SAN FRANCISCO—Adult stem cells injected into animals with bone fracture quickly home in on the site of injury and, mediated by insulin-like growth factor-1 (IGF-1), promote healing of the broken bone, researchers reported at the ENDO 2008 meeting.1 Ana Spagnoli, MD, reporting for the research team led by Froilan Granero-Molto, MD, said that the studies provide the evidence needed to move adult stem cell rescue into clinical trials for patients with nonhealing osteoporotic fracture and for children with brittle bone disease.

“This was an exciting finding because it was the first proof that stem cells are recruited by damaged tissue.”—Ana Spagnoli, MD
“Twenty percent of fractures do not heal, affecting 600,000 people in the US every year. Fifty percent of the women in that group have fracture due to osteoporosis. In these fragile patients and in children with brittle bone disease, this means long periods of immobilization, surgical procedures, pain, and even death,” Dr. Spagnoli said at a press briefing.

“We have suspected for many years that these patients are missing stem cells that would make their bones heal,” added Dr. Spagnoli, associate professor of pediatrics and biomedical engineering at the University of North Carolina, Chapel Hill. “Our study shows that adult stem cells can improve fracture healing.”

The researchers found that
  • adult stem cells are specifically recruited to the fracture site from the moment they are injected
  • migration depended on presence of the CXCR4 receptor
  • the factor needed for stem cell migration to occur is IGF-1
  • adding adult stem cells improves fracture healing

Dr. Spagnoli and colleagues used adult stem cells easily derived from bone marrow and obtained stem cells from transgenic mice constitutively expressing luciferase. This enabled them to track the migration of the injected cells in living animals by monitoring bioluminescence at 1,3,5,7, and 14 days postfracture. Stem cells were selected based on the presence (CXCR4+) or the absence (CXCR4-) of CXCR4; unselected stem cells were used as control. Stem cells were also obtained from mice engineered either to express human IGF-I or empty vector.

The experimental mice had stabilized tibia fractures and were transplanted either with stem cells by IV injection or with no cells. The healing tibias were analyzed at 14 days postfracture by distraction biomechanical testing and computed tomography. Calluses were analyzed for bone and cartilage markers.  

“Tracking cells in a living animal is difficult. Nature came to our help. We found that we could make stem cells that express luciferase, inject them into a mouse with a fracture, place the mouse in dark box, and follow the stem cells minute by minute, hour by hour, day by day. We found that stem cells in these living animals migrate specifically and directly to the fracture. This was an exciting finding because it was the first proof that stem cells are recruited by damaged tissue.” Cells lacking CXCR4 got lost in the body and did not reach the damaged tissue.

“Mice transplanted with stem cells with IGF-1 made more cartilage and bone, and the bones were stronger,” Dr. Spagnoli said. “We have shown that adult stem cells can be transplanted, and go [to damaged tissue]. We also now know what is needed for cells to be recruited to the site of injury and we know that they can improve fracture healing.”

Reference

1. Granero-Molto F, Weis JA, Landis B, et al. Mesenchymal stem cells (MSC) migrate to the fracture site and along with IGF-I improve the healing. Presented at: ENDO 2008; June 16, 2008; San Francisco, Calif. Abstract P2-652.