Researchers say stem cell may cause premature infant skull fusion

Key takeaways:

• Craniosynostosis can lead to abnormal brain development or intellectual disability.
• The condition, which affects one in 2,500 infants, may be caused by a previously unknown stem cell.

Craniosynostosis — the premature joining of bones in an infant’s skull — may be caused by an abnormal excess of a previously unknown type of bone-forming stem cell, according to findings from a preclinical study reported in Nature.

The condition, which constricts brain growth and can lead to abnormal brain development, intellectual disability and — in severe cases — fatal complications if not corrected surgically, occurs in about one in 2,500 infants.

In 2018, researchers at Weill Cornell Medicine reported in a study published in Nature that they had found a new stem cell, CTSK+, on the outer surface of bones and in the skulls of mice that forms bone directly with no cartilage formation.

“Based on that, we had a really simple idea,” Matthew Greenblatt, MD, PhD, a pathologist at the Hospital for Special Surgery in Manhattan and co-author of both studies, told Healio. “We thought if we found a major stem cell in the skull, that a number of cranial facial disorders could be due to defects in that cell, and maybe we could tell a simple story that this is a convergent cause for many of these disorders — defects in a stem cell. So, we took genes that are mutated and human disorders of development of the face and skull, and we targeted them for deletion in this stem cell that we reported.”

In the new study, Greenblatt and colleagues investigated the possibility that the cell could cause craniosynostosis by engineering mice in which CTSK+ stem cells lack one of the genes whose loss of function causes craniosynostosis. The gene deletion was expected to induce calvarial stem cells to increase production of a bone, which would fuse sutures in the skull that normally allow it to expand in infants.

Instead of this occurring, ultimately, the results pointed toward a different stem cell than the one the researchers originally found in 2018, called DDR2+, whose daughter cells make bone using a different process than that used by CTSK+ cells.

“That was surprising for sure,” Greenblatt said.

Greenblatt and colleagues also found that a similar skull fusion process appears to occur in human disorders of premature skull fusion, with cartilage present at the sites where the skull is fusing in patients.

“The formation of that cartilage appears to go hand in hand with the expansion or the presence of [DDR2+] driving that cartilage formation, and that's in the human specimens as well,” Greenblatt said. “So, despite this disorder having been studied for many, many years, we think this is a really important element to why it occurs, this cartilage formation that had been overlooked.”

Regarding future research, Greenblatt said thoughts “naturally lead” to whether there could be more possible stem cells.

“Neither the stem cell we found in 2018, nor the stem cell we report in this paper are able to form marrow,” Greenblatt said. “Yet, the skull does form marrow, and there's increasing interest in how that skull marrow may directly play a role in diseases of the skull and brain. and so now, we are looking for that third stem cell that is responsible for performing that skull marrow. That's the direction we're excited to pursue.”

“We are now positioned to think in a new way about disorders of premature skull fusion,” Greenblatt continued. “It's going to be really important to classify this family of disorders along the lines of how it impacts these two cells.”

References:

Bok S, et al. Nature. 2023;doi:10.1038/s41586-023-06526-2.

Debnath S, et al. Nature. 2023;doi:10.1038/s41586-018-0554-8.

Newly discovered bone stem cell causes premature skull fusion. https://news.weill.cornell.edu/news/2023/09/newly-discovered-bone-stem-cell-causes-premature-skull-fusion. Published Sept. 20, 2023. Accessed Sept. 20, 2023.