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Theranostics 2020; 10(15):6825-6838. doi:10.7150/thno.45170 This issue Cite

Research Paper

Osteoclast-derived apoptotic bodies show extended biological effects of parental cell in promoting bone defect healing

Qinyu Ma¹, Mengmeng Liang², Nathachit Limjunyawong³, Yang Dan⁴, Junchao Xing¹, Jianmei Li², Jianzhong Xu^1✉, Ce Dou^1,5✉

1. Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
2. Department of Biomedical Materials Science, Third Military Medical University, Chongqing 400038, China.
3. The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
4. Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
5. Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

✉ Corresponding authors: Jianzhong Xu. Department of Orthopedics, Southwest Hospital, Third Military Medical University, Gaotanyan Street No.30, Chongqing 400038, China. Email: xujianzhong1962com; Ce Dou. Department of Orthopedics, Southwest Hospital, Third Military Medical University, Gaotanyan Street No.30, Chongqing 400038, China. Email: lance.doucecom. More

Abstract

Apoptotic bodies (ABs) traditionally considered as garbage bags that enclose residual components of dead cells are gaining increasing attentions due to their potential roles in intercellular communications. In bone turn over, at the end of bone resorption phase, most osteoclasts undergo apoptosis, generating large amounts of ABs. However, it remains unclear of the role of osteoclast-derived ABs in bone remodeling.

Methods: Staurosporine (STS) was used to apoptotic induction and differential centrifugation was used to isolate ABs. Western blotting, flowcytometry and Transmission electron microscopy (TEM) were performed for ABs identification, while whole transcriptome of ABs from osteoclasts at different stages was detected by RNA-seq. VENN analysis and gene set enrichment analysis (GSEA) were performed to compare the profile similarities between ABs and parental cells. In vitro efficacy of ABs on angiogenesis and osteogenesis were evaluated by tube formation assay and ALP staining. In vivo, calvarial defect mice model was used to assess the effects of ABs-modified decalcified bone matrix (DBM) scaffolds on angiogenesis and osteogenesis.

Results: Here we mapped the whole transcriptome paralleled with small RNA profiling of osteoclast derived ABs at distinct differentiation stages. Whole transcriptome analysis revealed significant differences in RNA signatures among the ABs generated from osteoclasts at different stages. By comparing with parental osteoclast RNA profiles, we found that the transcriptome of ABs exhibited high similarities with the corresponding parental cells. Functionally, in vitro and in vivo studies showed that similar with the parental cells, pOC-ABs potentiated endothelial progenitor cell proliferation and differentiation, whereas mOC-ABs promoted osteogenic differentiation. The inherited biological effects of ABs were shown mediated by several enriched lncRNAs of which the interference abolished AB functions.

Conclusions: Our study revealed the total RNA profiles of osteoclast derived ABs and demonstrated their biological functions. Both gene set and functional analysis indicated that osteoclast derived ABs are biologically similar with the parental cells suggesting their bridging role in osteoclast-osteoblast coupling in bone remodeling.

Keywords: Apoptotic body, Osteoclast, Vesicle bioinformatics, Cell coupling, Bone remodeling

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