Open Collections

Girndt, Hanna Jane

University of British Columbia

Heterotopic ossification (HO) is a pathological condition characterized by abnormal bone formation in soft tissues, typically following trauma or surgery. Despite considerable research into HO, the precise cellular origins contributing to its formation remain incompletely defined. Understanding the identity and biology of the cells that contribute to HO is critical to the development of therapeutics for the treatment of traumatic and genetic HO. Previous research in our lab has shown that quiescent mesenchymal progenitors (MPs) are marked by the expression of Hypermethylated in cancer 1 (Hic1). To better understand the role of Hic1⁺ MPs in HO initiation and progression, we studied the contribution of Hic1⁺ MPs in HO using an inducible Cre recombinase reporter mouse line and demonstrated that Hic1⁺ MPs significantly contribute to all phases of HO, including the inflammatory response, cartilage formation, ossification, and the establishment of functional marrow. Specifically, Hic1⁺ MPs differentiated into chondrogenic and osteogenic lineages, supported immune cell recruitment, and mediated extracellular matrix (ECM) deposition, thereby sustaining both inflammatory and hematopoietic niches within the heterotopic bone. To determine the functional significance of Hic1, conditional knockout models were employed. Ubiquitous Hic1 deletion resulted in profound transcriptional dysregulation across key HO-associated pathways, significantly impairing osteoblast maturation, ECM production, and osteoclast function, ultimately leading to structurally compromised HO. Selective Hic1 deletion in PDGFRA⁺ fibro-adipogenic progenitors (FAPs) similarly disrupted HO development, primarily affecting cellular proliferation, immune cell recruitment, and marrow niche establishment. Additionally, lineage tracing and gene expression analyses revealed that adipocytes within the heterotopic marrow are predominantly derived from Hic1⁺ MPs, emphasizing the multilineage nature of these progenitors. These findings collectively identify Hic1⁺ MPs as a critical cellular source for multiple mesenchymal lineages associated with HO and underscore the importance of Hic1 in regulating the cellular dynamics and molecular pathways essential for HO formation. Further exploration of Hic1⁺ MP biology could inform novel therapeutic strategies targeting HO initiation and progression.

Text

2025-06-04

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/91272

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/