Upregulation of p16INK4A promotes cellular senescence of bone marrow-derived mesenchymal stem cells from systemic lupus erythematosus patients

Gu, Zhifeng; Cao, Xiaolei; Jiang, Jinxia; Li, Liren; Da, Zhanyun; Liu, Hong; Cheng, Chun

doi:10.1016/j.cellsig.2012.07.012

Cited by 67 publications

(48 citation statements)

References 48 publications

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“…As previously shown, BMMSCs from SLE patients exhibited senescent behavior [13,19]. SA-β-gal has been proposed to be a universal marker of senescence.…”

Section: Resultsmentioning

confidence: 71%

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JAK-STAT signaling mediates the senescence of bone marrow-mesenchymal stem cells from systemic lupus erythematosus patients

Meng

et al. 2017

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Previous studies have revealed that bone marrow-mesenchymal stem cells (BM-MSCs) from systemic lupus erythematosus (SLE) patients exhibited early signs of senescence, which may participate in the development of SLE. However, the molecular mechanisms about this phenomenon have not been fully elucidated. In the current study, we aimed to investigate whether Janus kinase (JAK)-signaling transducers and activators of transcription (STAT) signaling mediated the senescence of BM-MSCs from SLE patients. Twelve female SLE patients and healthy subjects were enrolled in the study. All BM-MSCs were isolated by density gradient centrifugation. Western blot analysis was used to test the expression of JAK-STAT signaling molecules. We observed the activity of β-gal of cells, the changes of cytoskeletal structure by F-actin staining, and the distribution of cell cycle by flow cytometry. BM-MSCs from SLE patients showed prominent features of senescence, and abnormal activation of JAK-STAT signaling transduction, high level of phosphorylated JAK2, and STAT3. After stimulation of IFN-γ in normal MSCs, JAK-STAT signaling was activated. The cell volume and the number of senescence-associated β-galactosidase (SA-β-gal) positive in SLE BM-MSCs were increased. The organization of cytoskeleton was nearly disordered. The rate of cell proliferation was decreased. AG490, the inhibitor of JAK2, and knockdown of STAT3 in BM-MSCs, could significantly reverse the senescence. In summary, our study indicated that JAK-STAT signaling pathway may play a critical role in the senescence of SLE BM-MSCs.

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“…As previously shown, BMMSCs from SLE patients exhibited senescent behavior [13,19]. SA-β-gal has been proposed to be a universal marker of senescence.…”

Section: Resultsmentioning

confidence: 71%

“…However, syngeneic MSCT was ineffective [11,12]. Recently, we reported that BM-MSCs from both untreated and treated SLE patients showed characteristics of senescence [13]. These studies revealed that senescent BM-MSCs may be associated with the pathogenesis of SLE, but the molecular mechanisms were not very clear.…”

Section: Introductionmentioning

confidence: 99%

JAK-STAT signaling mediates the senescence of bone marrow-mesenchymal stem cells from systemic lupus erythematosus patients

Meng

et al. 2017

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“…The MSCs derived from patients with systemic lupus erythematosus showed retarded proliferation, differentiation and immunosuppressive effects with upregulated p16 INK4A expression and downregulated CDK4, CDK6 and p-Rb expression. The knockdown of p16 INK4A expression reversed senescent features and impaired the properties of MSCs, suggesting that p16 INK4A plays an essential role in the aging process of patient-derived MSCs [20]. …”

Section: P16ink4amentioning

confidence: 99%

Aging-Related Genes in Mesenchymal Stem Cells: A Mini-Review

Kang

2013

Gerontology

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Adult stem cells in mammalian organs play pivotal roles in the maintenance and repair of these organs throughout the life of the adult and maintain the proper homeostasis of a tissue or organ. Among the adult stem cells described to date, mesenchymal stem cells (MSCs) are highlighted for clinical applications because MSCs have many advantages for cell therapy, including multilineage differentiation, homing, immune modulation and wound-healing effects. However, as the aging of MSCs leads to an age-associated decline in their number and function, it is important to clarify the age-associated factors and regulatory mechanism associated with the MSC aging process.In this review, we amass and discuss the recent data related to age-associated genes in MSCs. In particular, the activities of epigenetic regulatory factors, including histone acetylase and DNA methyltransferase, modulate gene expression and crosstalk with each other during the MSC senescence process. p16^INK4A and high-mobility group A2 play important age-associated roles in the regulation of MSC stemness, and lamin A- and prelamin A-dependent nuclear abnormalities have significant biological relevance in MSC aging. Taken together, the information described here, including the epigenetic regulatory factors, transcription factors and cell signaling, could be used toward the development of treatments for MSC aging and related defects.

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“…hBM-MSCs and hUC-MSCs were isolated and cultured from healthy donors as in previous studies [12,17]. The collection of hBM-MSCs and hUC-MSCs for this study was approved by the Ethics Committee of the Affiliated Hospital of Nantong University.…”

Section: Methodsmentioning

confidence: 99%

Human Umbilical Cord-Derived Mesenchymal Stem Cells Downregulate Inflammatory Responses by Shifting the Treg/Th17 Profile in Experimental Colitis

Liu

et al. 2013

Pharmacology

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Background/Aims: The aim of this study was to evaluate the effect and mechanisms of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) on immune responses in murine colitis. Methods: Mice with dextran sulfate sodium (DSS)-induced colitis were injected intraperitoneally with hUC-MSCs or human bone marrow-derived MSCs. The cytokine levels from lamina propria mononuclear cells (LPMCs) and colon tissue were measured using ELISA. Treg and Th17 cells were analyzed using flow cytometry. The proliferation of LPMCs was assessed using Cell Counting Kit-8. Results: hUC-MSCs ameliorate DSS-induced colitis via the downregulation of colon inflammatory responses. Furthermore, hUC-MSCs adjusted modulation of Treg/Th17 cells in the spleen and mesenteric lymph nodes. hUC-MSCs also inhibited LPMCs in vitro.Conclusion: hUC-MSCs may be an alternative source of stem cells and are worthy of study in long-term clinical trials.

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Upregulation of p16INK4A promotes cellular senescence of bone marrow-derived mesenchymal stem cells from systemic lupus erythematosus patients

Cited by 67 publications

References 48 publications

JAK-STAT signaling mediates the senescence of bone marrow-mesenchymal stem cells from systemic lupus erythematosus patients

JAK-STAT signaling mediates the senescence of bone marrow-mesenchymal stem cells from systemic lupus erythematosus patients

Aging-Related Genes in Mesenchymal Stem Cells: A Mini-Review

Human Umbilical Cord-Derived Mesenchymal Stem Cells Downregulate Inflammatory Responses by Shifting the Treg/Th17 Profile in Experimental Colitis

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