Extracellular vesicles from  deciduous pulp stem cells recover bone loss by regulating telomerase activity in an osteoporosis mouse model

Sonoda, Soichiro; Murata, Sara; Nishida, Kimiaki; Kato, Hiroki; Uehara, Norihisa; Kyumoto, Yukari; Yamaza, Haruyoshi; Takahashi, Ichiro; Kukita, Toshio; Yamaza, Takayoshi

doi:10.21203/rs.3.rs-20407/v1

Cited by 4 publications

(9 citation statements)

References 37 publications

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“…SHED-releasing EVs (SHED-EVs) participate in intercellular communication to exert therapeutic effects via bioactive molecules, such as proteins and miRNAs, in acute inflammation, brain injury, and Parkinson disease (2123). Our study showed that SHED-EVcontaining RNA rescued the telomerase activity of recipient BMMSCs in estrogen-deficient mice, leading to the suppression of bone resorption through an improved osteoblastic function in recipient BMMSCs (24). However, whether SHED-EVs participate in the treatment of SLE and their potential mechanism of action have not yet to be elucidated.…”

Section: Targeting Of Deciduous Tooth Pulp Stem Cellderived Extracell...mentioning

confidence: 80%

“…Given that the frequency of engrafted SHED is not significant in the BM of MRL/lpr mice (3,24), we hypothesized that indirect communication of donor SHED is involved in the rescue of BMMSC functions in MRL/lpr mice. We focused on EVs because diverse trophic factors within MSC-releasing EVs are known to contribute to cellcell communication in MSC-based therapy (29,30).…”

Section: Systemic Administration Of Shed-evs Rescued Sle-like Disorde...mentioning

confidence: 99%

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Targeting of Deciduous Tooth Pulp Stem Cell–Derived Extracellular Vesicles on Telomerase-Mediated Stem Cell Niche and Immune Regulation in Systemic Lupus Erythematosus

Sonoda

Murata

Kato

et al. 2021

The Journal of Immunology

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Systemic transplantation of stem cells from human exfoliated deciduous teeth (SHED) is used to treat systemic lupus erythematosus (SLE)–like disorders in MRL/lpr mice. However, the mechanisms underlying the SHED-based therapy remain unclear. In this study, we hypothesized that trophic factors within SHED-releasing extracellular vesicles (SHED-EVs) ameliorate the SLE-like phenotypes in MRL/lpr mice. SHED-EVs were isolated from the culture supernatant of SHED. SHED-EVs were treated with or without RNase and systemically administered to MRL/lpr mice. Subsequently, recipient bone marrow mesenchymal stem cells (BMMSCs) isolated from SHED-EV–administered MRL/lpr mice were examined for the in vitro and in vivo activity of hematopoietic niche formation and immunoregulation. Furthermore, the recipient BMMSCs were secondarily transplanted into MRL/lpr mice. The systemic SHED-EV infusion ameliorated the SLE-like phenotypes in MRL/lpr mice and improved the functions of recipient BMMSCs by rescuing Tert mRNA-associated telomerase activity, hematopoietic niche formation, and immunoregulation. The secondary transplantation of recipient BMMSCs recovered the immune condition and renal functions of MRL/lpr mice. The RNase treatment depleted RNAs, such as microRNAs, within SHED-EVs, and the RNA-depleted SHED-EVs attenuated the benefits of SHED-EVs in MRL/lpr mice. Collectively, our findings suggest that SHED-secreted RNAs, such as microRNAs, play a crucial role in treating SLE by targeting the telomerase activity of recipient BMMSCs.

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Section: Targeting Of Deciduous Tooth Pulp Stem Cellderived Extracell...mentioning

confidence: 80%

Section: Systemic Administration Of Shed-evs Rescued Sle-like Disorde...mentioning

confidence: 99%

Targeting of Deciduous Tooth Pulp Stem Cell–Derived Extracellular Vesicles on Telomerase-Mediated Stem Cell Niche and Immune Regulation in Systemic Lupus Erythematosus

Sonoda

Murata

Kato

et al. 2021

The Journal of Immunology

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“…The reasons why SHED-Heps exhibit the short-term survival and engraftment in the recipient animals are considered due to the immature hepatic differentiation and immunogenicity of donor cells, the xenograft system in immunocompetent animals without any immunosuppressive drug, and the chronical cytotoxic condition after transplantation. On the other hand, SHED-secreting trophic factors including cytokines and extracellular vesicle-containing RNA contents affect immunosuppressive functions [43,44]. The effect of stanniocalcin 1 secreted from SHED-Heps is anti-hepatitis [14].…”

