DMP1 POSITIVE ASTROCYTES MAINTAIN BLOOD-BRAIN BARRIER VIA TRANSFERRING MITOCHONDRIA TO VASCULAR ENDOTHELIAL CELLS

D. Liu; J. Gao; M. Zheng; P. Liao; H. Li; C. Zhang

doi:10.1302/1358-992X.2023.7.114

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DMP1 POSITIVE ASTROCYTES MAINTAIN BLOOD-BRAIN BARRIER VIA TRANSFERRING MITOCHONDRIA TO VASCULAR ENDOTHELIAL CELLS

The International Combined Orthopaedic Research Societies (ICORS), World Congress of Orthopaedic Research, Edinburgh, Scotland, 7–9 September 2022. Part 1 of 3.

D. Liu
J. Gao
M. Zheng
P. Liao
H. Li
C. Zhang

DMP1 POSITIVE ASTROCYTES MAINTAIN BLOOD-BRAIN BARRIER VIA TRANSFERRING MITOCHONDRIA TO VASCULAR ENDOTHELIAL CELLS

Liu D, Gao J, Zheng M, Liao P, Li H, Zhang C. DMP1 POSITIVE ASTROCYTES MAINTAIN BLOOD-BRAIN BARRIER VIA TRANSFERRING MITOCHONDRIA TO VASCULAR ENDOTHELIAL CELLS. Orthop Procs. 2023;105-B(SUPP_7):114-114. doi:10.1302/1358-992X.2023.7.114

Liu, D., et al. “DMP1 POSITIVE ASTROCYTES MAINTAIN BLOOD-BRAIN BARRIER VIA TRANSFERRING MITOCHONDRIA TO VASCULAR ENDOTHELIAL CELLS.” Orthopaedic Proceedings, vol. 105-B, no. SUPP_7, 2023, pp. 114-114., https://doi.org/10.1302/1358-992X.2023.7.114

Liu, D., Gao, J., Zheng, M., Liao, P., Li, H., & Zhang, C. (2023). DMP1 POSITIVE ASTROCYTES MAINTAIN BLOOD-BRAIN BARRIER VIA TRANSFERRING MITOCHONDRIA TO VASCULAR ENDOTHELIAL CELLS. Orthopaedic Proceedings, 105-B(SUPP_7), 114-114. https://doi.org/10.1302/1358-992X.2023.7.114

Liu, D., Gao, J., Zheng, M., Liao, P., Li, H. and Zhang, C. (2023) “DMP1 POSITIVE ASTROCYTES MAINTAIN BLOOD-BRAIN BARRIER VIA TRANSFERRING MITOCHONDRIA TO VASCULAR ENDOTHELIAL CELLS.” Orthopaedic Proceedings, 105-B(SUPP_7), pp. 114-114. Available at: https://doi.org/10.1302/1358-992X.2023.7.114

Liu, D., J. Gao, M. Zheng, P. Liao, H. Li, and C. Zhang. “DMP1 POSITIVE ASTROCYTES MAINTAIN BLOOD-BRAIN BARRIER VIA TRANSFERRING MITOCHONDRIA TO VASCULAR ENDOTHELIAL CELLS.” Orthopaedic Proceedings 105-B, no. SUPP_7 (2023): 114-114. https://doi.org/10.1302/1358-992X.2023.7.114

Liu D, Gao J, Zheng M, Liao P, Li H, Zhang C. DMP1 POSITIVE ASTROCYTES MAINTAIN BLOOD-BRAIN BARRIER VIA TRANSFERRING MITOCHONDRIA TO VASCULAR ENDOTHELIAL CELLS. Orthop Procs. 2023 Apr 4;105-B(SUPP_7):114-114. https://doi.org/10.1302/1358-992X.2023.7.114

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Abstract

Though dentin matrix protein 1 (Dmp1) is known to play critical role in mediating bone mineralization, it has also been validated to be expressed in brain and helps maintain blood brain barrier (BBB). Our study aims to clarify the expression pattern of Dmp1 in mouse brain and explore whether intercellular mitochondrial transfer occurs between Dmp1 positive astrocytes (DPAs) and endothelial cells, and thus acting as a mechanism in maintaining BBB during aging.

Single cell RNA sequencing (scRNAseq) of 1 month, 6 month, and 20 month old mice brain (n=1, respectively) was employed to identify Dmp1 positive cell types. Dmp1^Cre-mGmT and Dmp1^Cre-COX8a fluorescent mice were generated to visualize DPAs and investigate their mitochondrial activities. A 3D noncontact coculture system and mitochondrial transplantation were applied to study the role of mitochondrial transfer between astrocytes and bEnd.3 endothelial cells. Dmp1^Cre-Mfn2^f/f mice were generated by depleting the ER-mitochondria tethering protein Mfn2 in DPAs.

Dmp1 was mainly expressed in astrocytes at different ages. GO analysis revealed that cell projection and adhesion of DPAs were upregulated. Confocal imaging on Dmp1^Cre-mGmT mice indicated that DPAs are a cluster of astrocytes that closely adhere to blood vessels (n=3). Bioinformatics analysis revealed that mitochondrial activity of DPAs were compromised during aging. Enriched scRNAseq of fluorescent cells from Dmp1^Cre-COX8a mice (n=2) and immunofluorescent imaging (n=3) validated the acquisition of extrinsic mitochondria in endothelial cells. 3D coculture of astrocytes and bEnd.3 and direct mitochondrial transplantation revealed the rescue effect of mitochondrial transfer on damaged bEnd.3. BBB was impaired after depleting Mfn2 in DPAs, expressing a similar phenotype with aging brain.

Astrocytes that express Dmp1 play a significant role in maintaining BBB via transferring mitochondria to vascular endothelial cells. Compromised mitochondrial transfer between DPAs and endothelial cells might be the potential mechanism of impaired BBB during aging.

Email: liudelin_doc@126.com