Sirtuin‑1 protects hair follicle stem cells from TNFα-mediated inflammatory stress via activating the MAPK-ERK-Mfn2 pathway.

Abstract

OBJECTIVE:

Stem cell transplantation is a promising tool to treat burn injuries. However, the inflammatory microenvironment in damaged skin limits the efficiency of stem cell-based therapy via poorly understood mechanisms. The aim of our study is to explore the contribution and mechanism of Sirtuin-1 (Sirt1) in TNFα-mediated inflammatory stress in hair follicle stem cells (HFSCs).

METHODS:

Cellular viability was determined using the MTT assay, TUNEL staining, western blot analysis and LDH release assay. Adenovirus-loaded Sirt1 was transduced into HFSCs to overexpress Sirt1 in the presence of TNFα. Mitochondrial function was determined using JC-1 staining, mitochondrial ROS staining, immunofluorescence staining and western blotting.

RESULTS:

Sirt1 was downregulated in response to the TNFα treatment. Additionally, TNFα stress reduced the viability, mobility and proliferation of HFSCs, and these effects were reversed by the overexpression of Sirt1. At the molecular level, Sirt1 overexpression attenuated TNFα-mediated mitochondrial damage, as evidenced by increased mitochondrial energy metabolism, decreased mitochondrial ROS generation, stabilized mitochondrial potential and blockage of the mitochondrial apoptotic pathway. Furthermore, Sirt1 modulated mitochondrial homeostasis by activating the MAPK-ERK-Mfn2 axis; inhibition of this pathway abrogated the protective effects of Sirt1 on HFSC survival, migration and proliferation.

SIGNIFICANCE:

Based on our results, the inflammatory stress-mediated HFSC injury may be associated with a decrease in Sirt1 expression and subsequent mitochondrial dysfunction. Accordingly, strategies designed to enhance Sirt1 expression would be an effective approach to enhance the survival of HFSCs in the inflammatory microenvironment.

• Authors: Jingjing Liu, Yuxuan Xu, Qiaofang Wu, Qi Ding, Weixin Fan
• Journal: Life sciences (Life Sci) Vol. 212 Pg. 213-224 (Nov 01 2018) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 30292830 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Mitochondrial Proteins
• Protective Agents
• Reactive Oxygen Species
• Tumor Necrosis Factor-alpha
• SIRT1 protein, human
• Sirtuin 1
• GTP Phosphohydrolases
• MFN2 protein, human

Topics

• Apoptosis (drug effects)
• Cells, Cultured
• GTP Phosphohydrolases (metabolism)
• Gene Expression Regulation (drug effects)
• Hair Follicle (cytology, drug effects, metabolism)
• Humans
• Inflammation (chemically induced, drug therapy)
• MAP Kinase Signaling System (drug effects)
• Membrane Potential, Mitochondrial (drug effects)
• Mitochondria (drug effects)
• Mitochondrial Proteins (metabolism)
• Protective Agents (pharmacology)
• Reactive Oxygen Species (metabolism)
• Sirtuin 1 (genetics, metabolism)
• Stem Cells (cytology, drug effects, metabolism)
• Tumor Necrosis Factor-alpha (pharmacology)