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In Vitro Culture Expansion Impairs Chondrogenic Differentiation and Therapeutic Effect of Mesenchymal Stem Cells by Regulation of Unfolded Protein Response

39 Pages Posted: 18 Sep 2018

See all articles by Chong Shen

Chong Shen

Guangxi Medical University - Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration; Guangxi Medical University - Department of Orthopaedics Trauma and Hand Surgery

Tongmeng Jiang

Guangxi Medical University - Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration; Guangxi Medical University - Department of Orthopaedics Trauma and Hand Surgery

Bo Zhu

Guangxi Medical University - Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration

Yiguan Le

Guangxi Medical University - Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration; Guangxi Medical University - Department of Orthopaedics Trauma and Hand Surgery

Jianwei Liu

Guangxi Medical University - Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration

Zainen Qin

Guangxi Medical University - Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration

Haimin Chen

Guangxi Medical University - Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration

Gang Zhong

Guangxi Medical University - Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration; Guangxi Medical University - Department of Orthopaedics Trauma and Hand Surgery

Li Zheng

Guangxi Medical University - Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration

Jinmin Zhao

Guangxi Medical University - Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration; Guangxi Medical University - Department of Orthopaedics Trauma and Hand Surgery; Guangxi Medical University - First Affiliated Hospital

Xingdong Zhang

Sichuan University - National Engineering Research Center for Biomaterials

More...

Abstract

In vitro expansion of mesenchymal stem cells (MSCs) has been implicated in loss of multipotency, leading to impaired chondrogenic potential and eventually therapeutic effect, as reported in our previous study. However, the precise regulatory mechanism is still unclear. Here, we demonstrate that endoplasmic reticulum (ER) stress and unfolded protein response (UPR) were highly enriched in in vitro-cultured bone marrow MSCs at passage 3 (P3 BMSCs) vs. flesh P0 BMSCs by microarray analysis. Indeed, RT-PCR and western blot analysis showed significantly lower expression levels of three key UPR-related molecules, ATF4, ATF6 and XBP1 in P3 BMSCs than P0 BMSCs. Further, we found that UPR suppression by  4-phenylbutyrate (4-PBA) impaired chondrogenesis and cartilage repair in P0 BMSCs, and UPR induction by tunicamycin (TM) enhanced chondrogenic differentiation and cartilage regeneration in in vitro-cultured P3 BMSCs. Thus, the decline of chondrogenic potential of stem cells after in vitro culture and expansion may be due to the change of ER stress and UPR pathway.

Funding: This study was financially supported by National key research and development program of China (2016YFB0700804), National Natural Science Fund of China (Grant No. 81760326 and 81460345), the Guangxi Scientific Research and Technological Development Foundation (Grant No. GuikeAB16450003) and the Guangxi Science and Technology Major Project (Guike AA17204085), High level innovation teams and outstanding scholars in Guangxi Universities (The third batch), the Distinguished Young Scholars Program of Guangxi Medical University, and the Key scientific research collaboration program of Guangxi Biomedical Collaborative Innovation Center (GCICB-SR-2017002).

Declaration of Interest: No conflict of interests exists in this study.

Ethical Approval: The experiments were approved by Animal Care and Experiment Committee of Guangxi Medical University (protocol number: 2014-12-3).

Suggested Citation

Shen, Chong and Jiang, Tongmeng and Zhu, Bo and Le, Yiguan and Liu, Jianwei and Qin, Zainen and Chen, Haimin and Zhong, Gang and Zheng, Li and Zhao, Jinmin and Zhang, Xingdong, In Vitro Culture Expansion Impairs Chondrogenic Differentiation and Therapeutic Effect of Mesenchymal Stem Cells by Regulation of Unfolded Protein Response (July 30, 2018). Available at SSRN: https://ssrn.com/abstract=3223106 or http://dx.doi.org/10.2139/ssrn.3223106

Chong Shen (Contact Author)

Guangxi Medical University - Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration ( email )

Nanning
China

Guangxi Medical University - Department of Orthopaedics Trauma and Hand Surgery

Nanning
China

Tongmeng Jiang

Guangxi Medical University - Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration

Nanning
China

Guangxi Medical University - Department of Orthopaedics Trauma and Hand Surgery

Nanning
China

Bo Zhu

Guangxi Medical University - Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration

Nanning
China

Yiguan Le

Guangxi Medical University - Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration

Nanning
China

Guangxi Medical University - Department of Orthopaedics Trauma and Hand Surgery

Nanning
China

Jianwei Liu

Guangxi Medical University - Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration

Nanning
China

Zainen Qin

Guangxi Medical University - Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration

Nanning
China

Haimin Chen

Guangxi Medical University - Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration

Nanning
China

Gang Zhong

Guangxi Medical University - Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration

Nanning
China

Guangxi Medical University - Department of Orthopaedics Trauma and Hand Surgery

Nanning
China

Li Zheng

Guangxi Medical University - Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration ( email )

Nanning
China

Jinmin Zhao

Guangxi Medical University - Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration ( email )

Nanning
China

Guangxi Medical University - Department of Orthopaedics Trauma and Hand Surgery

Nanning
China

Guangxi Medical University - First Affiliated Hospital

Guangxi, 530021
China

Xingdong Zhang

Sichuan University - National Engineering Research Center for Biomaterials

Chengdu, Sichuan 610064
China

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