Stem cells don't come emblazoned with a label marked “progenitor,” and yet it was by appearance alone that Alexander Mauro identified satellite cells as a possible muscle stem cell (Mauro, 1961). It was the same year that the clonal nature of hematopoietic stem cells (HSCs) was proven by Till and McCulloch (1961). Mauro did not have proof for the nature of his stem cell, but rather some electron microscopy (EM) images that he felt “might be of interest to students of muscle histology and furthermore, as we shall suggest, might be pertinent to the vexing problem of skeletal muscle regeneration.”
The problem was vexing because of the syncytial nature of muscle. Any tear of a muscle fiber would expose all the nuclei of a multinucleate myofiber to the unfriendly extracellular environment. Earlier investigators suggested that these nuclei might “gather up” cytoplasm and membrane around themselves as a first step in regenerating muscle. But Lee Peachey (University of Pennsylvania, Philadelphia, PA), a graduate student with Keith Porter at the time, says: “That didn't make any sense to me at all—you don't make cell membrane out of nothing.”
Mauro's alternative to the gathering idea was a mononucleate cell type, which he named the satellite cell. He reported seeing these cells under the basement membrane of the muscle fiber but not fused with the main muscle fiber. Their location underneath the basement membrane made it less likely that they were fibroblasts or lymphocytes. Rather, wrote Mauro, they might be “dormant myoblasts that failed to fuse with other myoblasts and are ready to recapitulate the embryonic development of [the] skeletal muscle fiber when the main multinucleate cell is damaged.”
The paper is an unusual one: just three pages, with five references, three of which are personal communications that report the same data as the paper's main text. Peachey is the source of one of those personal communications. He had also seen the nonfused cells. “At some point in a conversation with Alex I showed him these pictures,” says Peachey. “I'm not sure who said what to whom. I had the opinion that these cells might be a source of regeneration, although that part was extremely speculative.”
The speculation turned out to be correct, although further progress was elusive. Interest in satellite cells revived with a publication from Gussoni et al. (1999), who isolated dye-excluding side population (SP) cells from muscle and showed that they could act as both HSCs and muscle stem cells. Since then, others have found that SP and satellite cells are a heterogeneous lot, with varying potentials for differentiation.
It remains unclear where SP cells reside in muscle, and whether SP cells are (as suspected) the precursors of satellite cells. But, with the work on both cell types, “the interest in satellite cells exploded in the last four years,” says Grace Pavlath (Emory University, Atlanta, GA). The work may lead to basic insights into the nature of quiescence, self-renewal and differentiation (Conboy et al., 2003), and help identify the best cell type for use in gene therapy applications.