Section: Discussionmentioning

confidence: 99%

Cholangiogenic potential of human deciduous pulp stem cell-converted hepatocyte-like cells

et al. 2021

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Background Stem cells from human exfoliated deciduous teeth (SHED) have been reported to show the in vivo and in vitro hepatic differentiation, SHED-Heps; however, the cholangiogenic potency of SHED-Heps remains unclear. Here, we hypothesized that SHED-Heps contribute to the regeneration of intrahepatic bile duct system in chronic fibrotic liver. Methods SHED were induced into SHED-Heps under cytokine stimulation. SHED-Heps were intrasplenically transplanted into chronically CCl4-treated liver fibrosis model mice, followed by the analysis of donor integration and hepatobiliary metabolism in vivo. Immunohistochemical assay was examined for the regeneration of intrahepatic bile duct system in the recipient liver. Furthermore, SHED-Heps were induced under the stimulation of tumor necrosis factor alpha (TNFA). Results The intrasplenic transplantation of SHED-Heps into CCl4-treated mice showed that donor SHED-Heps behaved as human hepatocyte paraffin 1- and human albumin-expressing hepatocyte-like cells in situ and ameliorated CCl4-induced liver fibrosis. Of interest, the integrated SHED-Heps not only expressed biliary canaliculi ATP-binding cassette transporters including ABCB1, ABCB11, and ABCC2, but also recruited human keratin 19- (KRT19-) and KRT17-positive cells, which are considered donor-derived cholangiocytes, regenerating the intrahepatic bile duct system in the recipient liver. Furthermore, the stimulation of TNFA induced SHED-Heps into KRT7- and SRY-box 9-positive cells. Conclusions Collectively, our findings demonstrate that infused SHED-Heps showed cholangiogenic ability under the stimulation of TNFA in CCl4-damaged livers, resulting in the regeneration of biliary canaliculi and interlobular bile ducts in chronic fibrotic liver. Thus, the present findings suggest that SHED-Heps may be a novel source for the treatment of cholangiopathy.

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“…Furthermore, lots of factors regulated by osteoclasts, like Wnt10b, sema3a, smad1/5/8, and so on, had been widely demonstrated to mediate the differentiation and function of osteoblasts [21,40,41].…”

Section: Discussionmentioning

confidence: 99%

DZNep Promotes Mouse Bone Defect Healing via Enhancing Both Osteogenesis and Osteoclastogenesis

Cao¹,

He²,

Rong³

et al. 2021

Preprint

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Background: EZH2 (Enhancer of zeste homolog 2) is a novel oncogene that can specifically trimethylate the histone H3 lysine 27 (H3K27me3) to transcriptionally inhibit the expression of downstream tumor-suppressing genes. As a small molecular inhibitor of EZH2, 3-Deazaneplanocin (DZNep) has been widely studied due to the role of tumor suppression. With the roles of epigenetic regulation of bone cells emerged in past decades, the property and molecular mechanism of DZNep on enhancing osteogenesis had been reported and attracted a great deal of attention recently. this study aims to elucidate the role of DZNep on EZH2-H3K27me3 axis and downstream factors during both osteoclasts and osteoblasts formation and the therapeutic possibility of DZNep on bone defect healing.Methods: Bone marrow drived macrophages (BMMs) cells were cultured and their responsiveness to DZNep was evaluated by Cell Counting Kit-8, TRAP staining assay, Bone Resorption Assay, Podosome Actin Belt. Bone marrow drived mesenchymal stem cells (BMSC) were cultured and their responsiveness to DZNep was evaluated by Cell Counting Kit-8, ALP and AR staining assay. The expression of nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), Wnt signaling pathway was determined by qPCR and western blotting. Mouse bone defect models were created, rescued by DZNep injection and the effectiveness was evaluated by X-ray and Micro-CT and Histological staining.Results: Consistent with the previous study that DZNep enhances osteogenesis via Wnt family member 1(Wnt1), Wnt6, and Wnt10a, our results showed that DZNep also promotes osteoblasts differentiation and mineralization through the EZH2-H3K27me3-Wnt4 axis. Furthermore, we identified that DZNep promoted the receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast formation via facilitating the phosphorylation of IKKα/β, IκB, and subsequently NF-κB nuclear translocation, which credit to the EZH2-H3K27me3-Foxc1 axis. More importantly, the enhanced osteogenesis and osteoclastogenesis result in accelerated mice bone defect healing in vivo.Conclusion: DZNep targeting EZH2-H3K27me3 axis facilitated the healing of mice bone defect via simultaneously enhancing osteoclastic bone resorption and promoting osteoblastic bone formation.

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Extracellular vesicles from deciduous pulp stem cells recover bone loss by regulating telomerase activity in an osteoporosis mouse model

Cited by 4 publications

References 37 publications

Targeting of Deciduous Tooth Pulp Stem Cell–Derived Extracellular Vesicles on Telomerase-Mediated Stem Cell Niche and Immune Regulation in Systemic Lupus Erythematosus

Targeting of Deciduous Tooth Pulp Stem Cell–Derived Extracellular Vesicles on Telomerase-Mediated Stem Cell Niche and Immune Regulation in Systemic Lupus Erythematosus

Cholangiogenic potential of human deciduous pulp stem cell-converted hepatocyte-like cells

DZNep Promotes Mouse Bone Defect Healing via Enhancing Both Osteogenesis and Osteoclastogenesis

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