A decade-long effort led by Stanford University School of Medicine scientists has been rewarded with the identification of the human skeletal stem cell
The cell, which can be isolated from human bone or generated from specialized cells in fat, gives rise to progenitor cells that can make new bone, the spongy stroma of the bone's interior and the cartilage that helps our knees and other joints function smoothly and painlessly.
The discovery allowed the researchers to create a kind of family tree of stem cells important to the development and maintenance of the human skeleton. It could also pave the way to treatments for regenerating bone and cartilage in people.
"Everyday children and adults need normal bone, cartilage, and stromal tissue," said Michael Longaker, MD, professor of plastic and reconstructive surgery. "There are 75 million Americans with arthritis, for example. Imagine if we could turn readily available fat cells from liposuction into stem cells that could be injected into their joints to make new cartilage, or if we could stimulate the formation of new bone to repair fractures in older people."
Longaker, the Deane P. and Louise Mitchell Professor in the School of Medicine and the co-director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine, is the senior author.
'True, multipotential, self-renewing'
The skeletal stem cells are distinct from another cell type called the mesenchymal stem cell, which can generate skeletal tissues, fat, and muscle. Mesenchymal stem cells, which can be isolated from blood, bone marrow or fat, are considered by some clinicians to function as all-purpose stem cells.
They have been tested, with limited success, in clinical trials and as unproven experimental treatments for their ability to regenerate a variety of tissues. Recently, three elderly patients in Florida were blinded or lost most of their sight after mesenchymal stem cells from fat were injected into their eyes as an experimental treatment for macular degeneration.
"Mesenchymal stem cells are loosely characterized and likely to include many populations of cells, each of which may respond differently and unpredictably to differentiation signals," Chan said.
"In contrast, the skeletal stem cell we have identified possesses all of the hallmark qualities of true, multipotential, self-renewing, tissue-specific stem cells. They are restricted regarding their fate potential to just skeletal tissues, which is likely to make them much more clinically useful."
Skeletal regeneration is an important capability for any bony animal evolving in a rough-and-tumble world where only the fittest, or the fastest-healing, are likely to survive very long into adulthood. Some vertebrates, such as newts, can regenerate entire limbs if necessary, but the healing ability of other animals, such as mice and humans, is more modest.
Adult stem cells lineage-restricted
Unlike embryonic stem cells, which are present only in the earliest stages of development, adult stem cells are thought to be found in all major tissue types, where they bide their time until needed to repair damage or trauma. Each adult stem cell is lineage-restricted—that is, it makes progenitor cells that give rise only to the types of cells that naturally occur in that tissue. For our skeleton, that means cells that make bone, cartilage, and stroma.
Chan, Longaker and their colleagues had hoped to use what they learned from identifying the mouse skeletal stem cell to isolate its human counterpart quickly. But the quest turned out to be more difficult than they had anticipated.
Most cell isolation efforts focus on using a technology called fluorescence-activated cell sorting to separate cells based on the expression of proteins on their surface. Often, similar cell types from different species share some key cell surface markers.
But the human skeletal stem cell turned out to share few markers with its mouse counterpart. Instead, the researchers had to compare the gene expression profiles of the mouse skeletal stem cell with those of several human cell types found at the growing ends of developing human bone.
Doing so, they were able to identify a cell population that made many of the same proteins as the mouse skeletal stem cell. They then worked backward to identify markers on the surface of the human cells that could be used to isolate and study them as a pure population.
"This was quite a bioinformatics challenge, and it required a big team of interdisciplinary researchers, but eventually Chuck and his colleagues were able to identify a series of markers that we felt had great potential," Longaker said. "Then they had to prove two things: Can these cells self-renew, or make more of themselves indefinitely, and can they make the three main lineages that comprise the human skeleton?"
The researchers showed that the human skeletal stem cell they identified is both self-renewing and capable of making bone, cartilage and stromal progenitors. It is found at the end of developing bone, as well as in increased numbers near the site of healing fractures. Not only can it be isolated from fracture sites, but it can also be generated by reprogramming human fat cells or induced pluripotent stem cells to assume a skeletal fate.