Fibroblast fate regulation by time dependent TGF-β1 and IL-10 stimulation in biomimetic 3D matrices

Sapudom, Jiranuwat; Wu, Xiancheng; Chkolnikov, Marina; Ansorge, Michael; Anderegg, Ulf; Pompe, Tilo

doi:10.1039/c7bm00286f

Cited by 55 publications

(68 citation statements)

References 54 publications

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“…In addition, our results suggest that M -IL-4/-IL-13 appears to have a characteristic of the M2a phenotype, similar to other reports that cultured their cells on 2D surfaces [27], since these cells secreted high amounts of TGF-β1 and in turn triggered fibroblast differentiation [67,86]. This hypothesis is also supported by a very low secreted amount of IL-10, which can dedifferentiate myofibroblast back into fibroblasts, as previously reported [69,76].…”

Section: General Discussion and Conclusionsupporting

confidence: 90%

“…However, TGF-β1 secretion was much higher in M -IL-4/-IL-13 , than M -PMA and M -LPS/-IFNγ , suggesting that the M -IL-4/-IL-13 might have a potential capability to trigger fibroblast differentiation. The high production of TGF-β1 by M -IL-4/-IL-13 is in line with other reports [66,67]. In the co-culture condition with M -IL-4/-IL-13 , an increased amount of TGF-β1 was detected ( Supplementary Figure S3), indicating that myofibroblasts additively secreted TGF-β1 to maintain fibroblast differentiation in a matrix density dependent manner.…”

Section: Il-4/il-13 Triggers Fibroblast Differentiation Into Myofibsupporting

confidence: 91%

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Collagen Fibril Density Modulates Macrophage Activation and Cellular Functions during Tissue Repair

Sapudom¹,

Mohamed

Garcia-Sabaté³

et al. 2020

Bioengineering

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Monocytes circulate in the bloodstream, extravasate into the tissue and differentiate into specific macrophage phenotypes to fulfill the immunological needs of tissues. During the tissue repair process, tissue density transits from loose to dense tissue. However, little is known on how changes in tissue density affects macrophage activation and their cellular functions. In this work, monocytic cell line THP-1 cells were embedded in three-dimensional (3D) collagen matrices with different fibril density and were then differentiated into uncommitted macrophages (MPMA) using phorbol-12-myristate-13-acetate (PMA). MPMA macrophages were subsequently activated into pro-inflammatory macrophages (MLPS/IFNγ) and anti-inflammatory macrophages (MIL-4/IL-13) using lipopolysaccharide and interferon-gamma (IFNγ), and interleukin 4 (IL-4) and IL-13, respectively. Although analysis of cell surface markers, on both gene and protein levels, was inconclusive, cytokine secretion profiles, however, demonstrated differences in macrophage phenotype. In the presence of differentiation activators, MLPS/IFNγ secreted high amounts of IL-1β and tumor necrosis factor alpha (TNFα), while M0PMA secreted similar cytokines to MIL-4/IL-13, but low IL-8. After removing the activators and further culture for 3 days in fresh cell culture media, the secretion of IL-6 was found in high concentrations by MIL-4/IL-13, followed by MLPS/IFNγ and MPMA. Interestingly, the secretion of cytokines is enhanced with an increase of fibril density. Through the investigation of macrophage-associated functions during tissue repair, we demonstrated that M1LPS/IFNγ has the potential to enhance monocyte infiltration into tissue, while MIL-4/IL-13 supported fibroblast differentiation into myofibroblasts via transforming growth factor beta 1 (TGF-β1) in dependence of fibril density, suggesting a M2a-like phenotype. Overall, our results suggest that collagen fibril density can modulate macrophage response to favor tissue functions. Understanding of immune response in such complex 3D microenvironments will contribute to the novel therapeutic strategies for improving tissue repair, as well as guidance of the design of immune-modulated materials.

