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Endoplasmic reticulum stress participates in the progress of senescence of bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus

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Abstract

Previous studies suggested that the senescence of bone marrow mesenchymal stem cells (BM-MSCs) played an important role in the pathological process of systemic lupus erythematosus (SLE). However, the molecular mechanisms that govern this phenomenon have not been fully elucidated. Recent studies reported the activation of endoplasmic reticulum stress (ERS) participated in the growth arrest in G1 phase of cell cycle. In this study, we aimed to investigate whether ERS would induce the senescence of BM-MSCs from SLE patients. We found that there was increased expression of Glucose Regulated Protein 78 (GRP 78) in BM-MSCs from SLE patients, which indicated the activation of ERS in BM-MSCs from SLE patients. Accumulation of p27 was also found in BM-MSCs from SLE patients. Interestingly, as a chemical chaperone helping the correct folding of proteins, 4-phenylbutyric acid (4-PBA) partly rescued the senescence of BM-MSCs from SLE patients and alleviated the level of p27. These results implicated ERS-mediated senescence as a critical determinant of BM-MSCs from SLE patients.

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Abbreviations

4-PBA:

4-phenylbutyric acid

ATF6:

Activating transcription factor-6

BM-MSCs:

Bone marrow mesenchymal stem cells

BM-MSCT:

Bone marrow MSC transplantation

ER:

Endoplasmic reticulum

ERS:

Endoplasmic reticulum stress

FBS:

Fetal bovine serum

FITC:

Fluorescein isothiocyanate

GRP 78:

Glucose regulated protein 78

IRE-1:

Inositol-requiring enzyme 1

L-DMEM:

Low-glucose Dulbecco’s Modified Eagle’s Medium

MSCT:

Mesenchymal stem cells transplantation

PBS:

Phosphate-buffered saline

PERK:

Phosphorylated PKR-like ER kinase

PFA:

Paraformaldehyde

PVDF:

Polyvinylidenedifluoride

SA-β-gal:

Senescence-associated β-galactosidase

SLE:

Systemic lupus erythematosus

SLEDAI:

Systemic lupus erythematosus disease activity index

UPR:

Unfolded protein response

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Acknowledgments

This study was supported by grants from the Chinese National Natural Science Foundation (Nos. 81172841 81202368 and 81471603); China Postdoctoral Science Foundation (2013 M541708); the project of “333 Natural Science Foundation” of Jiangsu Grant (BRA2013286); the “Top Six Types of Talents” Financial Assistance of Jiangsu Province Grant (No. 6); the project of Jiangsu Provincial Health Department (Z201005); the innovative project of Nantong University postgraduate students (13025043); and the Jiangsu province’s Outstanding Medical Academic Leader Program (LJ201136).

Conflicts of interest

There are no commercial affiliations or conflict of interests to disclose.

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Authors and Affiliations

  1. Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, 226001, China

    Zhifeng Gu, Yan Meng, Genkai Guo, Wei Tan & Yunfei Xia

  2. Department of Immunology, Medical College, Nantong University, Nantong, 226001, China

    Tao Tao & Chun Cheng

  3. Department of Hematology, Affiliated Hospital of Nantong University, Nantong, 226001, China

    Hong Liu

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  1. Zhifeng Gu
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  2. Yan Meng
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  3. Tao Tao
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  4. Genkai Guo
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  5. Wei Tan
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  7. Chun Cheng
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  8. Hong Liu
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Corresponding authors

Correspondence to Chun Cheng or Hong Liu.

Additional information

Zhifeng Gu and Yan Meng have contributed equally to this work.

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Supplementary figure

UPR cause senescence in BM-MSCs from normal patients. Normal cells were treated with 3 μM Tunicamycin (TM) for 24h. a–c Tunicamycin increased SA-β-gal-positive cell number. (Bar represents mean ± SD, n = 12, *P < 0.05 compared with the normal group). d, e The percentage of cells in G1 phase was also increased. (TIFF 3350 kb)

High Resolution (GIF 1187 kb)

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Gu, Z., Meng, Y., Tao, T. et al. Endoplasmic reticulum stress participates in the progress of senescence of bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus. Cell Tissue Res 361, 497–508 (2015). https://doi.org/10.1007/s00441-015-2131-x

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  • DOI: https://doi.org/10.1007/s00441-015-2131-x

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