Joslin and Stanford Researchers Find Key Clues to Muscle Regeneration; Discovery May One Day Lead to New Ways to Treat Degenerative Diseases.

BOSTON -- Scientists at Stanford University and Joslin Diabetes Center are providing new insights into how muscle cells regenerate--leading to powerful tools to help scientists better understand diseases such as muscular dystrophy.

Skeletal muscle contains a complex array of cell types. Among its principal components are multi-nucleated muscle fibers and muscle satellite cells--cells located in close association with muscle fibers and containing precursors capable of giving rise to new muscle fibers.

"Our studies show that only the satellite cells, located near muscle fibers, can give rise to new muscle cells. Contrary to previous studies, precursor cells from bone marrow or other blood-forming tissues did not change their destiny to become muscle cells," said Amy J. Wagers, Ph.D., Investigator in the Developmental and Stem Cell Biology Research Section at Joslin Diabetes Center and Assistant Professor of Pathology at Harvard Medical School, the principal investigator of a study published in the Nov. 12 edition of Cell. The research, which originated in the laboratory of Irving L. Weissman, M.D., at Stanford University, now continues at Joslin Diabetes Center in Boston.

Over the past few years, several research groups have reported that stem cells found in the bone marrow could repair damaged muscle cells. This had raised hopes that the well-characterized blood-forming stem cells could be used therapeutically to treat muscular diseases. Dr. Wagers' work disputes these past results, showing that bone marrow stem cells do move to the muscle but don't regularly participate in repairing muscle damage.

In the first part of the Dr. Wagers' latest study, the researchers isolated muscle satellite cells from mice and marked them with a substance that glows in fluorescent light. They also generated adult bone-marrow cells and blood-forming stem cells that carried the fluorescent markers. They then examined the capacity of these three different cell types to generate new muscle cells in cell culture or in mice that had injured muscle tissue.

"The results show that adult stem cells that are committed to the blood lineage do not normally differentiate into muscle cells," said Dr. Wagers. "The only cells that had full potential to generate muscle cells were derived from muscle, not from transplanted bone-marrow or blood-forming stem cells."

Armed with this information, the researchers looked for the exact cells involved. To do this, they developed a new method that uses a set of unique cell-surface markers. This method allowed them to isolate and distinguish a subset of muscle precursor cells that give rise, at high frequency, to new muscle cells.

They found a precise cell type--the precursor to new muscle growth. In fact, a single cell from this subset could alone generate a sizable colony of new muscle cells.

"Identifying this precursor of new muscle cells gives us new research tools for future studies, including those in humans," said Dr. Wagers. "As we learn more about the genes expressed by these cells and the pathways involved in regulating them, we can learn more about muscle cell injury and regeneration. This may give us a better understanding of what goes wrong in degenerative diseases such as muscular dystrophy, leading possibly to new ways to treat such diseases."

The Research Team

This research initiative, which originated at Stanford University, is now underway at Joslin Diabetes Center in the laboratory of Dr. Wagers. The study's first author was Richard I. Sherwood, currently a graduate student in the Department of Molecular and Cellular Biology at Harvard University. Other investigators included Julie L. Christensen, Ph.D., currently at Cellerant Therapeutics; Irina M. Conboy, Ph.D., an Assistant Professor in the Department of Bioengineering at University of California-Berkeley; Michael J. Conboy, Ph.D., a postdoctoral fellow at Stanford University; Thomas A. Rando, M.D., Ph.D., Associate Professor of Neurology and Neurological Sciences at Stanford; and Irving L. Weissman, M.D., Professor of Pathology and Developmental Biology at Stanford. Funding for this study was provided in part through grants from the National Institutes of Health, the Department of Veterans Affairs, and the Burroughs Wellcome Fund.