【演者】 Kathryn Cheah 先生（Professor , School of Biomedical Sciences The University of Hong Kong）【演題】Genetic and developmental control of skeletal lineages and progenitors in health and disease

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日時：令和6年4月16日（火）17:00-18:00 要旨：Progenitors are essential for the proper development and maintenance of the skeleton throughout life. In the spine, developmental lineage studies in mice show that the nucleus pulposus (NP) cells in the intervertebral disc are derived from the embryonic notochord. Little is known of the cellular heterogeneity and progenitors in the postnatal NP especially their roles in maintaining a healthy disc. The cellular and molecular changes that occur during the transition from the notochord to the NP in development, postnatal growth and degeneration induced by injury or aging are also unclear.

In endochondral bones, the hypertrophic chondrocyte (HC)-osteoblast differentiation continuum contributes to trabecular bone formation revealing the plasticity of these cells. Lineage studies in mice have shown that in the transition process HCs re-enter the cell cycle and contribute to skeletal progenitors, a major proportion of which take the osteogenic path and a minor proportion become adipocytes. However the intrinsic and extrinsic controls and signalling pathways which govern HC transition to progenitors, HC cell fate decisions and the physiological importance of the HC-derived lineage are inadequately understood.

In my talk I will describe molecular cellular and functional insights in regard to skeletal progenitors in the NP and in endochondral bone. By lineage tracing and single cell transcriptomics we found considerable cell heterogeneity in the adult mouse NP and identified a population of progenitors in the NP localized in the peripheral boundary of the NP (PeriNP) that go on to populate the whole NP. PeriNP cells and their descendants were diminished in aged NP or puncture-induced disc degeneration and may be NP progenitors that contribute to the maintenance of a healthy disc. By genetic manipulation of the HC lineage in mice we reveal the essential role of the Wnt - IRX3/5 gene regulatory axis on HC derived skeletal progenitors. We found that HC-specific loss of function of Wnt - IRX3/5 axis impacts on the early transition states from HC to skeletal progenitors, impaired osteogenesis, culminating in adoption of adipogenic cell fate and increased marrow adiposity. These changes impact on thermogenesis and the response to high fat diet. The HC-osteoblast lineage is therefore essential for bone homeostasis and physiology.