2. Academic Validation
  3. Melatonin induces the rejuvenation of long-term ex vivo expanded periodontal ligament stem cells by modulating the autophagic process

Melatonin induces the rejuvenation of long-term ex vivo expanded periodontal ligament stem cells by modulating the autophagic process

  • Stem Cell Res Ther. 2021 Apr 29;12(1):254. doi: 10.1186/s13287-021-02322-9.
Yi-Zhou Tan  # 1,  Xin-Yue Xu  # 1 2,  Ji-Min Dai  # 3 4,  Yuan Yin 1,  Xiao-Tao He 1,  Yi-Lin Zhang 1,  Tian-Xiao Zhu 1,  Ying An 5,  Bei-Min Tian 6,  Fa-Ming Chen 7
Affiliations

Affiliations

  • 1 Department of Periodontology, School of Stomatology, State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Fourth Military Medical University, 145th West Changle Road, Xi'an, 710032, Shaanxi, People's Republic of China.
  • 2 Shaanxi Key Laboratory of Free Radical Biology and Medicine, The Ministry of Education Key Laboratory of Hazard Assessment and Control in Special Operational Environments, Fourth Military Medical University, Xi'an, People's Republic of China.
  • 3 Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
  • 4 Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
  • 5 Department of Periodontology, School of Stomatology, State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Fourth Military Medical University, 145th West Changle Road, Xi'an, 710032, Shaanxi, People's Republic of China. anying@fmmu.edu.cn.
  • 6 Department of Periodontology, School of Stomatology, State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Fourth Military Medical University, 145th West Changle Road, Xi'an, 710032, Shaanxi, People's Republic of China. beimin24@163.com.
  • 7 Department of Periodontology, School of Stomatology, State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Fourth Military Medical University, 145th West Changle Road, Xi'an, 710032, Shaanxi, People's Republic of China. cfmsunhh@fmmu.edu.cn.
  • # Contributed equally.
PMID: 33926537 DOI: 10.1186/s13287-021-02322-9
Abstract

Background: Stem cells that have undergone long-term ex vivo expansion are most likely functionally compromised (namely cellular senescence) in terms of their stem cell properties and therapeutic potential. Due to its ability to attenuate cellular senescence, melatonin (MLT) has been proposed as an Adjuvant in long-term cell expansion protocols, but the mechanism underlying MLT-induced cell rejuvenation remains largely unknown.

Methods: Human periodontal ligament stem cells (PDLSCs) were isolated and cultured ex vivo for up to 15 passages, and cells from passages 2, 7, and 15 (P2, P7, and P15) were used to investigate cellular senescence and Autophagy change in response to long-term expansion and indeed the following MLT treatment. Next, we examined whether MLT could induce cell rejuvenation by restoring the autophagic processes of damaged cells and explored the underlying signaling pathways. In this context, cellular senescence was indicated by senescence-associated β-galactosidase (SA-β-gal) activity and by the expression of senescence-related proteins, including p53, p21, p16, and γ-H2AX. In parallel, cell autophagic processes were evaluated by examining autophagic vesicles (by transmission electronic microscopy), autophagic flux (by assessing mRFP-GFP-LC3-transfected cells), and autophagy-associated proteins (by Western blot assay of Atg7, Beclin-1, LC3-II, and p62).

Results: We found that long-term in vitro passaging led to cell senescence along with impaired Autophagy. As expected, MLT supplementation not only restored cells to a younger state but also restored Autophagy in senescent cells. Additionally, we demonstrated that Autophagy inhibitors could block MLT-induced cell rejuvenation. When the underlying signaling pathways involved were investigated, we found that the MLT receptor (MT) mediated MLT-related Autophagy restoration by regulating the PI3K/Akt/mTOR signaling pathway.

Conclusions: The present study suggests that MLT may attenuate long-term expansion-caused cellular senescence by restoring Autophagy, most likely via the PI3K/Akt/mTOR signaling pathway in an MT-dependent manner. This is the first report identifying the involvement of MT-dependent PI3K/Akt/mTOR signaling in MLT-induced Autophagy alteration, indicating a potential of autophagy-restoring agents such as MLT to be used in the development of optimized clinical-scale cell production protocols.

Keywords

Autophagy; Cell aging; Cell expansion; Cellular senescence; Melatonin; Translational medicine.

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