Mesenchymal stem cell transplantation in tight-skin mice identifies miR-151-5p as a therapeutic target for systemic sclerosis

• Published in: Cell research 2017-04, Vol.27 (4), p.559-577
• Main Authors: Chen, Chider, Wang, Dandan, Moshaverinia, Alireza, Liu, Dawei, Kou, Xiaoxing, Yu, Wenjing, Yang, Ruili, Sun, Lingyun, Shi, Songtao
• Format: Article
• Language: English
• Subjects: 631/337/384/331; 631/532/2074; 692/4023/1670/122/1801; 692/700/565/545/576/1955; Adenoviridae - metabolism; Adipogenesis; Animals; Biomedical and Life Sciences; Bone Diseases, Metabolic - pathology; Bone Diseases, Metabolic - therapy; Bone marrow; Bone Marrow Cells - cytology; Cell Biology; Cell Differentiation; Cell Lineage; Exosomes - metabolism; Female; Humans; Life Sciences; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells - cytology; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; MicroRNAs - blood; MicroRNAs - genetics; MicroRNAs - metabolism; Molecular Targeted Therapy; Original; original-article; Osteogenesis; Phenotype; Protein-Tyrosine Kinases - deficiency; Protein-Tyrosine Kinases - metabolism; Receptors, Interleukin-4 - metabolism; Scleroderma, Systemic - blood; Scleroderma, Systemic - genetics; Scleroderma, Systemic - therapy; Stem cells; TOR Serine-Threonine Kinases - metabolism
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/cr.2017.11

Systemic sclerosis （SSc）, an autoimmune disease, may cause significant osteopenia due to activation of the IL4Ra/ mTOR pathway. Mesenchymal stem cell transplantation （MSCT） can ameliorate immune disorders in SSc via in- ducing 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 IL4Ra expression, thus downregulating mTOR pathway activation to enhance osteogenic differentiation and reduce adipogenic differentiation. Moreover, systemic delivery of miR-151-5p is capa- ble 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 path- way.