Prostate cancer (PCa) is one of the most lethal cancers in men worldwide. The tumor microenvironment (TME) plays an important role in PCa development, which consists of tumor cells, fibroblasts, endothelial cells, and extracellular matrix. Hyaluronic acid (HA) and cancer-associated fibroblasts (CAFs) are the major components in the TME and are correlated with PCa proliferation and metastasis, while the underlying mechanism is still not fully understood due to the lack of biomimetic extracellular matrix components and coculture models. In this study, gelatin methacryloyl/chondroitin sulfate-based hydrogels were physically crosslinked with HA to develop a novel bioink for the three-dimensional (3D) bioprinting of a coculture model that can be used to investigate the effect of HA on PCa behaviors and the mechanism underlying PCa-fibroblasts interaction. PCa cells demonstrated distinct transcriptional profiles under HA stimulation, where cytokine secretion, angiogenesis, and epithelial to mesenchymal transition were significantly upregulated. Further coculture of PCa with normal fibroblasts activated CAF transformation, which could be induced by the upregulated cytokine secretion of PCa cells. These results suggested HA could not only promote PCa metastasis individually but also induce PCa cells to activate CAF transformation and form HA-CAF coupling effects to further promote PCa drug resistance and metastasis.

Peripheral nerve injury (PNI) is a common and severe clinical disease worldwide, which leads to a poor prognosis because of the complicated treatments and high morbidity. Autologous nerve grafting as the gold standard still cannot meet the needs of clinical nerve transplantation because of its low availability and limited size. The development of artificial nerve conduits was led to a novel direction for PNI treatment, while most of the currently developed artificial nerve conduits was lack biochemical cues to promote nerve regeneration. In this study, we designed a novel composite neural conduit by inserting decellularized the rat sciatic nerve or kidney in a poly (lactic-co-glycolic acid) (PLGA) grooved conduit. The nerve regeneration effect of all samples was analyzed using rat sciatic nerve defect model, where decellularized tissues and grooved PLGA conduit alone were used as controls. The degree of nerve regeneration was evaluated using the motor function, gastrocnemius recovery, and morphological and histological assessments suggested that the combination of a grooved conduit with decellularized tissues significantly promoted nerve regeneration compared with decellularized tissues and PLGA conduit alone. It is worth to note that the grooved conduits containing decellularized nerves have a promotive effect similar to that of autologous nerve grafting, suggesting that it could be an artificial nerve conduit used for clinical practice in the future. Graphical Abstract

Melanoma is a highly malignant tumor originating from melanocytes. The 5-year survival rate of primary melanoma is 98%, whereas the survival rate of metastatic melanoma is only 10%, which can be attributed to the insensitivity to existing treatments. Fibroblasts are the primary cells in the dermis that promote melanoma metastasis; however, the molecular mechanism underlying the fibroblast–melanoma interaction is yet to be completely understood. Herein, gelatin methacryloyl (GelMA) was used to construct a co-culture model for melanoma cells (A375) and fibroblasts. GelMA retains the good biological properties of collagen, which has been identified as the primary component of the melanoma tumor microenvironment. Fibroblasts were encapsulated in GelMA, whereas A375 cells were cultured on the GelMA surface, which realistically mimics the macrostructure of melanoma. A375 cells co-cultured with fibroblasts demonstrated a higher cellular proliferation rate, potentials of neoneurogenesis, overexpression of epithelial mesenchymal transition markers, and a faster migration rate compared with A375 cells cultured alone, which could be due to the cancer-associated fibroblast activation and the overexpression of transforming growth factor β1 and fibroblast growth factor-2 by fibroblasts. Overall, this study revealed the possible mechanisms of fibroblast–melanoma interaction and suggested that this co-culture model could be potentially further developed as a platform for screening chemotherapies in the future.

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Peripheral nerve injuries cause an absence or destruction of nerves. Decellularized nerves, acting as a replacement for autografts, have been investigated in the promotion of nerve repair and regeneration, always being incorporated with stem cells or growth factors. However, such a strategy is limited by size availability. The potential application in heterotopic transplantation of other decellularized tissues needs to be further explored. In this study, rat decellularized kidney (dK) was selected to be compared with decellularized peripheral nerve (dN), since dK has aboundant ECM components and growth factors. The PC-12 cells were cultured on dK and dN scaffolds, as shown in the similar behaviors of cell metabolism and viability, but have a more regular arrangement on dN compared to dK, indicating that the natural structure plays an important role in guiding cell extension. However, we found significant upregulation of axon–growth–associated genes and proteins of PC-12 cells in the dK group compared to the dN group by qRT-PCR, immunofluorescence, and western blotting. Furthermore, various neurotrophic factors and growth factors of acellular kidney and nerve were evaluated by ELISA assay. The lower expression of neurotrophic factors but higher expression of growth factors such as VEGF and HGF from dK suggests that axon growth and extension for PC-12 cells may be partially mediated by VEGF and HGF expression from decellularized kidney, which further points to a potential application in nerve repair and regeneration.