Abstract
Systemic sclerosis (SSc), an autoimmune disease, may cause significant osteopenia due to activation of the IL4Rα/mTOR pathway. Mesenchymal stem cell transplantation (MSCT) can ameliorate immune disorders in SSc via inducing immune tolerance. However, it is unknown whether MSCT rescues osteopenia phenotype in SSc. Here we show that MSCT can effectively ameliorate osteopenia in SSc mice by rescuing impaired lineage differentiation of the recipient bone marrow MSCs. Mechanistically, we show that donor MSCs transfer miR-151-5p to the recipient bone marrow MSCs in SSc mice to inhibit IL4Rα expression, thus downregulating mTOR pathway activation to enhance osteogenic differentiation and reduce adipogenic differentiation. Moreover, systemic delivery of miR-151-5p is capable of rescuing osteopenia, impaired bone marrow MSCs, tight skin, and immune disorders in SSc mice, suggesting that miR-151-5p may be a specific target for SSc treatment. Our finding identifies a previously unrecognized role of MSCT in transferring miRNAs to recipient stem cells to ameliorate osteopenia via rescuing a non-coding RNA pathway.
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Acknowledgements
This work was supported by grants from National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services (R01DE017449 and R01DE019932 to SS and K99DE025915 to CC), an NIH NIAMS fellowship (T32AR007442), and an Schoenleber Pilot Research Grant from University of Pennsylvania School of Dental Medicine. Clinical studies were supported by grants from the China Major International (Regional) Joint Project (81120108021 to LS) and Jiangsu Province Major Research and Development Program (BE 2015062 to LS). ClinicalTrials.gov Identifier: NCT00962923.
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( Supplementary information is linked to the online version of the paper on the Cell Research website.)
Supplementary information
Supplementary information, Table S1
miRNA hits on IL4Rα (PDF 1954 kb)
Supplementary information, Table S2
SSc Patients and Normal Controls Information (PDF 360 kb)
Supplementary information, Figure S1
Does responses of miR151-5p mimic and inhibitor. (PDF 92 kb)
Supplementary information, Figure S2
miR-151-5p characterization. (PDF 1465 kb)
Supplementary information, Figure S3
miR-151-5p inhibitor regulated human BMMSC lineage differentiation. (PDF 3461 kb)
Supplementary information, Figure S4
miR-151-5p mimic rescued IL4-induced lineage alteration in hMSCs. (PDF 5457 kb)
Supplementary information, Figure S5
Exosome-mediated miR-151-5p transfer. (PDF 274 kb)
Supplementary information, Figure S6
Blockage of Rab27a by siRNA reduced therapeutic effects of MSCT in Tsk/+ mice. (PDF 4635 kb)
Supplementary information, Figure S7
miR151-5p overexpression in EVs reduced EV dosage for disease treatment in Tsk/+ mice. (PDF 4260 kb)
Supplementary information, Figure S8
Ad-miR-151 treatment inhibited TH2 cell differentiation in Tsk/+ mice. (PDF 634 kb)
Supplementary information, Figure S9
Ad-miR-151 treatment ameliorated T cell infiltration and autoimmune index in Tsk/+ mice. (PDF 2988 kb)
Supplementary information, Figure S10
Ad-miR151 treatment rescued IL4-inhibited osteoclastogenesis. (PDF 808 kb)
Supplementary information, Figure S11
Schematic diagram of miR-151-5p transfer from donor MSCs to Tsk/+ recipient MSCs to regulate IL4Rα/mTOR signaling. (PDF 186 kb)
Supplementary information, Figure S12
Quantification and Characterization of EVs. (PDF 81 kb)
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Chen, C., Wang, D., Moshaverinia, A. et al. Mesenchymal stem cell transplantation in tight-skin mice identifies miR-151-5p as a therapeutic target for systemic sclerosis. Cell Res 27, 559–577 (2017). https://doi.org/10.1038/cr.2017.11
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DOI: https://doi.org/10.1038/cr.2017.11
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