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Nanosecond pulsed electric fields prime mesenchymal stem cells to peptide ghrelin and enhance chondrogenesis and osteochondral defect repair in vivo

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Abstract

Mesenchymal stem cells (MSCs) are important cell sources in cartilage tissue development and homeostasis, and multiple strategies have been developed to improve MSCs chondrogenic differentiation with an aim of promoting cartilage regeneration. Here we report the effects of combining nanosecond pulsed electric fields (nsPEFs) followed by treatment with ghrelin (a hormone that stimulates release of growth hormone) to regulate chondrogenesis of MSCs. nsPEFs and ghrelin were observed to separately enhance the chondrogenesis of MSCs, and the effects were significantly enhanced when the bioelectric stimulation and hormone were combined, which in turn improved osteochondral tissue repair of these cells within Sprague Dawley rats. We further found that nsPEFs can prime MSCs to be more receptive to subsequent stimuli of differentiation by upregulated Oct4/Nanog and activated JNK signaling pathway. Ghrelin initiated chondrogenic differentiation by activation of ERK1/2 signaling pathway, and RNA-seq results indicated 243 genes were regulated, and JAK-STAT signaling pathway was involved. Interestingly, the sequential order of applying these two stimuli is critical, with nsPEFs pretreatment followed by ghrelin enhanced chondrogenesis of MSCs in vitro and subsequent cartilage regeneration in vivo, but not vice versa. This synergistic prochondrogenic effects provide us new insights and strategies for future cell-based therapies.

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Acknowledgements

This work was supported by the National Key Research and Development Program of China (2019YFA0111900), and the National Natural Science Foundation of China (81772334). The authors would like to thank Mr. Kaile Wang for operating the nsPEFs equipment.

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Authors and Affiliations

  1. Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, 100871, China

    Kejia Li, Litong Fan & Zigang Ge

  2. Arthritis Clinical and Research Center, Peking University People’s Hospital, Beijing, 100044, China

    Jianjing Lin

  3. Arthritis Institute, Peking University, Beijing, 100871, China

    Jianjing Lin

  4. Peking University School of Stomatology, Beijing, 100081, China

    Boon Chin Heng

  5. Department of Orthopedics, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China

    Zhantao Deng & Qiujian Zheng

  6. Institute of Biomechanics and Biomedical Engineering, College of Engineering, Peking University, Beijing, 100871, China

    Jue Zhang

  7. Institute for Tissue Engineering and Regenerative Medicine, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, 999077, China

    Yangzi Jiang

  8. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, 999077, China

    Yangzi Jiang

  9. Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, 100871, China

    Zigang Ge

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  1. Kejia Li
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Correspondence to Yangzi Jiang or Zigang Ge.

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Li, K., Fan, L., Lin, J. et al. Nanosecond pulsed electric fields prime mesenchymal stem cells to peptide ghrelin and enhance chondrogenesis and osteochondral defect repair in vivo. Sci. China Life Sci. 65, 927–939 (2022). https://doi.org/10.1007/s11427-021-1983-y

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