Abstract
The cell cycle is known to be regulated by features such as the mechanical properties of the surrounding environment and interaction of cells with the adhering substrates. Here, we investigated the possibility of regulating cell-cycle progression of the cells on gelatin/hyaluronic acid composite hydrogels obtained through hydrogen peroxide (H2O2)-mediated cross-linking and degradation of the polymers by varying the exposure time to H2O2 contained in the air. The stiffness of the hydrogel varied with the exposure time. Human cervical cancer cells (HeLa) and mouse mammary gland epithelial cells (NMuMG) expressing cell-cycle reporter Fucci2 showed the exposure-time-dependent different cell-cycle progressions on the hydrogels. Although HeLa/Fucci2 cells cultured on the soft hydrogel (Young’s modulus: 0.20 and 0.40 kPa) obtained through 15 min and 120 min of the H2O2 exposure showed a G2/M-phase arrest, NMuMG cells showed a G1-phase arrest. Additionally, the cell-cycle progression of NMuMG cells was not only governed by the hydrogel stiffness, but also by the low-molecular-weight HA resulting from H2O2-mediated degradation. These results indicate that H2O2-mediated cross-linking and degradation of gelatin/hyaluronic acid composite hydrogel could be used to control the cell adhesion and cell-cycle progression.
Highlights
IntroductionRegulation of the cell cycle is fundamental to successful cell culture technology and tissue engineering
The content of Gelatin–Ph (3.0 w/v%) and hyaluronic acid (HA)–Ph (0.5 w/v%) in the composite hydrogels used in this study has been reported to allow the elongation of human adipose-derived stem cells (hASCs) and support the growth of the cells [49]
We found that Human cervical cancer cells (HeLa)/Fucci2 cells had lower F-actin assembly on soft hydrogel obtained through 15 min (0.20 kPa) and 120 min (0.40 kPa) of H2O2 exposure (Figure 5)
Summary
Regulation of the cell cycle is fundamental to successful cell culture technology and tissue engineering. Physical cues including mechanical properties of the substrate and biochemical cues in the form of cell-adhesive ligands are known to modulate cellular behaviors including adhesion [3,4] and proliferation [5–7]. The scaffolds composed of multiple polymers provide the microenvironment with multiple properties, attributed to each polymer. Gelatin/HA mixture could combine the celladhesive property of the arginine–glycine–aspartic acid (RGD) sequence and degradability of the gelatin with the physicochemical property and regulation of cell behavior and immune response function of HA. Various studies have reported the usefulness of gelatin/HA composite hydrogel scaffolds in tissue-engineering applications for biomimicking of the extracellular matrix (ECM) of the native tissues [10,14–16]
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