TGF-β1–Containing Exosomes from Injured Epithelial Cells Activate Fibroblasts to Initiate Tissue Regenerative Responses and Fibrosis

Borges, Fernanda Teixeira; Melo, Sónia A.; Özdemir, Berna C.; Kato, Noritoshi; Revuelta, Ignacio; Miller, Caroline; Gattone, Vincent H.; LeBleu, Valerie S.; Kalluri, Raghu

doi:10.1681/asn.2012101031

Cited by 352 publications

(325 citation statements)

References 27 publications

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“…44 Alternatively, the increased number of BM-derived EC that line the microvascular network of the kidney of the LV-126 mice could serve as a source of miR-126 via the production of microparticles 45 ; it was recently shown that, under certain conditions, such particles can cross the tubular basement membrane. 46 In addition, activated platelets may be involved because miR-126 is among the most abundant microRNAs in platelets, 47,48 and they could serve as a transporter of miR-126 to the site of injury. 49 Because EPCs can take up platelets and their molecular content, 50 platelets could also add to EPC function through miR-126 transfer.…”

Section: Discussionmentioning

confidence: 99%

Hematopoietic MicroRNA-126 Protects against Renal Ischemia/Reperfusion Injury by Promoting Vascular Integrity

Bijkerk¹,

Solingen²,

Boer³

et al. 2014

Journal of the American Society of Nephrology

101

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Ischemia/reperfusion injury (IRI) is a central phenomenon in kidney transplantation and AKI. Integrity of the renal peritubular capillary network is an important limiting factor in the recovery from IRI. facilitates vascular regeneration by functioning as an angiomiR and by modulating mobilization of hematopoietic stem/progenitor cells. We hypothesized that overexpression of miR-126 in the hematopoietic compartment could protect the kidney against IRI via preservation of microvascular integrity. Here, we demonstrate that hematopoietic overexpression of miR-126 increases neovascularization of subcutaneously implanted Matrigel plugs in mice. After renal IRI, mice overexpressing miR-126 displayed a marked decrease in urea levels, weight loss, fibrotic markers, and injury markers (such as kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin). This protective effect was associated with a higher density of the peritubular capillary network in the corticomedullary junction and increased numbers of bone marrow-derived endothelial cells. Hematopoietic overexpression of miR-126 increased the number of circulating Lin 2 /Sca-1 + /cKit + hematopoietic stem and progenitor cells. Additionally, miR-126 overexpression attenuated expression of the chemokine receptor CXCR4 on Lin 2 /Sca-1 + /cKit + cells in the bone marrow and increased renal expression of its ligand stromal cell-derived factor 1, thus favoring mobilization of Lin 2 /Sca-1 + /cKit + cells toward the kidney. Taken together, these results suggest overexpression of miR-126 in the hematopoietic compartment is associated with stromal cell-derived factor 1/CXCR4-dependent vasculogenic progenitor cell mobilization and promotes vascular integrity and supports recovery of the kidney after IRI.

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Section: Discussionmentioning

confidence: 99%

Hematopoietic MicroRNA-126 Protects against Renal Ischemia/Reperfusion Injury by Promoting Vascular Integrity

Bijkerk¹,

Solingen²,

Boer³

et al. 2014

Journal of the American Society of Nephrology

101

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“…17 The activation of TGF-b1 can increase the production of ECM, as well as suppress its degradation. In addition, TGF-b1 can activate myofibroblasts by activating resident fibroblasts, 18 inducing epithelial-to-mesenchymal transition 19 or endothelial-to-mesenchymal transition, 20 and initiating inflammatory responses. Moreover, blocking TGF-b1 with neutralizing TGF-b1 antibodies and antisense oligonucleotides prevents the progression of renal fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Oxymatrine inhibits renal fibrosis of obstructive nephropathy by downregulating the TGF-β1-Smad3 pathway

Wang¹,

Shi

et al. 2016

Renal Failure

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Oxymatrine inhibits renal fibrosis of obstructive nephropathy by downregulating the TGF-β1-Smad3 pathway, Renal Failure, 38:6,[945][946][947][948][949][950][951] DOI: 10.3109 This study investigated whether oxymatrine (OMT) treatment can ameliorate renal interstitial fibrosis in unilateral ureteral obstruction (UUO) mice model. Moreover, the potential mechanisms of such treatment were analyzed. Twenty-four C57/BL6 mice were randomly divided into three groups, namely sham group, vehicle plus unilateral ureteral obstruction (UUO)-treated group, and 100 mg/kg/d OMT plus UUO-treated group. All mice were euthanized seven days after surgery, and their kidneys were harvested. Renal injury, fibrosis, expression of proinflammatory cytokines, and the transforming growth factor-b1/Smads (TGF-b/Smads) and nuclear factor-kappa B (NF-jB)-signaling pathways were assessed. The results showed OMT significantly prevented kidney injury and fibrosis, as evidenced by decreased expression of collagen-1 and fibronectin. Furthermore, OMT administration inhibited the release of inflammatory factors including tumor necrosis factora, (TNF-a) interleukin-1b (IL-1b), and interleukin-6 (IL-6), as well as phosphorylated NF-jB p65. In addition, OMT blocked the activation of myofibroblasts by inhibiting the TGF-b/Smad3-signaling pathway. The findings indicate that OMT-attenuated renal fibrosis and inflammation, and this renoprotective effect may be ascribed to the inactivation of the TGF-b/Smad3 and NF-jB p65 pathways. ARTICLE HISTORY

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“…The expression of NKG2D, FasL, and membrane-bound TGF-β, a representative immunosuppressive cytokine, in these exosomes appears responsible for the immunosuppression (Bianco et al, 2007;Borges et al, 2013;Fagiolo, 2004;Yoshimura and Muto, 2011). TGF-β in tumorderived exosomes may also induce the development of regulatory T cells and myeloid-derived suppressor cells, which can negatively regulate the overall immune response against tumor cells (Peterson, 2012;Saas and Perruche, 2012).…”

Section: Physiological (Immunological) Roles Of Exosomesmentioning

confidence: 99%

Cell-Cell Communication Via Extracellular Membrane Vesicles and Its Role in the Immune Response

Hwang

2013

Molecules and Cells

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The host immune response involves a variety of cell types, including specialized immune and non-immune cells. The delicate coordination among these cells via close communication is central for the proper operation of immune system. Cell-cell communication is mediated by a complex network that includes soluble factors such as cytokines, chemokines, and metabolites exported from cells, as well as membrane-bound receptors and their ligands. Cell-cell communication is also mediated by membrane vesicles (e.g., exosomes, ectosomes), which are either shed by distant cells or exchanged by cells that are making direct contact. Intercellular communication via extracellular membrane vesicles has drawn much attention recently, as they have been shown to carry various biomolecules that modulate the activities of recipient cells. In this review, I will discuss current views on cell-cell communication via extra-cellular membrane vesicles, especially shedded membrane vesicles, and their effects on the control of the immune system.

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TGF-β1–Containing Exosomes from Injured Epithelial Cells Activate Fibroblasts to Initiate Tissue Regenerative Responses and Fibrosis

Cited by 352 publications

References 27 publications

Hematopoietic MicroRNA-126 Protects against Renal Ischemia/Reperfusion Injury by Promoting Vascular Integrity

Hematopoietic MicroRNA-126 Protects against Renal Ischemia/Reperfusion Injury by Promoting Vascular Integrity

Oxymatrine inhibits renal fibrosis of obstructive nephropathy by downregulating the TGF-β1-Smad3 pathway

Cell-Cell Communication Via Extracellular Membrane Vesicles and Its Role in the Immune Response

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