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Younesi FS, Hinz B. The Myofibroblast Fate of Therapeutic Mesenchymal Stromal Cells: Regeneration, Repair, or Despair? Int J Mol Sci 2024; 25:8712. [PMID: 39201399 PMCID: PMC11354465 DOI: 10.3390/ijms25168712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 07/31/2024] [Accepted: 08/06/2024] [Indexed: 09/02/2024] Open
Abstract
Mesenchymal stromal cells (MSCs) can be isolated from various tissues of healthy or patient donors to be retransplanted in cell therapies. Because the number of MSCs obtained from biopsies is typically too low for direct clinical application, MSC expansion in cell culture is required. However, ex vivo amplification often reduces the desired MSC regenerative potential and enhances undesired traits, such as activation into fibrogenic myofibroblasts. Transiently activated myofibroblasts restore tissue integrity after organ injury by producing and contracting extracellular matrix into scar tissue. In contrast, persistent myofibroblasts cause excessive scarring-called fibrosis-that destroys organ function. In this review, we focus on the relevance and molecular mechanisms of myofibroblast activation upon contact with stiff cell culture plastic or recipient scar tissue, such as hypertrophic scars of large skin burns. We discuss cell mechanoperception mechanisms such as integrins and stretch-activated channels, mechanotransduction through the contractile actin cytoskeleton, and conversion of mechanical signals into transcriptional programs via mechanosensitive co-transcription factors, such as YAP, TAZ, and MRTF. We further elaborate how prolonged mechanical stress can create persistent myofibroblast memory by direct mechanotransduction to the nucleus that can evoke lasting epigenetic modifications at the DNA level, such as histone methylation and acetylation. We conclude by projecting how cell culture mechanics can be modulated to generate MSCs, which epigenetically protected against myofibroblast activation and transport desired regeneration potential to the recipient tissue environment in clinical therapies.
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Affiliation(s)
- Fereshteh Sadat Younesi
- Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada;
- Keenan Research Institute for Biomedical Science, St. Michael’s Hospital, Toronto, ON M5B 1T8, Canada
| | - Boris Hinz
- Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada;
- Keenan Research Institute for Biomedical Science, St. Michael’s Hospital, Toronto, ON M5B 1T8, Canada
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Gopal A, Gangadaran P, Rajendran RL, Oh JM, Lee HW, Hong CM, Kalimuthu S, Han MH, Lee J, Ahn BC. Extracellular vesicle mimetics engineered from mesenchymal stem cells and curcumin promote fibrosis regression in a mouse model of thioacetamide-induced liver fibrosis. Regen Ther 2024; 26:911-921. [PMID: 39502438 PMCID: PMC11535984 DOI: 10.1016/j.reth.2024.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 09/30/2024] [Accepted: 10/10/2024] [Indexed: 11/08/2024] Open
Abstract
Recent research suggests that advanced liver fibrosis could be reversed, but the therapeutic agents needed for the prevention of liver fibrosis remain to be elucidated. The beneficial effects of mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (EVs) on liver fibrosis have been reported. However, the large-scale production of MSC-EVs remains challenging. The present study investigated the therapeutic effects of mouse MSC-derived EV mimetics (MEVMs) in combination with curcumin (antifibrotic compound) using a mouse model of thioacetamide-induced liver fibrosis. MEVMs were prepared through the serial extrusion of MSCs. These MEVMs were similar in size and morphology to the EVs. The biodistribution study showed that fluorescently labeled MEVMs predominantly accumulated in the liver. The establishment of liver fibrosis was confirmed via increased collagen (histology), liver fibrosis score, α-smooth muscle actin (α-SMA), and vimentin proteins levels. Treatment with MEVMs, curcumin, or their combination decreased the amount of collagen in liver tissues, with the antifibrotic effects of MEVMs being further confirmed by the liver fibrosis score. All treatments decreased the expression of collagen 1α, α-SMA, and vimentin. MEVMs showed superior effects than curcumin. Thus, MSC-derived EVMs could be a potential alternative for the treatment of liver fibrosis.
