Saturday, May 4, 2024
5/4/2024
Summary Injuries to the growth plate (GP) remain a major cause of morbidity in children, often leading to angular limb deformities and even complete growth arrest. Slipped Capital Femoral Epiphysis (SCFE), a transverse Salter-Harris type 1 (SH1) fracture, where the spherical femoral head of the hip joint slips backwards off the femoral neck, is a common and debilitating disorder, affecting the hip in children and adolescents and often culminating in painful arthritis in adults. A vertical Salter Harris type 2-4 (SH2-4) fracture, in which the fissure plane extends in the metaphysis or epiphysis, leads to an osseous bridge formation in lieu of cartilage, and angular deformities. This highlights the need for novel therapeutic strategies to prevent bone formation at the injury site and to allow epiphyseal cartilage to resume growth. One avenue to promote local cartilage repair, would be through mobilization of resident stem cells in response to injury. Current literature describes the GP-RZ as a stem cell-rich region, which give rise to the GP appositionally. We recently discovered that a population of FoxA2+ long-term stem cells (LTSSC) is located in the top compartment of the RZ. FoxA2+LTSSC have higher longevity, clonogenicity, and are mutually exclusive with the previously characterized PTHrP+ short-term stem cells (STSSC), located at the bottom of the RZ. A horizontal SH1 injury successfully heals with hyaline cartilage and involves the expansion of FoxA2+ LTSSC. A large vertical SH4 fracture heals through a "bony bar", while a small SH4 lesion heals with hyaline cartilage. FoxA2+ LTSSC line the outside of a large SH4 wound, but infiltrate the small SH4 lesion. This suggests other cell types (e.g osteoprogenitors) may create a physical barrier or a signaling niche, which hinders FoxA2+ LTSSC healing of large defects. In both injuries, a transient pulse of TGFß signaling, induced in cartilage remnants at D1, precedes FoxA2+ LTSSC expansion at D3. This indicates a potential role for TGFß, in promoting FoxA2+ LTSSC expansion and differentiation into chondrogenic progeny, for cartilage repair. These findings will allow us to investigate, for the first time, whether FoxA2+LTSSC contribute to GP cartilage repair following SH1 and SH4 injuries. To test this premise, we propose three aims. In Aim 1, we will determine if FoxA2+ cells can contribute to the repair of a small SH4 lesion, but fail to contribute to the repair of a large SH4 lesion. In Aim 2, we will determine if TGFß signaling drives FoxA2+LTSSC migration and differentiation into progeny to accommodate cartilage repair after SH1 injury. In Aim 3, we will determine if FoxA2+cells transplantation in a large SH4 lesion can prevent formation of a bony bar. Altogether, these results will provide a strong basis for development of bioengineering strategies for GP cartilage regeneration.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
