From Cell to Bone: The Discovery and Future of Skeletal Stem Cells
As stem-cell therapies become a reality for patients suffering from cancer, blood diseases, and immune disorders, the push to discover adult stem cells within major tissue groups has spread throughout research fields and interests. This, coupled with an increasing elderly population supported by advancing medical technologies, demonstrates that regenerative treatments for the skeletal system and the conditions that impact it — such as osteoporosis and arthritis — are needed now more than ever. In attempts to meet this demand, researchers at Stanford University’s School of Medicine published a September 2018 Cell paper announcing their discovery of self-renewing human skeletal stem cells.
The endeavor to find human skeletal stem cells began once these researchers successfully discovered skeletal stem cells in mice three years ago. To begin their search in human tissue, they harvested cells from both human adult and fetal growth plate zones and compared these cells to mouse samples. After identifying a population of human cells that produced similar gene signatures as mice via RNA sequencing, they performed a deeper analysis in the search of cell surface markers and eventually isolated PDPN+ CD73+ CD164+ CD146- cells.
Once isolated, these labeled cells were cultured as a pure population to test whether they could actually give rise to further cell types. They found that their suspected stem cells were indeed self-renewing and lineage-restricted, creating progenitors that could only give rise to cells occurring naturally in the skeletal tissue: bone, stroma, and cartilage. However, skeletal stem cells aren’t alone in their ability to produce skeletal tissue. In 1976, mesenchymal or “all-purpose” stem cells (MSCs) were discovered with the ability to generate skeletal tissues in addition to fat and muscle. Though MSCs are clinically useful, skeletal stem cells reduce the risk of unpredictable outcomes after differentiating and won’t produce fat instead of skeletal tissue, for example. Importantly, they also have the ability to be generated not only from the end of developing bone and fracture sites, but also from specialized fat cells and induced pluripotent stem cells (iPSCs) commonly used in therapeutics.
Not only did this research discover the existence of skeletal stem cells, but they also delved further into their function. Interestingly, stromal progenitors from skeletal stem cells created a nurturing environment in the bone marrow for hematopoietic stem cells, understood as cells that can differentiate into any type of blood cell. These cells were able to grow for up to two weeks without the addition of serum and its growth factors, potentially creating a better understanding of how skeletal stem cells interact with other cell types in the body.
After utilizing mouse models for initial steps in identifying and characterizing skeletal stem cells in humans, this study also worked to identify evolutionary conserved and divergent pathways of skeletal tissue development attributed to stem cells between mice and humans. Using a family tree of stem cells that are involved in its formation and maintenance, this study found a divergence in the Wnt signaling pathway present in humans and absent in mice, mainly used to modify bone formation. By understanding which mechanisms are conserved between humans and mouse models that are largely used to create and approve therapeutics, skeletal tissue growth and regeneration approaches can be more targeted and utilized more effectively.
As the aging process inhibits our ability to heal from bone fractures and leaves us without the ability to regrow any new cartilage, the application for skeletal stem cells is wide-reaching and could impact millions of people suffering with arthritis and invasive joint replacement surgeries. Yet, with the discovery of human skeletal stem cells occurring only this year, the road ahead to clinical approval and therapeutic treatment remains uncertain. Despite this, senior author Michael Longaker and lead author Charles K.F. Chain informed Stanford University’s School of Medicine News that they are already looking to future applications, envisioning the injection of skeletal stem cells via arthroscopy, a minimally invasive procedure used to treat damaged cartilage. As researchers work to make clinical leaps with skeletal stem cells, it’s not difficult to conceive a future where aging could come without the prolonged and debilitating aches and pains.
DOI: 10.1016/j.cell.2018.07.029