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Affiliation(s)
- Arunnehru Gopal
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Prakash Gangadaran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Cardiovascular Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Ramya Lakshmi Rajendran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Cardiovascular Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Ji Min Oh
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Cardiovascular Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Ho Won Lee
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Chae Moon Hong
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Cardiovascular Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea
- Department of Nuclear Medicine, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
| | - Senthilkumar Kalimuthu
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Man-Hoon Han
- Department of Pathology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Department of Pathology, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
| | - Jaetae Lee
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Department of Nuclear Medicine, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
| | - Byeong-Cheol Ahn
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Cardiovascular Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea
- Department of Nuclear Medicine, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
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Bak SH, Kim JH, Kim SU, Lee DS, Song YS, Lee HJ. Established Immortalized Cavernous Endothelial Cells Improve Erectile Dysfunction in Rats with Cavernous Nerve Injury. Pharmaceuticals (Basel) 2023; 16:ph16010123. [PMID: 36678621 PMCID: PMC9866507 DOI: 10.3390/ph16010123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 01/05/2023] [Accepted: 01/09/2023] [Indexed: 01/17/2023] Open
Abstract
The main cause of erectile dysfunction (ED) is the damage in penile cavernous endothelial cells (EC). Murine primary ECs have a limited growth potential, and the easy availability of murine ECs will facilitate the study of cavernous endothelial dysfunction in rats. This study was performed to establish immortalized rat penile cavernous ECs (rEC) and investigate how they could repair erectile dysfunction in rats with cavernous nerve injury (CNI). rEC was isolated enzymatically by collagenase digestion and were cultured. An amphotropic replication-incompetent retroviral vector encoding v-myc oncogene was used to transfect rEC for immortalization (vREC). Morphological and immunohistochemical properties of vREC were examined. Eight-week-old male Sprague-Dawley rats were divided into three groups of five rats each, including group 1 = sham operation, group 2 = bilateral CN injury, group 3 = vREC (1 × 106 cells) treatment after CNI. Erectile response was assessed at 2, 4 weeks after transplantation of vREC., Penile tissue were harvested at 4 weeks after transplantation and immune−histochemical examination was performed. vREC showed the expression of CD31, vWF, cell type-specific markers for EC by RT-PCR and flowcytometry. At 2, 4 weeks after transplantation, rats with CNI had significantly lower erectile function than control group (p < 0.05). The group transplanted with vREC showed higher erectile function than the group without vRECs (p < 0.05). vREC was established and repaired erectile dysfunction in rats with CNI. This cell line may be useful for studying mechanisms and drug screening of erectile dysfunction of rats.
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Affiliation(s)
- Sang Hong Bak
- Research Institute, Humetacell Inc., Bucheon 14786, Gyeonggi, Republic of Korea
| | - Jae Heon Kim
- Department of Urology, Soonchunhyang University School of Medicine, Seoul 04401, Republic of Korea
| | - Seung U. Kim
- Division of Neurology, Department of Medicine, UBC Hospital, University of British Columbia, Vancouver, BC V6T 2B5, Canada
| | - Dong-Seok Lee
- BK21 Plus KNU Creative BioResearch Group, School of Life Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
- School of Life Sciences & Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Yun Seob Song
- Department of Urology, Soonchunhyang University School of Medicine, Seoul 04401, Republic of Korea
- Correspondence: (Y.S.S.); or (H.J.L.); Tel.: +82-2-709-9114 (Y.S.S.)
| | - Hong J. Lee
- Research Institute, Humetacell Inc., Bucheon 14786, Gyeonggi, Republic of Korea
- Medical Research Institute, Chungbuk National University, Cheongju 28644, Chungbuk, Republic of Korea
- Correspondence: (Y.S.S.); or (H.J.L.); Tel.: +82-2-709-9114 (Y.S.S.)
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Han HT, Jin WL, Li X. Mesenchymal stem cells-based therapy in liver diseases. MOLECULAR BIOMEDICINE 2022; 3:23. [PMID: 35895169 PMCID: PMC9326420 DOI: 10.1186/s43556-022-00088-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/20/2022] [Indexed: 12/24/2022] Open
Abstract
Multiple immune cells and their products in the liver together form a complex and unique immune microenvironment, and preclinical models have demonstrated the importance of imbalances in the hepatic immune microenvironment in liver inflammatory diseases and immunocompromised liver diseases. Various immunotherapies have been attempted to modulate the hepatic immune microenvironment for the purpose of treating liver diseases. Mesenchymal stem cells (MSCs) have a comprehensive and plastic immunomodulatory capacity. On the one hand, they have been tried for the treatment of inflammatory liver diseases because of their excellent immunosuppressive capacity; On the other hand, MSCs have immune-enhancing properties in immunocompromised settings and can be modified into cellular carriers for targeted transport of immune enhancers by genetic modification, physical and chemical loading, and thus they are also used in the treatment of immunocompromised liver diseases such as chronic viral infections and hepatocellular carcinoma. In this review, we discuss the immunological basis and recent strategies of MSCs for the treatment of the aforementioned liver diseases. Specifically, we update the immune microenvironment of the liver and summarize the distinct mechanisms of immune microenvironment imbalance in inflammatory diseases and immunocompromised liver diseases, and how MSCs can fully exploit their immunotherapeutic role in liver diseases with both immune imbalance patterns.
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Affiliation(s)
- Heng-Tong Han
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, P. R, China
| | - Wei-Lin Jin
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, P. R, China
- Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, 730000, People's Republic of China
| | - Xun Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, P. R, China.
- Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, 730000, People's Republic of China.
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China.
- Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, 730000, People's Republic of China.
