Oral Presentation ANZBMS-MEPSA-ANZORS 2022

Regulation of blood-brain barrier by a subset of astrocytes that express osteocyte marker DMP-1 (#244)

Delin Liu 1 2 , Hao Li 3 , Peng Liao 3 , Youshui Gao 3 , Yigang Huang 3 , Linjing Shi 4 , Ziming Chen 1 , Changqing Zhang 3 , Ming-Hao Zheng 1 2 , Junjie Gao 3
  1. Centre for Orthopaedic Research, The University of Western Australia, Perth, Western Australia, Australia
  2. Perron Institute for Neurological and Translational Science, Perth, Western Australia, Australia
  3. Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Shanghai Sixth People’s Hospital, Shanghai, China
  4. Department of Orthopaedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China

Dentin matrix protein 1 (Dmp1), a marker of osteocyte that has been showed to be expressed in brain, but its biological function is still unknown1, 2. Using single cell RNA sequencing (scRNAseq) we revealed that Dmp1 was mainly expressed in astrocytes.  Gene oncology analysis showed distinct difference in cell adhesion and projection between DMP-1 positive astrocytes (astrocytesDMP-1) and Dmp1 negative astrocytes. In particular, astrocytesDMP-1 express much higher level of AQP4 compared to Dmp1 negative astrocytes. To investigate the role of astrocytesDMP-1, we generated several mice lines including Dmp1Cre-mGmT and Dmp1Cre-COX8aDendra2 fluorescent mice. In vivo confocal imaging indicated that astrocytesDMP-1 were mostly located around blood vessels and astrocytesDMP-1 transfer mitochondria through end-feet to endothelial cells. Interestingly, mitochondrial activity of astrocytesDMP-1 were decreased with increased aging. Co-culture of astrocytes and bEnd.3 endothelial cells demonstrated that astrocytes rescue endothelial oxidative stress via transferring mitochondria. Senescence of astrocytes compromised mitochondrial transfer efficiency in vitro, which is correlated with disrupted endoplasmic (ER)-mitochondria contact in astrocytes. Depletion of ER-mitochondria tethering protein Mfn2 in astrocytesDMP-1 resulted in dramatic blood-brain barrier (BBB) leakage in vivo. Mitochondrial transplantation assay showed that mitochondria acquired from astrocytes restored oxidative stress and wound healing ability of endothelial cells. In conclusion, we have identified a subset of astrocytes that express Dmp1. AstrocytesDMP-1 play a critical role in maintaining BBB via transferring mitochondria to vascular endothelial cells.

 

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  1. Terasawa M, Shimokawa R, Terashima T, Ohya K, Takagi Y, Shimokawa H. Expression of dentin matrix protein 1 (DMP1) in nonmineralized tissues. J Bone Miner Metab. 2004;22(5):430-438.
  2. Lim J, Burclaff J, He G, Mills JC, Long F. Unintended targeting of Dmp1-Cre reveals a critical role for Bmpr1a signaling in the gastrointestinal mesenchyme of adult mice. Bone Res. 2017;5:16049.