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Liao L.,PLA Fourth Military Medical University | Yang X.,PLA Fourth Military Medical University | Yang X.,Zunyi Medical College | Su X.,Xian Jiaotong University | And 8 more authors.
Cell Death and Disease | Year: 2013

During the process of aging, especially for postmenopausal females, the cell lineage commitment of mesenchymal stem cells (MSCs) shift to adipocyte in bone marrow, resulting in osteoporosis. However, the cell-intrinsic mechanism of this cell lineage commitment switch is poorly understood. As the post-transcription regulation by microRNAs (miRNAs) has a critical role in MSCs differentiation and bone homeostasis, we performed comprehensive miRNAs profiling and found miR-705 and miR-3077-5p were significantly enhanced in MSCs from osteoporosis bone marrow. Both miR-705 and miR-3077-5p acted as inhibitors of MSCs osteoblast differentiation and promoters of adipocyte differentiation, by targeting on the 3′untranslated region (3′UTR) of HOXA10 and RUNX2 mRNA separately. Combined inhibition of miR-705 and miR-3077-5p rescued the cell lineage commitment disorder of MSCs through restoring HOXA10 and RUNX2 protein level. Furthermore, we found excessive TNFα and reactive oxygen species caused by estrogen deficiency led to the upregulation of both miRNAs through NF-κB pathway. In conclusion, our findings showed that redundant miR-705 and miR-3077-5p synergistically mediated the shift of MSCs cell lineage commitment to adipocyte in osteoporosis bone marrow, providing new insight into the etiology of osteoporosis at the post-transcriptional level. Moreover, the rescue of MSCs lineage commitment disorder by regulating miRNAs expression suggested a novel potential therapeutic target for osteoporosis as well as stem cell-mediated regenerative medicine. © 2013 Macmillan Publishers Limited All rights reserved.


Yang N.,PLA Fourth Military Medical University | Wang G.,PLA Fourth Military Medical University | Hu C.,PLA Fourth Military Medical University | Hu C.,Engineering Technology Center for Tissue Engineering of xiAn | And 13 more authors.
Journal of Bone and Mineral Research | Year: 2013

Inflammatory cytokines, especially tumor necrosis factor α (TNF-α), have been shown to inhibit osteogenic differentiation of mesenchymal stem cells (MSCs) and bone formation in estrogen deficiency-induced osteoporosis, but the mechanism responsible remains poorly understood. MicroRNAs (miRNAs) have been shown to regulate MSC differentiation. Here, we identified a novel mechanism whereby TNF-α, suppressing the functional axis of a key miRNA (miR-21) contributes to estrogen deficiency-induced osteoporosis. In this study, we screened differentially expressed miRNAs in MSCs derived from estrogen deficiency-induced osteoporosis and found miR-21 was significantly downregulated. miR-21 was suppressed by TNF-α during the osteogenesis of MSCs. Furthermore, miR-21 was confirmed to promote the osteoblast differentiation of MSCs by repressing Spry1, which can negatively regulate the osteogenic differentiation of MSCs. Upregulating miR-21 partially rescued TNF-α-impaired osteogenesis of MSCs. Blocking TNF-α ameliorated the inflammatory environment and significantly enhanced bone formation with increased miR-21 expression and suppressed Spry1 expression in ovariectomized (OVX) mice. Our results revealed a novel function for miR-21 and suggested that suppressed miR-21 may contribute to impaired bone formation by elevated TNF-α in estrogen deficiency-induced osteoporosis. This study may indicate a molecular basis for novel therapeutic strategies against osteoporosis and other inflammatory bone diseases. © 2013 American Society for Bone and Mineral Research.


Luo H.,Engineering Technology Center for Tissue Engineering of xiAn | Zhang Y.,PLA Fourth Military Medical University | Zhang Y.,Engineering Technology Center for Tissue Engineering of xiAn | Zhang Z.,Engineering Technology Center for Tissue Engineering of xiAn | Jin Y.,PLA Fourth Military Medical University
Biomaterials | Year: 2012