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Section: General Discussion and Conclusionsupporting

confidence: 90%

Section: Il-4/il-13 Triggers Fibroblast Differentiation Into Myofibsupporting

confidence: 91%

Collagen Fibril Density Modulates Macrophage Activation and Cellular Functions during Tissue Repair

Sapudom¹,

Mohamed

Garcia-Sabaté³

et al. 2020

Bioengineering

Self Cite

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“…Additionally, human dermal fibroblasts can be “transiently” activated to go forward to myofibroblast differentiation (αSMA expression) [ 88 , 89 ]. Permanent or sequential presence of TGF-β1 and IL-10 might modify the proliferation and migration of fibroblasts and their activated form-myofibroblasts [ 90 ]. Study has shown that the removal of TGF-β1 after initial stimulation resulted in an increase of apoptosis of myofibroblasts [ 90 ].…”

Section: Estrogen Signaling On the Proliferation Processmentioning

confidence: 99%

“…Permanent or sequential presence of TGF-β1 and IL-10 might modify the proliferation and migration of fibroblasts and their activated form-myofibroblasts [ 90 ]. Study has shown that the removal of TGF-β1 after initial stimulation resulted in an increase of apoptosis of myofibroblasts [ 90 ]. TGF-β1 stimulation followed by IL-10 treatment did not result in increased cell apoptosis, but instead led to a significant increase of cell motility and a reduction of myofibroblasts [ 90 ].…”

Section: Estrogen Signaling On the Proliferation Processmentioning

confidence: 99%

Estrogen Effects on Wound Healing

Horng

Chang

Yeh

et al. 2017

IJMS

124

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Wound healing is a physiological process, involving three successive and overlapping phases—hemostasis/inflammation, proliferation, and remodeling—to maintain the integrity of skin after trauma, either by accident or by procedure. Any disruption or unbalanced distribution of these processes might result in abnormal wound healing. Many molecular and clinical data support the effects of estrogen on normal skin homeostasis and wound healing. Estrogen deficiency, for example in postmenopausal women, is detrimental to wound healing processes, notably inflammation and re-granulation, while exogenous estrogen treatment may reverse these effects. Understanding the role of estrogen on skin might provide further opportunities to develop estrogen-related therapy for assistance in wound healing.

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“…This was consistent with differences in the Tgfβ1:Tgfβ3 expression ratio between the combination treatments, where a delay in Tgfβ1 expression was observed following the viral protein treatment. Viral ovIL-10 has been shown to share the anti-fibrotic effects of mammalian IL-10, reducing both Tgfβ1 and αSMA production [29,43,[62][63][64][65]. Pericytes are a major source of myofibroblasts [66], and the maturation of blood vessels is critical to the resolution of fibrosis in the lung and liver [67][68][69].…”

Section: Discussionmentioning

confidence: 99%

Orf Virus IL-10 and VEGF-E Act Synergistically to Enhance Healing of Cutaneous Wounds in Mice

Wise

Stuart

Jones

et al. 2020

JCM

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Orf virus (OV) is a zoonotic parapoxvirus that causes highly proliferative skin lesions which resolve with minimal inflammation and scarring. OV encodes two immunomodulators, vascular endothelial growth factor (VEGF)-E and interleukin-10 (ovIL-10), which individually modulate skin repair and inflammation. This study examined the effects of the VEGF-E and ovIL-10 combination on healing processes in a murine wound model. Treatments with viral proteins, individually and in combination, were compared to a mammalian VEGF-A and IL-10 combination. Wound biopsies were harvested to measure re-epithelialisation and scarring (histology), inflammation, fibrosis and angiogenesis (immunofluorescence), and gene expression (quantitative polymerase chain reaction). VEGF-E and ovIL-10 showed additive effects on wound closure and re-epithelialisation, and suppressed M1 macrophage and myofibroblast infiltration, while allowing M2 macrophage recruitment. The viral combination also increased endothelial cell density and pericyte coverage, and improved collagen deposition while reducing the scar area. The mammalian combination showed equivalent effects on wound closure, re-epithelialisation and fibrosis, but did not promote blood vessel stabilisation or collagen remodeling. The combination treatments also differentially altered the expression of transforming growth factor beta isoforms, Tgfβ1 and Tgfβ3. These findings show that the OV proteins synergistically enhance skin repair, and act in a complimentary fashion to improve scar quality.

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Fibroblast fate regulation by time dependent TGF-β1 and IL-10 stimulation in biomimetic 3D matrices

Cited by 55 publications

References 54 publications

Collagen Fibril Density Modulates Macrophage Activation and Cellular Functions during Tissue Repair

Collagen Fibril Density Modulates Macrophage Activation and Cellular Functions during Tissue Repair

Estrogen Effects on Wound Healing

Orf Virus IL-10 and VEGF-E Act Synergistically to Enhance Healing of Cutaneous Wounds in Mice

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