Autophagy Promotes the Survival of Adipose Mesenchymal Stem/Stromal Cells and Enhances Their Therapeutic Effects in Cisplatin-Induced Liver Injury via Modulating TGF-β1/Smad and PI3K/AKT Signaling Pathways
Autophagy is a key metabolic process where cells can recycle its proteins and organelles to regenerate its own cellular building blocks. Chemotherapy is indispensable for cancer treatment but associated with various side-effects, including organ damage. Stem cell-based therapy is a promising approac...
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MDPI AG
2021-09-01
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| author | Eman Mohamad El Nashar Mansour Abdullah Alghamdi Wardah Abdullah Alasmari Mohamed M. A. Hussein Eman Hamza Reham Ismail Taha Mona M. Ahmed Khulood Mohammed Al-Khater Ahmed Abdelfattah-Hassan |
| author_facet | Eman Mohamad El Nashar Mansour Abdullah Alghamdi Wardah Abdullah Alasmari Mohamed M. A. Hussein Eman Hamza Reham Ismail Taha Mona M. Ahmed Khulood Mohammed Al-Khater Ahmed Abdelfattah-Hassan |
| author_sort | Eman Mohamad El Nashar |
| collection | DOAJ |
| description | Autophagy is a key metabolic process where cells can recycle its proteins and organelles to regenerate its own cellular building blocks. Chemotherapy is indispensable for cancer treatment but associated with various side-effects, including organ damage. Stem cell-based therapy is a promising approach for reducing chemotherapeutic side effects, however, one of its main culprits is the poor survival of transplanted stem cells in damaged tissues. Here, we aimed to test the effects of activating autophagy in adipose-derived mesenchymal stem/stromal cells (ADSCs) on the survival of ADSCs, and their therapeutic value in cisplatin-induced liver injury model. Autophagy was activated in ADSCs by rapamycin (50 nM/L) for two hours before transplantation and were compared to non-preconditioned ADSCs. Rapamycin preconditioning resulted in activated autophagy and improved survival of ADSCs achieved by increased autophagosomes, upregulated autophagy-specific LC3-II gene, decreased protein degradation/ubiquitination by downregulated p62 gene, downregulated mTOR gene, and finally, upregulated antiapoptotic BCL-2 gene. In addition, autophagic ADSCs transplantation in the cisplatin liver injury model, liver biochemical parameters (AST, ALT and albumin), lipid peroxidation (MDA), antioxidant profile (SOD and GPX) and histopathological picture were improved, approaching near-normal conditions. These promising autophagic ADSCs effects were achieved by modulation of components in TGF-β1/Smad and PI3K-AKT signaling pathways, besides reducing NF-κB gene expression (marker for inflammation), reducing TGF-β1 levels (marker for fibrosis) and increasing SDF-1 levels (liver regeneration marker) in liver. Therefore, current results highlight the importance of autophagy in augmenting the therapeutic potential of stem cell therapy in alleviating cisplatin-associated liver damage and opens the path for improved cell-based therapies, in general, and with chemotherapeutics, in particular. |
| first_indexed | 2024-03-10T07:48:07Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T07:48:07Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj.art-285d3410d018437f94e1f9b7a607f07c2023-11-22T12:26:49ZengMDPI AGCells2073-44092021-09-01109247510.3390/cells10092475Autophagy Promotes the Survival of Adipose Mesenchymal Stem/Stromal Cells and Enhances Their Therapeutic Effects in Cisplatin-Induced Liver Injury via Modulating TGF-β1/Smad and PI3K/AKT Signaling PathwaysEman Mohamad El Nashar0Mansour Abdullah Alghamdi1Wardah Abdullah Alasmari2Mohamed M. A. Hussein3Eman Hamza4Reham Ismail Taha5Mona M. Ahmed6Khulood Mohammed Al-Khater7Ahmed Abdelfattah-Hassan8Department of Anatomy, College of Medicine, King Khalid University, Abha 61421, Saudi ArabiaDepartment of Anatomy, College of Medicine, King Khalid University, Abha 61421, Saudi ArabiaDepartment of Anatomy, Faculty of Medicine, Umm Al-Qura University, Makkah 24230, Saudi ArabiaBiochemistry Department, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, EgyptDepartment of Medical Biochemistry, Faculty of Medicine, Mansoura University, Mansoura 35516, EgyptDepartment of Anatomy, Faculty of Medicine, Mansoura University, Mansoura 35516, EgyptForensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, EgyptDepartment