Oral Presentation ANZBMS-MEPSA-ANZORS 2022

Endothelial cells require mitochondrial transfer from osteocytes to promote vascularization in cortical bone (#6)

Peng Liao 1 , Long Chen 2 , Hao Zhou 3 , Jiong Mei 1 , Guangyi Li 1 , Changqing Zhang 1 , Ming-Hao Zheng 4 5 , Delin Liu 4 5 , Junjie Gao 1
  1. Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Shanghai Sixth People’s Hospital, Shanghai, China
  2. State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
  3. Department of Orthopedics,The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
  4. Centre for Orthopaedic Research, Medical School, The University of Western Australia, Perth, Western Australia, Australia
  5. Perron Institute for Neurological and Translational Science, Perth, Western Australia, Australia

Vascularization is an energy-consuming process which highly relies on mitochondria to orchestrate ROS level in endothelial cells1,2. Transcellular mitochondrial movement has been previously demonstrated to coordinate tissue homeostasis, survival and repair3. Here, we reported that osteocytes play critical roles in maintaining mature network of trans-cortical blood vessels (TCVs), and that endothelial cells of TCVs require osteocytes-derived mitochondria to facilitate vascularization. We first showed that osteocytes extend dendritic network to TCVs in cortical bone by confocal imaging analyses. Using Dmp1cre-DTAki/wt mice we showed that ablation of osteocytes in cortical bone cause regression of TCVs accompanying with the decreased expression of angiogenic genes. Using osteocyte-specific mitochondrial fluorescent mice we showed that acquisition of osteocytes-derived mitochondria by endothelial cells was integral to the structure of TCVs. Co-culture of osteocyte MLO-Y4 transfected with mitochondrial fluorescent protein Dendra2 and endothelial cells (bEnd.3) showed that osteocytes transfer mitochondria to rescue damaged endothelial cells evidenced by decreasing oxidative stress, increasing proliferation and wound healing ability of endothelial cells. Finally, conditional knockout of Miro1, the critical mitochondrial transport machinery protein, in mouse osteocytes resulted in significant compromise of TCVs morphological network. In conclusion, our studies demonstrated that the vascularization of endothelial cells in cortical bone relies on the osteocytes and their dendritic network. Osteocytes transfer mitochondria to endothelial cells for the maintenance of TCV integrity. Our results provide a new insight for bone-blood vessel interaction in mineralized tissue.

 

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  1. Jezek, P., and Hlavatá, L. (2005). Mitochondria in homeostasis of reactive oxygen species in cell, tissues, and organism. Int J Biochem Cell Biol 37, 2478-2503.
  2. Reichard, A., and Asosingh, K. (2019). The role of mitochondria in angiogenesis. Mol Biol Rep 46, 1393-1400.
  3. Gao, J., Qin, A., Liu, D., Ruan, R., Wang, Q., Yuan, J., Cheng, T.S., Filipovska, A., Papadimitriou, J.M., Dai, K., et al. (2019). Endoplasmic reticulum mediates mitochondrial transfer within the osteocyte dendritic network. Sci Adv 5, eaaw7215.