Premature Skull Fusion: Bone Stem Cell

Craniosynostosis, the premature fusion of the top of the skull in infants, is caused by an abnormal excess of a previously unknown type of bone-forming stem cell, according to a preclinical study led by researchers at Weill Cornell Medicine.

Craniosynostosis arises from one of several possible gene mutations, and occurs in about one in 2,500 babies. By constricting brain growth, it can lead to abnormal brain development if not corrected surgically. In complex cases, multiple surgeries are needed.

In the study, which appears Sept. 20 in Nature, the researchers examined in detail what happens in the skull of mice with one of the most common mutations found in human craniosynostosis. They found that the mutation drives premature skull fusion by inducing the abnormal proliferation of a type of bone-making stem cell — the DDR2+ stem cell — that had never been described before.

In a study published in Nature in 2018, Drs. Debnath and Greenblatt and their colleagues, described the discovery of a type of bone-forming stem cell they called the CTSK+ stem cell. Because this type of cell is present in the top of the skull, or “calvarium,” in mice, they suspected that it has a role in causing craniosynostosis.

In the new study, they investigated that possibility by engineering mice in which CTSK+ stem cells lack one of the genes whose loss of function causes craniosynostosis. They expected that the gene deletion somehow would induce these calvarial stem cells to go into bone-making overdrive. This new bone would fuse the flexible, fibrous material called sutures in the skull that normally allow it to expand in infants.

The unexpected finding led the team to hypothesize that another type of bone-forming stem cell was driving the abnormal suture fusion. After further experiments, and a detailed analysis of the cells present at fusing sutures, they identified the culprit: the DDR2+ stem cell, whose daughter cells make bone using a different process than that utilized by CTSK+ cells.

The team found that CTSK+ stem cells normally suppress the production of the DDR2+ stem cells. But the craniosynostosis gene mutation causes the CTSK+ stem cells to die off, allowing the DDR2+ cells to proliferate abnormally.

The researchers found the human versions of DDR2+ stem cells and CTSK+ stem cells in calvarial samples from craniosynostosis surgeries — underscoring the likely clinical relevance of their findings in mice.

The findings suggest that inappropriate DDR2+ stem cell proliferation in the calvarium, in infants with craniosynostosis-linked gene mutations, could be treated by suppressing this stem cell population, through mimicking the methods that CTSK+ stem cells normally use to prevent expansion of DDR2+stem cells. The researchers found that the CTSK+ stem cells achieve this suppression by secreting a growth factor protein called IGF-1, and possibly other regulatory proteins.

In addition to treatment-oriented research, he and his colleagues now are looking for other bone-forming stem cell populations in the skull.

“This work has uncovered much more complexity in the skull than we ever imagined, and we suspect the complexity doesn’t end with these two stem cell types,” Dr. Greenblatt said.

Sources:

Seoyeon Bok, Alisha R. Yallowitz, Jun Sun, Jason McCormick, Michelle Cung, Lingling Hu, Sarfaraz Lalani, Zan Li, Branden R. Sosa, Tomas Baumgartner, Paul Byrne, Tuo Zhang, Kyle W. Morse, Fatma F. Mohamed, Chunxi Ge, Renny T. Franceschi, Randy T. Cowling, Barry H. Greenberg, David J. Pisapia, Thomas A. Imahiyerobo, Shenela Lakhani, M. Elizabeth Ross, Caitlin E. Hoffman, Shawon Debnath, Matthew B. Greenblatt. A multi-stem cell basis for craniosynostosis and calvarial mineralization. Nature, 2023; DOI: 10.1038/s41586-023-06526-2

Weill Cornell Medicine. (2023, September 20). Newly discovered bone stem cell causes premature skull fusion. ScienceDaily. Retrieved September 20, 2023 from www.sciencedaily.com/releases/2023/09/230920152224.htm

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