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陈晓

性别:男
职称:副教授
单位:医学院

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陈晓

研究成果

 

 

               1.      Yin Zi#; Hu Jia-jie#; Yang Long; Zheng Ze-Feng; An Cheng-rui; Wu Bing-bing; Zhang Can; Shen Wei-Liang; Liu Huan-huan; Chen Jia-lin; Heng Boon Chin; Guo Guo-ji; Chen Xiao*and Ouyang Hong-Wei*. Single-cell analysis reveals a nestin+tendon stem/progenitor cell population with strong tenogenic potentiality. Scince Advances2016. Science 子刊, 共同通讯).

 

 

Abstract

  The repair of injured tendons remains a formidable clinical challenge because of our limited understanding of tendon stem cells and the regulation of tenogenesis. With single-cell analysis to characterize the gene expression profiles of individual cells isolated from tendon tissue, a subpopulation of nestin+ tendon stem/progenitor cells (TSPCs) was identified within the tendon cell population. Using Gene Expression Omnibus datasets and immunofluorescence assays, we found that nestin expression was activated at specific stages of tendon development. Moreover, isolated nestin+ TSPCs exhibited superior tenogenic capacity compared to nestin TSPCs. Knockdown of nestin expression in TSPCs suppressed their clonogenic capacity and reduced their tenogenic potential significantly both in vitro and in vivo. Hence, these findings provide new insights into the identification of subpopulations of TSPCs and illustrate the crucial roles of nestin in TSPC fate decisions and phenotype maintenance, which may assist in future therapeutic strategies to treat tendon disease

 

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         2.       Hu JiaJie#, Yin Zi#,  Shen Weiliang,  Xie Yubin,  Zhu Ting,  Lu Ping,  Cai Youzhi, Kong Minjian,  Heng Boon Chin,  Zhou Yiting,  Chen Weishan,  Chen Xiao* and Ouyang Hongwei*, Pharmacological Regulation of In Situ Tissue Stem Cells Differentiation for Soft Tissue Calcification Treatment. Stem Cells 2016,34: 1083–1096. (IF= 5.902, 共同通讯).

 

Abstract

Calcification of soft tissues, such as heart valves and tendons, is a common clinical problem with limited therapeutics. Tissue specific stem/progenitor cells proliferate to repopulate injured tissues. But some of them become divergent to the direction of ossification in the local pathological microenvironment, thereby representing a cellular target for pharmacological approach. We observed that HIF-2alpha (encoded by EPAS1 inclined form) signaling is markedly activated within stem/progenitor cells recruited at calcified sites of diseased human tendons and heart valves. Proinflammatory microenvironment, rather than hypoxia, is correlated with HIF-2alpha activation and promoted osteochondrogenic differentiation of tendon stem/progenitor cells (TSPCs). Abnormal upregulation of HIF-2alpha served as a key switch to direct TSPCs differentiation into osteochondral-lineage rather than teno-lineage. Notably, Scleraxis (Scx), an essential tendon specific transcription factor, was suppressed on constitutive activation of HIF-2alpha and mediated the effect of HIF-2alpha on TSPCs fate decision. Moreover, pharmacological inhibition of HIF-2alpha with digoxin, which is a widely utilized drug, can efficiently inhibit calcification and enhance tenogenesis in vitro and in the Achilles's tendinopathy model. Taken together, these findings reveal the significant role of the tissue stem/progenitor cells fate decision and suggest that pharmacological regulation of HIF-2alpha function is a promising approach for soft tissue calcification treatment.

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         3.       Chen Xiao#GuShen#Chen BifengShenWeiliangYin ZiXuGuoweiHu JiajieZhu TingLi GangWan ChaoOuyangHongweiLee Tin Lap*Chan Wai Yee*Nanoparticle delivery of stable miR-199a-5p agomir improve the osteogenesis of Human Mesenchymal stem cells via the HIF1a pathway. Biomaterials 2015, 53:239-250IF=8.978

 

 

Abstract

Elucidating the regulatory mechanisms of osteogenesis of human mesenchymal stem cell (hMSC) is important for the development of cell therapies for bone loss and regeneration. Here we showed that hsa-miR-199a-5p modulated osteogenic differentiation of hMSCs at both early and late stages through HIF1a pathway. hsa-miR-199a expression was up-regulated during osteogenesis for both of two mature forms, miR-199a-5p and -3p. Over-expression of miR-199a-5p but not -3p enhanced differentiation of hMSCs in vitro, whereas inhibition of miR-199a-5p reduced the expression of osteoblast-specific genes, alkaline phosphatase (ALP) activity, and mineralization. Furthermore, over-expression of miR-199a enhanced ectopic bone formation in vivo. Chitosan nanoparticles were used for delivery of stable modified hsa-miR-199a-5p (agomir) both in vitro and in vivo, as a proof-of-concept for stable agomir delivery on bone regeneration. The hsa-mir199a-5p agomir were mixed with Chitosan nanoparticles to form nanoparticle/hsa-mir199a-5p agomir plasmid (nanoparticle/agomir) complexes, and nanoparticle/agomir complexes could improve the in vivo regeneration of bone. Further mechanism studies revealed that hypoxia enhanced osteogenesis at early stage and inhibited osteogenesis maturation at late stage through HIF1a-Twistl pathway. At early stage of differentiation, hypoxia induced HIF1a-Twistl pathway to enhance osteogenesis by up-regulating miR-199a-5p, while at late stage of differentiation, miR-199a-5p enhanced osteogenesis maturation by inhibiting HIF1 alpha-Twist1 pathway.

