Published online Jan 26, 2020. doi: 10.4252/wjsc.v12.i1.70
Peer-review started: April 14, 2019
First decision: May 16, 2019
Revised: August 16, 2019
Accepted: September 26, 2019
Article in press: September 26, 2019
Published online: January 26, 2020
The exclusive use of mesenchymal stem cell (MSC)-secreted molecules, named as the secretome, rather than stem cells have been evaluated for overcoming the limitations of cell-based therapy while maintaining its advantages. As recent studies have shown that this secretome has therapeutic effects similar to stem cells, the secretome has become the basis of cell-free therapy.
The composition of the secretome is influenced by various external factors, including the cell source, type of culture media, culturing period, and preconditioning treatment. Previous studies suggest that MSCs can be induced to generate a specialized secretome customized to a specific disease. We herein defined induced secretome (isecretome) as the secretome released from MSCs that had been stimulated by disease-causing materials to treat the specific disease.
Thioacetamide (TAA) is a well-known hepatotoxin. We thus attempted to validate the higher therapeutic effects of the secretome induced by TAA (TAA-isecretome) compared to the naïve secretome, specifically in mice with TAA-induced hepatic failure. If the superiority of the isecretome over the naïve secretome is demonstrated, it could provide a foundation for producing a disease-specific isecretome applicable to specific diseases.
We collected the secretory materials (named as inducers) released from AML12 hepatocytes that had been pretreated with TAA and generated the TAA-isecretome after stimulating ASCs with the inducers. The TAA-isecretome was intravenously administered to mice with TAA-induced hepatic failure and those with partial hepatectomy. In addition, we generated an HBx-isecretome using hepatitis X antigens as inducers and compared the components of the naïve secretome, TAA-isecretome, and HBx-isecretome using liquid chromatography–mass spectrometry.
Compared to the naïve secretome infusion, TAA-isecretome infusion showed higher therapeutic potential in terms of (1) restoring disorganized hepatic tissue to normal tissue; (2) Inhibiting proinflammatory cytokines (interleukin-6 and tumor necrosis factor-α); and (3) Reducing abnormally elevated liver enzymes (aspartate aminotransferase and alanine aminotransferase) in mice with TAA-induced hepatic failure. However, the TAA-isecretome showed inferior therapeutic potential for restoring hepatic function in partially hepatectomized mice. Proteomic analysis of the TAA-isecretome identified that antioxidant processes were the most predominant enriched biological networks of the proteins exclusively identified in the TAA-isecretome. In addition, peroxiredoxin-1, a potent antioxidant protein, was found to be one of the representative components of the TAA-isecretome.
We showed that the TAA-isecretome was superior to the naïve secretome in restoring hepatic function while minimizing inflammatory processes in mice with TAA-induced hepatic failure. However, such superiority was not observed in the mouse model of partial hepatectomy, suggesting disease-specificity of the TAA-isecretome. Free radicals are principal pathogenic agents in the pathogenesis of TAA-induced hepatic injury. Proteomic analysis of TAA-isecretome identified that antioxidant processes were the most predominantly enriched biological networks of the proteins exclusively identified in the TAA-isecretome. In addition, Prdx-1, a potent antioxidant protein, was found to be one of the representative components of the TAA-isecretome.
Our results suggest that appropriate stimulation of MSCs with pathogenic agents can lead to the production of a secretome specialized for protecting against the pathogen. This approach is expected to open a new way of developing various specific therapeutics based on the high plasticity and responsiveness of MSCs.