Post-death Vesicles of Senescent Bone Marrow Mesenchymal Stromal Polyploids Promote Macrophage Aging and Breast Cancer

Xie, B.; Fan, M.; Wang, C. X.; Zhang, Y.; Xu, S.; Mizenko, R.; Lin, T.-y.; Duan, Y.; Huang, J.; Berg, J. I.; Wu, D.; Li, A.; Hao, D.; Gao, K.; Sun, Y.-h.; Tepper, C. G.; Carney, R. P.; Li, Y.; Wang, A.; Gong, Q.; Daly, M.; Jao, L.-E.; Monjazeb, A. M.; Fierro, F. A.; Li, J. J.

doi:10.1101/2024.03.06.583755

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bioRxiv · 10.1101/2024.03.06.583755

Post-death Vesicles of Senescent Bone Marrow Mesenchymal Stromal Polyploids Promote Macrophage Aging and Breast Cancer

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Abstract

Potential systemic factors contributing to aging-associated breast cancer (BC) remain elusive. Here, we reveal that the polyploid giant cells (PGCs) that contain more than two sets of genomes prevailing in aging and cancerous tissues constitute 5-10% of healthy female bone marrow mesenchymal stromal cells (fBMSCs). The PGCs can repair DNA damage and stimulate neighboring cells for clonal expansion. However, dying PGCs in advanced-senescent fBMSCs can form "spikings" which are then separated into membraned mtDNA-containing vesicles (Senescent PGC-Spiking Bodies; SPSBs). SPSB-phagocytosed macrophages accelerate aging with diminished clearance on BC cells and protumor M2 polarization. SPSB-carried mitochondrial OXPHOS components are enriched in BC of elder patients and associated with poor prognosis. SPSB-incorporated breast epithelial cells develop aggressive characteristics and PGCs resembling the polyploid giant cancer cells (PGCCs) in clonogenic BC cells and cancer tissues. These findings highlight an aging BMSC-induced BC risk mediated by SPSB-induced macrophage dysfunction and epithelial cell precancerous transition. SIGNIFICANCEMechanisms underlying aging-associated cancer risk remain unelucidated. This work demonstrates that polyploid giant cells (PGCs) in bone marrow mesenchymal stromal cells (BMSCs) from healthy female bone marrow donors can boost neighboring cell proliferation for clonal expansion. However, the dying-senescent PGCs in the advanced-senescent fBMSCs can form "spikings" which are separated into mitochondrial DNA (mtDNA)-containing spiking bodies (senescent PGC-spiking bodies; SPSBs). The SPSBs promote macrophage aging and breast epithelial cell protumorigenic transition and form polyploid giant cancer cells. These results demonstrate a new form of ghost message from dying-senescent BMSCs, that may serve as a systemic factor contributing to aging-associated immunosuppression and breast cancer risk. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/583755v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@f07b60org.highwire.dtl.DTLVardef@33ef98org.highwire.dtl.DTLVardef@1b720c8org.highwire.dtl.DTLVardef@1c9514d_HPS_FORMAT_FIGEXP M_FIG Xie et al demonstrate that the polyploid giant cells (PGCs) in the juvenile phase expansion of female bone marrow mesenchymal stromal cells (fBMSCs) can boost neighboring cell proliferation for clonal expansion. However, when fBMSCs enter to the advanced-senescent phase, the dying-senescent PGCs form "spikings" which are then separated into membraned vesicles termed Senescent PGC spiking bodies, SPSBs). The SPSBs carrying fragmented mitochondrial elements and OXPHOS proteins can be phagocytosed by macrophage and breast epithelial cells leading to macrophage aging and breast epithelial protumorigenic transition. The SPSBs are demonstrated to be a new form of post-cell death vesicle from aging BMSCs and may serve as a systemic factor contributing to aging-associated immunosuppression and breast cancer risk. C_FIG

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Xie, B., Fan, M., Wang, C. X., Zhang, Y., Xu, S., Mizenko, R., Lin, T.-y., Duan, Y., Huang, J., Berg, J. I., Wu, D., Li, A., Hao, D., Gao, K., Sun, Y.-h., Tepper, C. G., Carney, R. P., Li, Y., Wang, A., Gong, Q., Daly, M., Jao, L.-E., Monjazeb, A. M., Fierro, F. A., Li, J. J.. 2024-03-08. Post-death Vesicles of Senescent Bone Marrow Mesenchymal Stromal Polyploids Promote Macrophage Aging and Breast Cancer. https://doi.org/10.1101/2024.03.06.583755

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