Scientist discover four major subtypes

Whether you are a competitive athlete or an older adult, strong bones are essential—not only for movement, but also for overall health. Now, a new study has shed new light on how our bones are maintained and repaired by stem cells—and how that process is disrupted with age and in situations of poor healing. The findings could open doors to therapies that speed recovery from injuries, improve bone health, and boost performance longevity.

“Stem cells are the source of all new bone formation, and so work like this is really the foundation of developing new treatments for conditions of poor skeletal health and delayed or impaired fracture regeneration,” said Thomas Ambrosi, who led this study while he was a postdoctoral fellow in Charles Chan’s laboratory at Stanford University and later in his current position as an assistant professor of Orthopedic Surgery at UC Davis. The study was published in Cell Stem Cell.

“This work exemplifies the mission of the Wu Tsai Human Performance Alliance to advance science that helps people stay healthy, recover faster, and achieve peak performance,” said Michael Longaker, MD, a senior author on the study, a professor in the School of Medicine at Stanford University, and a member of the Wu Tsai Human Performance Alliance at Stanford.

“By uncovering how skeletal stem cells change with age and how to restore their function, we’re building a foundation for regenerative therapies that can enhance recovery and restore mobility after injury.”

Stem cells are specialized cells that can continuously generate new tissues. In the past, scientists studying bone formation and healing have focused on the role of ill-defined mesenchymal stromal cells (MSCs), found in bone marrow and elsewhere in the body. But clinical studies testing benefits of MSCs in bone health have largely come up empty.

Ambrosi and his colleagues suspected that a much rarer, harder-to-study type of cell embedded in bone tissue—called skeletal stem cells—may play a more central role.

To explore this idea, Ambrosi and collaborators at Stanford, UC Davis, UC San Diego, the University of Alabama at Birmingham, and the Chan Zuckerberg Biohub analyzed skeletal stem cells from ten regions of the developing human skeleton and compared them to cells from adult patients throughout life, including people with fractures that failed to heal and people with bone diseases.

They discovered four major subtypes of skeletal stem cells, each specialized for building bone, cartilage, supportive bone marrow stroma, or fibrous tissue providing scaffolding. The researchers also created the first spatial map of where these stem cells reside within bones, helping explain how different parts of the skeleton fulfill distinct functions, maintain their structure, and respond to damage.

In youth, these skeletal stem cell subtypes are balanced in a way that supports strong, flexible bones. But as people age—or when healing goes awry after injury—the balance shifts. Stem cells increasingly favor a fibrous tissue fate, producing scar-like material instead of bone.

“This shift is part of why bones become more fragile with age and fail to heal properly,” Ambrosi explained.

To understand this change with aging, and the source of the different stem cell types, the team developed a new computational approach to analyze which genes were turned up or down in the different populations of skeletal stem cells. This let them pinpoint specific networks of genes involved in balancing the reduction and promotion of bone formation.

Armed with this insight, the researchers identified a combination of two small molecules that together pushed aged or dysfunctional stem cells back toward a bone-building state. In lab dishes and mouse models, human stem cells treated with the cocktail of molecules produced more bone, supported improved fracture healing, and mimicked the behavior of young, healthy cells.

“The compounds worked as implied by our computational approach,” said Ambrosi. “They led to a tremendous increase in stem-cell-mediated bone formation at the fracture site.”

Ambrosi emphasized that the new results are not yet ready for clinical application—and that most currently advertised stem cell treatments for bone health are not grounded in rigorous science. But his findings lay the broader groundwork for future studies on how to generate bone or cartilage from skeletal stem cells.

“Bones are not only the scaffold that provides shape and structure for our bodies, but what allow us to conduct movement, store essential minerals, and support blood cell production,” he said. “Understanding the basic biology of the skeleton is important to understanding overall health.”