Biomimetic tissue models reveal the role of hyaluronan in melanoma proliferation and invasion

Sapudom, Jiranuwat; Nguyen, Khiet-Tam; Martin, Steve; Wippold, Tom; Möller, Stephanie; Schnabelrauch, Mathias; Anderegg, Ulf; Pompe, Tilo

doi:10.1039/c9bm01636h

Cited by 21 publications

(27 citation statements)

References 62 publications

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“…The current in vitro cell culture models, although far more simplified than the in vivo models in terms of biochemical and biophysical properties, decouple the necessary parameter of interest, namely tissue/fibril density. As our collagen matrices allow for additional modifications with other ECM components, for example fibronectin [26] and glycosaminoglycans [87,88], as well as a stepwise increase of matrix stiffness via crosslinker [23], we are capable of performing further studies on how matrix characteristics of higher complexities modulate macrophage phenotypes and functions. Additionally, further study will focus on spatio-temporal dynamics of cell-cell interactions during the tissue repair phase at a single cell resolution using label-free cell tracking [89].…”

Section: General Discussion and Conclusionmentioning

confidence: 99%

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 Conclusionmentioning

confidence: 99%

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

Sapudom¹,

Mohamed

Garcia-Sabaté³

et al. 2020

Bioengineering

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“…Currently, less is known about matrix composition that might increase matrix stiffening. We previously reported that incorporation of fibronectin into 3D collagen matrices did not change matrix stiffness [11], while the presence of low-and high-molecular-weight HA enhanced the matrix elastic modulus [14,31]. Since activated fibroblastic cells might secrete a broad range of matrix proteins or crosslinking proteins (e.g., lysyl oxidase or transglutaminase) [51] that might contribute to increase of the matrix stiffening as well, we did not further characterize elastic modulus of decellularized matrix in dependence of HA depletion or other influences of composition or crosslinking.…”

Section: Tgf-β1 Enhanced Matrix Stiffening But Did Not Affect Proliferation and Asma Expression In Cafmentioning

confidence: 96%

“…One of the ECM components that has been discussed to be an important player in cancer progression is hyaluronan (HA) [13,14]. HA is a non-sulfated glycosaminoglycan composed of D-glucuronic and N-acetyl-D-glucosamine.…”

Section: Introductionmentioning

confidence: 99%

“…3D fibrillar collagen matrices are a versatile platform to adjust composition, microstructure and mechanics of 3D cell culture scaffolds and are widely used to mimic interstitial tissue [28,30]. Also, there have been works on how HA affects cancer cell behavior in the cancer microenvironment using 3D collagen matrices [14,31]. However, less is known about the differential behavior of wound-healing related myofibroblasts and CAF in term of proliferation, matrix remodeling potential, and HA production in 3D cell culture settings.…”

Section: Introductionmentioning

confidence: 99%

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Matrix Remodeling and Hyaluronan Production by Myofibroblasts and Cancer-Associated Fibroblasts in 3D Collagen Matrices

Sapudom

Müller

Nguyen

et al. 2020

Gels

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The tumor microenvironment is a key modulator in cancer progression and has become a novel target in cancer therapy. An increase in hyaluronan (HA) accumulation and metabolism can be found in advancing tumor progression and are often associated with aggressive malignancy, drug resistance and poor prognosis. Wound-healing related myofibroblasts or activated cancer-associated fibroblasts (CAF) are assumed to be the major sources of HA. Both cell types are capable to synthesize new matrix components as well as reorganize the extracellular matrix. However, to which extent myofibroblasts and CAF perform these actions are still unclear. In this work, we investigated the matrix remodeling and HA production potential in normal human dermal fibroblasts (NHFB) and CAF in the absence and presence of transforming growth factor beta -1 (TGF-β1), with TGF-β1 being a major factor of regulating fibroblast differentiation. Three-dimensional (3D) collagen matrix was utilized to mimic the extracellular matrix of the tumor microenvironment. We found that CAF appeared to response insensitively towards TGF-β1 in terms of cell proliferation and matrix remodeling when compared to NHFB. In regards of HA production, we found that both cell types were capable to produce matrix bound HA, rather than a soluble counterpart, in response to TGF-β1. However, activated CAF demonstrated higher HA production when compared to myofibroblasts. The average molecular weight of produced HA was found in the range of 480 kDa for both cells. By analyzing gene expression of HA metabolizing enzymes, namely hyaluronan synthase (HAS1-3) and hyaluronidase (HYAL1-3) isoforms, we found expression of specific isoforms in dependence of TGF-β1 present in both cells. In addition, HAS2 and HYAL1 are highly expressed in CAF, which might contribute to a higher production and degradation of HA in CAF matrix. Overall, our results suggested a distinct behavior of NHFB and CAF in 3D collagen matrices in the presence of TGF-β1 in terms of matrix remodeling and HA production pointing to a specific impact on tumor modulation.

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“…The main advantages of 2D tissue plastic cell culture are easier environmental control cell observation, measurement, and eventual manipulation in comparison with 3D cell culture models. As a major consequence non-physiological cell behavior and failure in the translation of cell culture results have been reported [126][127][128][129][130]. To better simulate the in vivo situation, more complex 3D models have been introduced for example using collagen, alginate, or PEG [38,[131][132][133][134].…”

Section: Technological Advances For Future Microgravity Researchmentioning

confidence: 99%

May the Force Be with You (Or Not): The Immune System under Microgravity

ElGindi

Sapudom

Ibrahim

et al. 2021

Cells

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All terrestrial organisms have evolved and adapted to thrive under Earth’s gravitational force. Due to the increase of crewed space flights in recent years, it is vital to understand how the lack of gravitational forces affects organisms. It is known that astronauts who have been exposed to microgravity suffer from an array of pathological conditions including an impaired immune system, which is one of the most negatively affected by microgravity. However, at the cellular level a gap in knowledge exists, limiting our ability to understand immune impairment in space. This review highlights the most significant work done over the past 10 years detailing the effects of microgravity on cellular aspects of the immune system.

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Biomimetic tissue models reveal the role of hyaluronan in melanoma proliferation and invasion

Abstract: Biomimetic matrix models demonstrate the role of the size-dependent effect of hyaluronan in melanoma progression and reveal an alternative explanation for in vivo findings of hyaluronan dependent melanoma growth.

Cited by 21 publications

References 62 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

Matrix Remodeling and Hyaluronan Production by Myofibroblasts and Cancer-Associated Fibroblasts in 3D Collagen Matrices

May the Force Be with You (Or Not): The Immune System under Microgravity

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