of Anatomy, College of Medicine, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi ArabiaDepartment of Anatomy and Embryology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, EgyptAutophagy is a key metabolic process where cells can recycle its proteins and organelles to regenerate its own cellular building blocks. Chemotherapy is indispensable for cancer treatment but associated with various side-effects, including organ damage. Stem cell-based therapy is a promising approach for reducing chemotherapeutic side effects, however, one of its main culprits is the poor survival of transplanted stem cells in damaged tissues. Here, we aimed to test the effects of activating autophagy in adipose-derived mesenchymal stem/stromal cells (ADSCs) on the survival of ADSCs, and their therapeutic value in cisplatin-induced liver injury model. Autophagy was activated in ADSCs by rapamycin (50 nM/L) for two hours before transplantation and were compared to non-preconditioned ADSCs. Rapamycin preconditioning resulted in activated autophagy and improved survival of ADSCs achieved by increased autophagosomes, upregulated autophagy-specific LC3-II gene, decreased protein degradation/ubiquitination by downregulated p62 gene, downregulated mTOR gene, and finally, upregulated antiapoptotic BCL-2 gene. In addition, autophagic ADSCs transplantation in the cisplatin liver injury model, liver biochemical parameters (AST, ALT and albumin), lipid peroxidation (MDA), antioxidant profile (SOD and GPX) and histopathological picture were improved, approaching near-normal conditions. These promising autophagic ADSCs effects were achieved by modulation of components in TGF-β1/Smad and PI3K-AKT signaling pathways, besides reducing NF-κB gene expression (marker for inflammation), reducing TGF-β1 levels (marker for fibrosis) and increasing SDF-1 levels (liver regeneration marker) in liver. Therefore, current results highlight the importance of autophagy in augmenting the therapeutic potential of stem cell therapy in alleviating cisplatin-associated liver damage and opens the path for improved cell-based therapies, in general, and with chemotherapeutics, in particular.https://www.mdpi.com/2073-4409/10/9/2475ADSCscell-based therapyrapamycinapoptosisliver damagehepatoprotective pathways |
| spellingShingle | Eman Mohamad El Nashar Mansour Abdullah Alghamdi Wardah Abdullah Alasmari Mohamed M. A. Hussein Eman Hamza Reham Ismail Taha Mona M. Ahmed Khulood Mohammed Al-Khater Ahmed Abdelfattah-Hassan Autophagy Promotes the Survival of Adipose Mesenchymal Stem/Stromal Cells and Enhances Their Therapeutic Effects in Cisplatin-Induced Liver Injury via Modulating TGF-β1/Smad and PI3K/AKT Signaling Pathways Cells ADSCs cell-based therapy rapamycin apoptosis liver damage hepatoprotective pathways |
| title | Autophagy Promotes the Survival of Adipose Mesenchymal Stem/Stromal Cells and Enhances Their Therapeutic Effects in Cisplatin-Induced Liver Injury via Modulating TGF-β1/Smad and PI3K/AKT Signaling Pathways |
| title_full | Autophagy Promotes the Survival of Adipose Mesenchymal Stem/Stromal Cells and Enhances Their Therapeutic Effects in Cisplatin-Induced Liver Injury via Modulating TGF-β1/Smad and PI3K/AKT Signaling Pathways |
| title_fullStr | Autophagy Promotes the Survival of Adipose Mesenchymal Stem/Stromal Cells and Enhances Their Therapeutic Effects in Cisplatin-Induced Liver Injury via Modulating TGF-β1/Smad and PI3K/AKT Signaling Pathways |
| title_full_unstemmed | Autophagy Promotes the Survival of Adipose Mesenchymal Stem/Stromal Cells and Enhances Their Therapeutic Effects in Cisplatin-Induced Liver Injury via Modulating TGF-β1/Smad and PI3K/AKT Signaling Pathways |
| title_short | Autophagy Promotes the Survival of Adipose Mesenchymal Stem/Stromal Cells and Enhances Their Therapeutic Effects in Cisplatin-Induced Liver Injury via Modulating TGF-β1/Smad and PI3K/AKT Signaling Pathways |
| title_sort | autophagy promotes the survival of adipose mesenchymal stem stromal cells and enhances their therapeutic effects in cisplatin induced liver injury via modulating tgf β1 smad and pi3k akt signaling pathways |
| topic | ADSCs cell-based therapy rapamycin apoptosis liver damage hepatoprotective pathways |
| url | https://www.mdpi.com/2073-4409/10/9/2475 |
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