RESUMEN
Biophysical cues of the cellular microenvironment tremendously influence cell behavior by mechanotransduction. However, it is still unclear how cells sense and transduce the mechanical signals from 3D geometry to regulate cell function. Here, the mechanotransduction of human mesenchymal stem cells (MSCs) triggered by 3D micropatterns and its effect on the paracrine of MSCs are systematically investigated. Our findings show that 3D micropattern force could influence the spatial reorganization of the cytoskeleton, leading to different local forces which mediate nucleus alteration such as orientation, morphology, expression of Lamin A/C and chromatin condensation. Specifically, in the triangular prism and cuboid micropatterns, the ordered F-actin fibers are distributed over and fully transmit compressive forces to the nucleus, which results in nuclear flattening and stretching of nuclear pores, thus enhancing the nuclear import of YES-associated protein (YAP). Furthermore, the activation of YAP significantly enhances the paracrine of MSCs and upregulates the secretion of angiogenic growth factors. In contrast, the fewer compressive forces on the nucleus in cylinder and cube micropatterns cause less YAP entering the nucleus. The skin repair experiment provides the first in vivo evidence that enhanced MSCs paracrine by 3D geometry significantly promotes tissue regeneration. The current study contributes to understanding the in-depth mechanisms of mechanical signals affecting cell function and provides inspiration for innovative design of biomaterials.
RESUMEN
Skin defect is common in daily life, but repairing large skin defects remains a challenge. Using biomaterials to deliver biochemical or physical factors to promote skin tissue regeneration is of great significance for accelerating wound healing. Specific surface micropatterns on biomaterials could affect cell behavior and tissue regeneration. However, few studies have focused on the construction of wound healing biomaterials with surface micropatterns and their role in skin tissue regeneration. In the present study, gelatin-polycaprolactone/silk fibroin composite membranes with different micropatterns were fabricated by photolithography, including line, grid and plane micropatterns. In vitro cell experiments demonstrated that the line micropattern on the composite membrane could guide cell-oriented growth, and more importantly, promote the expression of angiogenesis-related markers and α-smooth muscle actin (α-SMA) at both gene level and protein level. In the rat full-thickness skin defect model, the composite membrane with line micropatterns increased α-SMA production and neovascularization in wounds, leading to accelerated wound contraction and healing. The current study not only suggests that composite membranes with specific micropatterns can be promising wound repair materials but also provides new insights into the importance of biomaterial surface topology for tissue regeneration.
RESUMEN
The tumor microenvironment with overexpressed hydrogen peroxide (H2O2) and reinforced antioxidative system (glutathione, GSH) becomes a double-edged sword for the accessibility of nano-therapy. Since reactive oxygen species (ROS) are easily quenched by the developed antioxidative network, ROS-based treatments such as chemodynamic therapy (CDT) and radiotherapy (RT) for killing cancer cells are severely attenuated. To overcome such limitations, a bioactive nanosphere system is developed to regulate intracellular oxidative stress for enhanced radio-chemodynamic combination therapy by using bovine serum albumin (BSA) based bioactive nanospheres that are BSA assembled with in situ generated copper-bismuth sulfide nanodots and diallyl trisulfide (DATS). The copper-bismuth sulfide nanodots react with H2O2 to produce â¢OH and release Cu2+. Then, the Cu2+ further depletes GSH to generate Cu+ for more â¢OH generation in the way of Fenton-like reaction. Such a cascade reaction can initiate â¢OH generation and GSH consumption to realize CDT. The elevation of ROS triggered by the DATS from BBCD nanospheres further augments the breaking of redox balance for the increased oxidative stress in 4T1 cells. With the sensitization of increased oxidative stress and high Z element Bi, an enhanced radio-chemodynamic combination therapy is achieved. The current work provides an enhanced radio-chemodynamic combination treatment for the majority of solid tumors by using the co-assembled bioactive nanospheres as an amplifier of oxidative stress.