Our previous report demonstrated that autologous adipose-derived mesenchymal stem cells (ADSCs) combined with xenogeneic acellular nerve matrix (XANM) can support the regeneration of defective nerves. Although ADSCs had the potential to replace Schwann cells in engineered-tissue nerves, apoptosis easily obstructed the ability to treat serious nerve injury in the host, such as a >50-mm-long nerve defect. In the present study, we found that, in combination with transforming growth factor β1 (TGFβ1), an ADSCs-XANM graft was sufficient to support the regeneration of a 50-mm sciatic nerve defect, which was not achieved using an ADSCs-XANM graft alone. Based on this finding, we further investigated how TGFβ1 coordinated with ADSCs to enhance nerve regeneration. In vitro, cell culture experiments demonstrated that TGFβ1 did not have a direct effect on ADSC proliferation, apoptosis, the cell cycle, or neural differentiation. The expression of VEGF, however, was significantly increased in ADSCs cultured with TGFβ1. In vivo, fluorescence labeling experiments demonstrated that the survival of transplanted ADSCs inoculated with XANM-TGFβ1 was higher than with XANM. Further study showed that TGFβ1 was capable of impairing the host immune response that was trigged by transplanted XANM. Additionally, we discovered that XANM-ADSCs in immunodeficient mice had apoptosis rates similar to XANM-ADSCs-TGFβ1 over a short time course (7 days). Once we blocked VEGF with a neutralizing antibody, the protective effect of TGFβ1 was impaired over a long time course (28 days). These results suggested that TGFβ1 was capable of enhancing the regenerative capacity of an XANM-ADSCs graft, mainly by protecting transplanted ADSCs from apoptosis. This effect was achieved in part through decreasing inflammation and promoting VEGF-dependent angiogenesis. © 2012 Elsevier Ltd.


Shang F.,PLA Fourth Military Medical University | Ming L.,PLA Fourth Military Medical University | Ming L.,Engineering Technology Center for Tissue Engineering of xiAn | Ming L.,Institute for Tissue Engineering and Regenerative Medicine Research of Xian | And 6 more authors.
Biomaterials | Year: 2014

Treatment of weight-bearing bones fractures with defects is critical for patients with osteoporosis's rehabilitation. Although various tissue engineering methods were reported, the best treating strategy for tissue engineering remains to be identified as the limitation of enhancing the ability of the osteogenetic differentiation potential of seed cell is one of the cardinal issues to be solved. The objective of this study is to investigate the feasibility of applying licochalcone-A (L-A) and bone marrow mesenchymal stem cells (BMSC)-aggregate in bone repairing tissue engineering and further study the biological effects of L-A on the cell aggregate formation and osteogenic properties. 80 female SpragueDawley rats underwent bilateral ovariectomy were made with a 3.5mm femurs bone defects without any fixation. These rats were then randomly assigned to five different treatment groups: (1) empty defect (n=16), (2) CA-LA (n=16), (3) CA-N (n=16), (4) CA-L (n=16), (5) CA-S (n=16) and 16 female SD rats were treated as a control. Data showed that L-A administrated cell aggregate had a stronger osteogenic differentiation and mineralized formation potential than non-administrated group both invitro and invivo. For invitro study, L-A administrated group had a more significant expression of ECM, osteogenic associated maker in addition with more mineralized area and higher ALP activity compared with the control group. For invivo study, 3D reconstruction of micro-CT, HE staining and bone strength results showed that newly formed bone in groups administrated by L-A was significant higher than that in Sham group at 2, 4, 8 and 12 weeks after transplantation, especially for groups which was systematically injected with L-A at 8 weeks. Results of our study demonstrated that LA could positively affect cell behavior in cell-aggregate engineering and could be a promising strategy in treating osteoporotic weight-bearing bones fractures with defects. © 2014 Elsevier Ltd.


Luo H.,PLA Fourth Military Medical University | Luo H.,Engineering Technology Center for Tissue Engineering of xiAn | Lu Y.,PLA Fourth Military Medical University | Lu Y.,Engineering Technology Center for Tissue Engineering of xiAn | And 6 more authors.
Biomaterials | Year: 2013

Although acellular corneas have been reported to be a potential substitute for allogeneic cornea transplantation to treat corneal injury, severe corneal injury is hard to repair due to inflammation and neovascularization. The use of the amniotic membrane as a graft in ocular surface reconstruction has become widespread because of the anti-inflammatory and anti-angiogenic properties of amniotic epithelial cells (AECs). Our objective was to construct a tissue-engineered cornea (TEC) composed of an acellular porcine cornea (APC) and AECs to repair severe corneal injury. Corneal cells were completely removed from the prepared APC, and the microstructure, mechanical properties, and stability of a natural porcine cornea (NPC) was maintained. Invitro, MTT and flow cytometry analyses showed that the APC did not negatively affect cell viability and apoptosis. Invivo, corneal pocket and subcutaneous transplantation demonstrated that the APC was incapable of trigging accepted immune response. AECs isolated from the human amniotic membrane have proliferation potential and present healthy morphology before 6 passages. After 7 days of culture on the surface of the APC, the AECs were stratified into 5-6 layers. We found that the AECs reconstituted the basement membrane that had been disrupted by the decellularization process. ELISA results showed that after culturing the TEC, the culture medium contained anti-inflammatory and anti-angiogenic growth factors, such as MIF, IL6, Fas-L, and PDEF. Finally, the results of lamellar keratoplasty to treat an alkali burn showed that the transplanted TEC was transparent and completely inoculated into the host cornea. However, the transplanted APC was degraded due to host rejection. Therefore, we conclude that a TEC composed of AECs and an APC holds great potential for the repair of severe corneal injury. © 2013 Elsevier Ltd.

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