3D Scaffold‐Based Macrophage Fibroblast Coculture Model Reveals IL‐10 Dependence of Wound Resolution Phase

Ullm, Franziska; Riedl, Philipp; Amorim, Alexandrina Machado de; Patzschke, Aline; Weiß, Reinhold; Hauschildt, Sunna; Franke, Katja; Anderegg, Ulf; Pompe, Tilo

doi:10.1002/adbi.201900220

Cited by 32 publications

(42 citation statements)

References 77 publications

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“…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]. In addition, a recent report demonstrated that low IL-10 concentration of 120 pg/mL is able to fully de-differentiate myofibroblasts in a co-culture model with macrophages with M2c characteristics [30]. To summarize, the effect of collagen fibril density regulates macrophage-associated functions in a tissue repair context, and a schematic illustration of our findings is depicted in Figure 6.…”

Section: General Discussion and Conclusionsupporting

confidence: 70%

“…It suggests that a dense fibrillar matrix might act as a negative feedback for myofibroblasts to prevent an excessive production of matrix proteins and remodeling in physiological conditions [74]. Furthermore, the results from the co-culture with fibroblasts supported the observed very low secretion of IL-10 in M -IL-4/-IL-13 , since the presence of IL-10 in a picogram range could de-differentiate myofibroblast back into fibroblast, as reported in fibroblast mono-culture [69,75,76] and co-culture with macrophages [30].…”

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

confidence: 76%

“…THP-1 cells were embedded into the well-defined 3D collagen matrices, differentiated and activated into specific subtypes of macrophages, M PMA , M LPS/IFNγ and M IL-4/IL-13 . Cell embedding did not affect the fibrillation and topological properties of the collagen matrix [ 29 , 30 ]. All macrophage subtypes appeared to exhibit a rounded morphology and no matrix-dependent cell morphological differences could be observed ( Figure 1 D).…”

Section: Resultsmentioning

confidence: 99%

“…All these studies were performed on 2D cell culture plastic. Furthermore, CD163 was found to be hardly presented at the cell surface of peripheral blood mononuclear cell (PBMC)-derived macrophages both in 3D and 2D culture models [30]. It has also been reported that CD163 is expressed in macrophages activated by IL-10 rather than IL-4 in vitro [35].…”

Section: Dense Matrix Enhanced Expression Of Mhc-ii Cd163 and Cd206mentioning

confidence: 99%

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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: 70%

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

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Section: Dense Matrix Enhanced Expression Of Mhc-ii Cd163 and Cd206mentioning

confidence: 99%

See 2 more Smart Citations

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

Sapudom¹,

Mohamed

Garcia-Sabaté³

et al. 2020

Bioengineering

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“…In addition to fibroblasts, endothelial cells, fibrocytes, and tissue‐resident MSCs are found in both healthy and fibrotic stroma. Fibroblast–macrophage interactions in in vitro models of skin [133,134], hepatic fibrosis [135,136], and scaffold‐free 3D spheroid models [137], as well as computational models [138], have shown (bidirectional) feedback mechanisms between these cell types. While direct cell–cell communications in fibrotic disease are outside the scope of this review, the influence of fibrotic stroma on these interactions now emerges as another key player in fibrosis.…”

Section: Stromal Regulation Of Macrophage–cell Interactions In Fibrosismentioning

confidence: 99%

Macrophage–stroma interactions in fibrosis: biochemical, biophysical, and cellular perspectives

Vasse

Nizamoglu

Heijink

et al. 2021

The Journal of Pathology

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Fibrosis results from aberrant wound healing and is characterized by an accumulation of extracellular matrix, impairing the function of an affected organ. Increased deposition of extracellular matrix proteins, disruption of matrix degradation, but also abnormal post‐translational modifications alter the biochemical composition and biophysical properties of the tissue microenvironment – the stroma. Macrophages are known to play an important role in wound healing and tissue repair, but the direct influence of fibrotic stroma on macrophage behaviour is still an under‐investigated element in the pathogenesis of fibrosis. In this review, the current knowledge on interactions between macrophages and (fibrotic) stroma will be discussed from biochemical, biophysical, and cellular perspectives. Furthermore, we provide future perspectives with regard to how macrophage–stroma interactions can be examined further to ultimately facilitate more specific targeting of these interactions in the treatment of fibrosis. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

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Immunomodulatory Microgels Support Proregenerative Macrophage Activation and Attenuate Fibroblast Collagen Synthesis

Mohammadi

Ravanbakhsh

Taheri

et al. 2022

Adv Healthcare Materials

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Scars composed of fibrous connective tissues are natural consequences of injury upon incisional wound healing in soft tissues. Hydrogels that feature a sustained presentation of immunomodulatory cytokines are known to modulate wound healing. However, existing immunomodulatory hydrogels lack interconnected micropores to promote cell ingrowth. Other limitations include invasive delivery procedures and harsh synthesis conditions that are incompatible with drug molecules. Here, hybrid nanocomposite microgels containing interleukin‐10 (IL‐10) are reported to modulate tissue macrophage phenotype during wound healing. The intercalation of laponite nanoparticles in the polymer network yields microgels with tissue‐mimetic elasticity (Young's modulus in the range of 2–6 kPa) and allows the sustained release of IL‐10 to promote the differentiation of macrophages toward proregenerative phenotypes. The porous interstitial spaces between microgels promote fibroblast proliferation and fast trafficking (an average speed of ≈14.4 µm h−1). The incorporation of hyaluronic acid further enhances macrophage infiltration. The coculture of macrophages and fibroblasts treated with transforming growth factor‐beta 1 resulted in a twofold reduction in collagen‐I production for microgels releasing IL‐10 compared to the IL‐10 free group. The new microgels show potential toward regenerative healing by harnessing the antifibrotic behavior of host macrophages.

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3D Scaffold‐Based Macrophage Fibroblast Coculture Model Reveals IL‐10 Dependence of Wound Resolution Phase

Cited by 32 publications

References 77 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

Macrophage–stroma interactions in fibrosis: biochemical, biophysical, and cellular perspectives

Immunomodulatory Microgels Support Proregenerative Macrophage Activation and Attenuate Fibroblast Collagen Synthesis

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