Expression and role of Toll-like receptors on human umbilical cord mesenchymal stromal cells

Chen, Dandan; Ma, Fen; Xu, Shuxia; Yang, Shaoguang; Chen, Fang; Rong, Lijuan; Cheng, Ying; Zhao, Qinjun; Lu, Shihong; Han, Zhibo; Pang, Aiming; Han, Zhongchao

doi:10.1016/j.jcyt.2012.12.001

Cited by 29 publications

(51 citation statements)

References 53 publications

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“…MSCs express Toll-like receptors (TLRs) that activate the TLR signalling pathway ex vivo , impacting the proliferation, immunomodulation, and migration of these cells [23,24,25,26,27]. The functions of adult MSCs, such as hBW-MSCs and hAT-MSCs, were modulated by the TLR4-LPS signalling pathway ex vivo , and LPS stimulation resulted in the increased production of such inflammatory cytokines and chemokines as IL-1β, IL-6, and IL-8 [17,23,24,25,28].…”

Section: Discussionmentioning

confidence: 99%

“…The functions of adult MSCs, such as hBW-MSCs and hAT-MSCs, were modulated by the TLR4-LPS signalling pathway ex vivo , and LPS stimulation resulted in the increased production of such inflammatory cytokines and chemokines as IL-1β, IL-6, and IL-8 [17,23,24,25,28]. However, for the role of TLR4 in hWJ-MSCs, two early reports came to the opposite conclusion [27,29]. Raicevic et al explored the details of the hWJ-MSCs TLRs expression profiles and found that TLR4 is not expressed in these cells at transcription level or protein level and consequently do not respond to LPS activation [29].…”

Section: Discussionmentioning

confidence: 99%

“…Raicevic et al explored the details of the hWJ-MSCs TLRs expression profiles and found that TLR4 is not expressed in these cells at transcription level or protein level and consequently do not respond to LPS activation [29]. In contrast, report by Chen et al demonstrated the presence of TLR4 on the surface of human umbilical cord-derived MSCs (hUC-MSCs) at a very low level (5%-6%) by flow cytometry analysis but further confirmed that LPS engagement induced NF-NκB translocation and resulted in the up-regulation of IL-6, IL-8, and IFN-γ mRNA expression in hUC-MSCs, which indicated TLR4 is a functional receptor [27]. Because of that LPS stimulation increased the TLR4 mRNA expression in MSCs at low concentration but decreased at very high concentration [31].…”

Section: Discussionmentioning

confidence: 99%

“…To date, 10 TLRs have been identified in humans, and all TLRs (except TLR3) induce the production of TNF-α, IL-1, IL-6, and other cytokines [21,22]. Recently, the TLR profiles in hMSCs derived from various tissues (including hWJ-MSCs) have been explored, and their regulatory effects on MSC differentiation, proliferation, and immunomodulation have been described [23,24,25,26,27]. However, MSCs derived from various sources display different TLRs profiles, functional properties, and responses to stimulation by TLRs' agonists [23,24,25,26,27,28,29].…”

Section: Introductionmentioning

confidence: 99%

“…It has been used to investigate the response of human adipose tissue-derived MSCs (hAD-MSCs), hBW-MSCs, and human cord blood-derived MSCs (hCB-MSCs) to TLR4 triggering ex vivo , and it was found that TLR4 expressed at a high level and is a functional receptor in these cells [23,25,26]. In contrast, the presence and functional properties of TLR4 in hWJ-MSCs remains controversial [27,29]. Therefore, this study aimed to investigate the expression profile of TLR4 in hWJ-MSCs and to evaluate the inductive effect of TLR4 agonist on the proliferation, apoptosis, paracrine profiles, and immunosuppressive properties of hWJ-MSCs.…”

Section: Introductionmentioning

confidence: 99%

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Lipopolysaccharides Shapes the Human Wharton's Jelly-Derived Mesenchymal Stem Cellsin Vitro

Mei¹,

Zhou²,

Zhang³

et al. 2013

Cell Physiol Biochem

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Background: Although the expression of toll-like receptors (TLRs) on different types of human mesenchymal stem cells (hMSCs) has recently been reported, controversy remains regarding the presence of TLR4 as well as its engagement and impact on human Wharton's jelly-derived MSCs (hWJ-MSCs). Methods: In the present study, the expression and role of TLR4 in hWJ-MSCs was investigated using a model of lipopolysaccharide (LPS). Proliferation, apoptosis, and the expression of paracrine factors in hWJ-MSCs primed with LPS were analysed. Results: The expression of TLR4 was high at the RNA level but very low at the protein level. hWJ-MSCs responded to LPS stimulation and initiated a marked up-regulation of inflammatory cytokine (IL-1α, IL-1β, IL-6, and IL-8) production. Moreover, hWJ-MSCs LPS stimulation resulted in the up-regulation of indoleamine 2,3-dioxygenase [IDO]-1, Cox2, interferon [IFN]-β, and matrix metalloproteinase (MMP)-2 but a down-regulation of MMP-9, which affect the immunosuppressive potential of hWJ-MSCs. Conclusions: These data suggest that LPS engagement shapes hWJ-MSCs and results in the production of pro-inflammatory cytokines and inhibitory immune mediators, showing TLR4 agonist induces the hWJ-MSCs polarization to a pro-inflammatory and immunosuppressive state, which may be beneficial for the exploration of the clinical potential of hWJ-MSCs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Lipopolysaccharides Shapes the Human Wharton's Jelly-Derived Mesenchymal Stem Cellsin Vitro