 

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         4.       Liu Huanhuan, Zhang Can, Zhu Shouan, Lu Ping, Zhu Ting, Gong Xiaonan, Hu Jiajie, Yin Zi, Chen Xiao*, OuyangHongwei*. Mohawk promotes the tenogenesis of mesenchymal stem cells through activation of the TGFβ signaling pathway. Stem Cells. 2015,33(2):443-55 (IF= 6.53, 共同通讯).

 

Abstract

The transcription factor Mohawk (Mkx) is expressed in developing tendons and is an important regulator of tenogenic differentiation. However, the exact roles of Mkx in tendinopathy and tendon repair remain unclear. Using gene expression Omnibus datasets and immunofluorescence assays, we found that Mkx expression level was dramatically lower in human tendinopathy tissue and it is activated at specific stages of tendon development. In mesenchymal stem cells (MSCs), ectopic Mkx expression strikingly promoted tenogenesis more efficiently than Scleraxis (Scx), a well-known master transcription factor of tendon. Significantly higher levels of tenogenic gene expression and collagen fibril growth were observed with Mkx versus Scx. Interestingly, it was observed that Mkx dramatically upregulated Scx through binding to the Tgfb2 promoter. Additionally, the transplantation of Mkx-expressing-MSC sheets promoted tendon repair in a mouse model of Achilles-tendon defect. Taken together, these data shed light on previously unrecognized roles of Mkx in tendinopathy, tenogenesis, and tendon repair as well as in regulating the TGFβ pathway.

 

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         5.       Tang QM, Chen JL, Shen WL, Yin Z, Liu HH, Fang Z, Heng BC, Ouyang HW* and Chen X*.Fetal and adult fibroblasts display intrinsic differences in tendon tissue engineering and regeneration. Sci Rep, 2014,4:5515.(IF =5.578) Nature asia网站highlight

 

 

Abstract

Injured adult tendons do not exhibit optimal healing through a regenerative process, whereas fetal tendons can heal in a regenerative fashion without scar formation. Hence, we compared FFs (mouse fetal fibroblasts) and AFs (mouse adult fibroblasts) as seed cells for the fabrication of scaffold-free engineered tendons. Our results demonstrated that FFs had more potential for tendon tissue engineering, as shown by higher levels of tendon-related gene expression. In the in situ AT injury model, the FFs group also demonstrated much better structural and functional properties after healing, with higher levels of collagen deposition and better microstructure repair. Moreover, fetal fibroblasts could increase the recruitment of fibroblast-like cells and reduce the infiltration of inflammatory cells to the injury site during the regeneration process. Our results suggest that the underlying mechanisms of better regeneration with FFs should be elucidated and be used to enhance adult tendon healing. This may assist in the development of future strategies to treat tendon injuries.

 

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         6.       Chen X#, Yin Z#, Chen JL, Shen WL, Liu HH, Tang QM, Fang Z, Lu LR, Ji J*, Ouyang HW*. Mechanical force and scleraxis synergistically promote the commitment of human embryonic stem cells to tenocytes for functional tendon regeneration.Sci Rep, 2012, 2, 977.(IF= 5.578)(第十届国际韧带会议青年学者奖

 

Abstract

As tendon stem/progenitor cells were reported to be rare in tendon tissues, tendons as vulnerable targets of sports injury possess poor self-repair capability. Human ESCs (hESCs) represent a promising approach to tendon regeneration. But their teno-lineage differentiation strategy has yet to be defined. Here, we report that force combined with the tendon-specific transcription factor scleraxis synergistically promoted commitment of hESCs to tenocyte for functional tissue regeneration. Force and scleraxis can independently induce tendon differentiation. However, force alone concomitantly activated osteogenesis, while scleraxis alone was not sufficient to commit, but augment tendon differentiation. Scleraxis synergistically augmented the efficacy of force on teno-lineage differentiation and inhibited the osteo-lineage differentiation by antagonized BMP signaling cascade. The findings not only demonstrated a novel strategy of directing hESC differentiation to tenocyte for functional tendon regeneration, but also offered insights into understanding the network of force, scleraxis and bmp2 controlling tendon-lineage differentiation.

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