Background In the bone marrow microenvironment of postmenopausal osteoporosis (PMOP), bone marrow mesenchymal stem cell (BMSC)-derived exosomal miRNAs play an important role in bone formation and bone resorption, although the pathogenesis has yet to be clarified. Methods BMSC-derived exosomes from ovariectomized rats (OVX-Exo) and sham-operated rats (Sham-Exo) were co-cultured with bone marrow-derived macrophages to study their effects on osteoclast differentiation. Next-generation sequencing was utilized to identify the differentially expressed miRNAs (DE-miRNAs) between OVX-Exo and Sham-Exo, while target genes were analyzed using bioinformatics. The regulatory effects of miR-27a-3p and miR-196b-5p on osteogenic differentiation of BMSCs and osteoclast differentiation were verified by gain-of-function and loss-of-function analyses. Results Osteoclast differentiation was significantly enhanced in the OVX-Exo treatment group compared to the Sham-Exo group. Twenty DE-miRNAs were identified between OVX-Exo and Sham-Exo, among which miR-27a-3p and miR-196b-5p promoted the expressions of osteogenic differentiation markers in BMSCs. In contrast, knockdown of miR-27a-3p and miR-196b-5p increased the expressions of osteoclastic markers in osteoclast. These 20 DE-miRNAs were found to target 11435 mRNAs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that these target genes were involved in several biological processes and osteoporosis-related signaling pathways. Conclusion BMSC-derived exosomal miR-27a-3p and miR-196b-5p may play a positive regulatory role in bone remodeling.
Dendritic cells release bioactive exosomes involved in immune regulation. Long non-coding RNAs (lncRNAs) are implicated in a number of immunoregulatory mechanisms. However, the roles of lncRNAs in dendritic cell-derived exosomes remain to be elucidated. The present study aimed to investigate the roles of lncRNAs in exosomes derived from mature and immature dendritic cells and to find specific lncRNAs with immunoregulatory function. The expression profiles of lncRNAs in exosomes derived from bone marrow dendritic cells of C57 mice were illustrated. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses and Gene Set Enrichment Analysis were performed to identify potential targets correlated with immune regulation. In addition, lncRNA-miRNA-mRNA networks were predicted using bioinformatics methods. Representative lncRNAs were further validated via reverse transcription-quantitative PCR. A total of 437 lncRNAs were analyzed using RNA-seq. Among these, the expression of ~87 lncRNAs was upregulated and 21 lncRNAs was downregulated in mature dendritic cell-derived exosomes (Dex) compared with immature Dex. GO analyses indicated the involvement of upregulated lncRNAs in multiple biological functions, such as the immune system process, while downregulated lncRNAs were involved in poly(A) RNA binding. Analysis of the KEGG pathway identified the relationship of TNF signaling and ribosome pathway with upregulated lncRNAs and downregulated lncRNAs, respectively. The results of gene set enrichment analysis identified that three lncRNA-associated transcripts (Procr-203, Clec4e-202 and Traf1-203) were highly associated with immunoregulatory functions including T helper cell differentiation and Janus kinase-STAT signaling pathway. The results indicated the involvement of candidate lncRNAs in immunoregulation and suggested a new perspective on the modulation of lncRNAs in Dex.
Sang H, Zhao R, Lai G, et al. Bone marrow mesenchymal stem cell-derived exosomes attenuate the maturation of dendritic cells and reduce the rejection of allogeneic transplantation [published online as ahead of print on March 7, 2023].
Background Bone mesenchymal stem cells (BMSCs)-derived exosomes (B-exos) are attractive for applications in enabling alloantigen tolerance. An in-depth mechanistic understanding of the interaction between B-exos and dendritic cells (DCs) could lead to novel cell-based therapies for allogeneic transplantation. Herein, the potential of a B-exos-based application combined with DCs was explored for inducing allogeneic transplant tolerance. Methods After mixed culture of BMSCs and DCs for 48 hours, DCs from the upper layer were collected to analyze the expression levels of surface markers and mRNAs of inflammation-related cytokines. Then the DCs were co-cultured with B-exo before being collected to detect the mRNA and protein expression levels of indoleamine 2,3-dioxygenase (IDO). The treated DCs from different groups were co-cultured with naïve CD4 + T cells from the mouse spleen. The proliferation of CD4 + T cells and the proportion of CD4 + CD25 + Foxp3 + T cells were analyzed. Finally, the skins of BALB/c mice were transplanted to the back of C57 mice to establish a mouse allogeneic skin transplantation model. Results The coculture of DCs with BMSCs in a trans-well system downregulated the expression of the major histocompatibility complex class II (MHC-II) and CD80/86 costimulatory molecules on DCs, as well as the mRNA expression of interleukin-10 (IL-10), IL-12, and transforming growth factor-β (TGF-β). However, these findings were abolished when treated with GW4869. Moreover, B-exos (5 µg/mL) increased the expression of indoleamine 2,3-dioxygenase (IDO) in DCs treated with lipopolysaccharide (LPS) compared to the control cells. CD4 + CD25 + Foxp3 + T cells increased when cultured with B-exos-exposed DCs, which was attenuated by 1-methyl tryptophan (1MT). Mice recipients injected with B-exos-treated DCs significantly prolonged the skin allograft survival. The allografts showed slight cell infiltration and significantly preserved graft structure. Also, the level of CD4 + CD25 + Foxp3 + T cells was significantly higher in B-exos-exposed DCs recipient animals than that in other groups. Conclusions Taken together, these data suggested that the B-exos suppress the maturation of DCs and increase the expression of IDO, which might shed light on the role of B-exos in inducing alloantigen tolerance.
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