Mei¹,

Zhou²,

Zhang³

et al. 2013

Cell Physiol Biochem

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TLR activation inhibits the osteogenic potential of human periodontal ligament stem cells through Akt signaling in a Myd88‐ or TRIF‐dependent manner

Zhu

Zhou

et al. 2018

Journal of Periodontology

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Background This study investigated the effects of Toll‐like receptors (TLRs) on human periodontal ligament stem cells (hPDLSCs) osteogenic differentiation and the associated mechanisms. Methods TLR1, TLR3, TLR4, and TLR6 expression in hPDLSCs was evaluated by real‐time reverse transcriptase polymerase chain reaction (RT‐PCR) and flow cytometry, whereas their functional roles were assessed based on nuclear factor (NF)‐κB activation and proinflammatory cytokine expression. The osteogenic effects of these TLRs were analyzed by alkaline phosphatase (ALP) staining, ALP activity, and alizarin red staining. The roles of Myd88, TRIF, and downstream molecules mitogen‐activated protein kinases (MAPKs) and protein kinase B (Akt) in TLR‐mediated impaired osteogenic differentiation were examined by real‐time RT‐PCR and western blotting using specific small interfering RNA siRNA and pharmacologic inhibitors. The involvement of Akt activation in restoring TLR1‐, 4‐, and 6‐mediated osteogenic suppression was verified using the Akt activator SC‐79. Results TLR1, TLR3, TLR4, and TLR6 were highly expressed functionally in hPDLSCs and high doses of TLR ligands inhibited osteogenic potential. Furthermore, blocking Myd88 partly rescued the decrease in osteogenesis mediated by TLR1, TLR4, and TLR6 activation by enhancing Akt phosphorylation; likewise, TRIF suppression partially rescued lipopolysaccharide (LPS)‐mediated osteogenic inhibition through ERK and Akt activation. Moreover, Akt activation restored the TLR‐mediated inhibition of hPDLSC osteogenic differentiation. Conclusions High doses of TLR1, TLR4, and TLR6 ligands suppress hPDLSC osteogenic differentiation by inhibiting Akt activation through Myd88‐ or TRIF‐dependent signaling pathways. Blocking these adaptors or reactivating Akt could restore the TLR‐mediated decrease in hPDLSC osteogenesis, and might be an ideal strategy for periodontitis treatment.

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Protective Role of Adipose-Derived Stem Cells in Staphylococcus aureus-Induced Lung Injury is Mediated by RegIIIγ Secretion

Qian

Zhao

et al. 2016

Stem Cells

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Effective and specific therapeutic approaches are still needed for treating acute lung injury caused by severe pneumonia. Adipose-derived stem cells (ADSCs) are well-characterized adult stem cells that have antibacterial and anti-inflammatory effects. In this study, we evaluated the therapeutic effect of ADSCs on Staphylococcus aureus-induced acute lung injury in mice. Our results showed that intratracheal injection of ADSCs could attenuate the severity of lung inflammation, and reduce the bacterial load as well as mortality among infected mice. Our experiments also revealed that the secretion of regenerating islet-derived IIIc (RegIIIc) is responsible for the protective effect of ADSCs. Moreover, the expression of RegIIIc requires TLR2, MyD88, and JAK2/STAT3 activation. In conclusion, ADSCs exhibit a direct antimicrobial activity that is mediated primarily by the TLR2-MyD88-JAK2/STAT3-dependent secretion of RegIIIc. STEM CELLS 2016;34:1947-1956 SIGNIFICANCE STATEMENTIntratracheal administration of adipose-derived stem cells (ADSCs) attenuated S. aureus-induced lung injury and improved survival of infected mice by means of reducing bacterial load and alleviating inflammatory responses. An antimicrobial peptide RegIIIc was found to be responsible for the protective effect of ADSCs. Moreover, upon S. aureus infection, RegIIIc expression in ADSCs was induced by activation of the TLR2-MyD88-JAK2/STAT3 intracellular signaling cascades and amplified by interaction with macrophages.

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Expression and role of Toll-like receptors on human umbilical cord mesenchymal stromal cells

Cited by 29 publications

References 53 publications

Lipopolysaccharides Shapes the Human Wharton's Jelly-Derived Mesenchymal Stem Cellsin Vitro

Lipopolysaccharides Shapes the Human Wharton's Jelly-Derived Mesenchymal Stem Cellsin Vitro

TLR activation inhibits the osteogenic potential of human periodontal ligament stem cells through Akt signaling in a Myd88‐ or TRIF‐dependent manner

Protective Role of Adipose-Derived Stem Cells in Staphylococcus aureus-Induced Lung Injury is Mediated by RegIIIγ Secretion

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