cells we were making in the lab were not as functional as the fully matured muscle stem cells found in humans," said Haibin Xi, first author of the new paper. "So we set out to generate this map as a reference that our lab and others can use to compare the genetic signatures of the cells we are creating to those of real human skeletal muscle tissue."

To create this resource, the group gathered highly specific data about two different groups of skeletal muscle cells. They then studied the genetic signatures of cells from both sources using high-throughput droplet-based single-cell RNA sequencing. Leveraging the power of this technology and team member’s bioinformatics expertise, the group identified the genetic signatures of various cell types from human tissues and pluripotent stem cells. They next developed computational methods to focus on muscle progenitor and stem cells and mapped out their gene networks associated with every developmental stage. This enabled the group to match the genetic signatures found in the pluripotent stem cell-derived muscle cells with their corresponding locations on the map of human muscle development.

The group found that pluripotent stem cell-derived muscle cells produced by all the methods they tried resembled muscle progenitor cells at an early developmental state and did not align to adult muscle stem cells.

In addition to pinning down the true maturity of the lab-produced cells, this analysis also provided details about the other cell types present in skeletal muscle tissue across development and in populations derived from human pluripotent stem cells. These cells could play an essential role in muscle cell maturation and could be critical to improving methods to generate and support muscle stem cells in a dish.