PT  - JOURNAL ARTICLE
AU  - Yang Li
AU  - Shuting Yang
AU  - Yang Liu
AU  - Ling Qin
AU  - Shuying Yang
TI  - IFT20 governs mesenchymal stem cell fate through positively regulating TGF-β-Smad2/3-Glut1 signaling mediated glucose metabolism
AID  - 10.1101/2022.02.28.482266
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.02.28.482266
4099  - http://biorxiv.org/content/early/2022/03/02/2022.02.28.482266.short
4100  - http://biorxiv.org/content/early/2022/03/02/2022.02.28.482266.full
AB  - Aberrant lineage allocation of mesenchymal stem cells (MSCs) could cause bone marrow osteoblast-adipocyte imbalance, and glucose as an important nutrient is required for the maintenance of the MSCs’ fate and function. Intraflagellar transport 20 (IFT20) is one of the IFT complex B protein which regulates osteoblast differentiation, and bone formation, but how IFT20 regulates MSCs’ fate remains undefined. Here, we demonstrated that IFT20 controls MSC lineage allocation through regulating glucose metabolism during skeletal development. IFT20 deficiency in the early stage of MSCs caused significantly shortened limbs, decreased bone mass and significant increase in marrow fat. However, deletion of IFT20 in the later stage of MSCs and osteocytes just slightly decreased bone mass and bone growth and increased marrow fat. Additionally, we found that loss of IFT20 in MSCs promotes adipocyte formation, which enhances RANKL expression and bone resorption. Conversely, ablation of IFT20 in adipocytes reversed these phenotypes. Mechanistically, loss of IFT20 in MSCs significantly decreased glucose tolerance and suppressed glucose uptake and lactate and ATP production. Moreover, loss of IFT20 significantly inhibited TGF-β-Smad2/3 signaling and decreased the binding activity of Smad2/3 to Glut1 promoter to downregulate Glut1 expression. These findings indicate that IFT20 plays essential roles for preventing MSC lineage allocation into adipocytes through controlling TGF-β-Smad2/3-Glut1 mediated glucose metabolism.Competing Interest StatementThe authors have declared no competing interest.