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Effect of Allogeneic Oral Mucosa Mesenchymal Stromal Cells on Equine Wound Repair. Vet Med Int 2021; 2021:5024905. [PMID: 34950446 PMCID: PMC8692048 DOI: 10.1155/2021/5024905] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 10/14/2021] [Accepted: 11/25/2021] [Indexed: 11/17/2022] Open
Abstract
Objective To assess the clinical value and safety of the application of allogeneic equine oral mucosa mesenchymal stromal cells (OM-MSCs) to wounds. Animals. 8 healthy adult horses without front limb skin lesions or musculoskeletal disease. Procedures. Stem cells were isolated from the oral mucosa of a donor horse. Horses were subjected to the creation of eight full-thickness cutaneous wounds, two on each distal forelimb (FL) and two on both sides of the thorax (TH). Each wound was subjected to one out of four treatments: no medication (T1), hyaluronic acid- (HA-) gel containing OM-MSC (T2), HA-gel containing OM-MSC secretome (T3), and HA-gel alone (T4). Gross macroscopic evaluation and laser digital photographic documentation were regularly performed to allow wound assessment including wound surface area. Full-thickness skin punch biopsy was performed at each site before wound induction (D0, normal skin) and after complete wound healing (D62, repaired skin). Results All wounds healed without adverse effect at D62. Distal limb wounds are slower to heal than body wounds. OM-MSC and its secretome have a positive impact on TH wound contraction. OM-MSC has a positive impact on the contraction and epithelialization of FL wounds. No significant difference between wound sites before and after treatment was noted at histological examination. Conclusion and Clinical Relevance. Using horse cells harvested from oral mucosa is a feasible technique to produce OM-MSC or its secretome. The gel produced by the combination of these biologic components with HA shows a positive impact when applied during the early stage of wound healing.
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Zhang L, Pu K, Liu X, Bae SDW, Nguyen R, Bai S, Li Y, Qiao L. The Application of Induced Pluripotent Stem Cells Against Liver Diseases: An Update and a Review. Front Med (Lausanne) 2021; 8:644594. [PMID: 34277651 PMCID: PMC8280311 DOI: 10.3389/fmed.2021.644594] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 06/04/2021] [Indexed: 11/13/2022] Open
Abstract
Liver diseases are a major health concern globally, and are associated with poor survival and prognosis of patients. This creates the need for patients to accept the main alternative treatment of liver transplantation to prevent progression to end-stage liver disease. Investigation of the molecular mechanisms underpinning complex liver diseases and their pathology is an emerging goal of stem cell scope. Human induced pluripotent stem cells (hiPSCs) derived from somatic cells are a promising alternative approach to the treatment of liver disease, and a prospective model for studying complex liver diseases. Here, we review hiPSC technology of cell reprogramming and differentiation, and discuss the potential application of hiPSC-derived liver cells, such as hepatocytes and cholangiocytes, in refractory liver-disease modeling and treatment, and drug screening and toxicity testing. We also consider hiPSC safety in clinical applications, based on genomic and epigenetic alterations, tumorigenicity, and immunogenicity.
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Affiliation(s)
- Lei Zhang
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Biological Therapy and Regenerative Medicine Transformation Gansu Province, Lanzhou, China
| | - Ke Pu
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, Lanzhou University, Lanzhou, China
| | - Xiaojun Liu
- Department of Medical Oncology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Sarah Da Won Bae
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney at Westmead Clinical School, Westmead, NSW, Australia
| | - Romario Nguyen
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney at Westmead Clinical School, Westmead, NSW, Australia
| | - Suyang Bai
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, Lanzhou University, Lanzhou, China
| | - Yi Li
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, Lanzhou University, Lanzhou, China
| | - Liang Qiao
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney at Westmead Clinical School, Westmead, NSW, Australia
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Wang LT, Liu KJ, Sytwu HK, Yen ML, Yen BL. Advances in mesenchymal stem cell therapy for immune and inflammatory diseases: Use of cell-free products and human pluripotent stem cell-derived mesenchymal stem cells. Stem Cells Transl Med 2021; 10:1288-1303. [PMID: 34008922 PMCID: PMC8380447 DOI: 10.1002/sctm.21-0021] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/31/2021] [Accepted: 04/20/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cell therapy (MSCT) for immune and inflammatory diseases continues to be popular based on progressive accumulation of preclinical mechanistic evidence. This has led to further expansion in clinical indications from graft rejection, autoimmune diseases, and osteoarthritis, to inflammatory liver and pulmonary diseases including COVID‐19. A clear trend is the shift from using autologous to allogeneic MSCs, which can be immediately available as off‐the‐shelf products. In addition, new products such as cell‐free exosomes and human pluripotent stem cell (hPSC)‐derived MSCs are exciting developments to further prevalent use. Increasing numbers of trials have now published results in which safety of MSCT has been largely demonstrated. While reports of therapeutic endpoints are still emerging, efficacy can be seen for specific indications—including graft‐vs‐host‐disease, strongly Th17‐mediated autoimmune diseases, and osteoarthritis—which are more robustly supported by mechanistic preclinical evidence. In this review, we update and discuss outcomes in current MSCT clinical trials for immune and inflammatory disease, as well as new innovation and emerging trends in the field.
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Affiliation(s)
- Li-Tzu Wang
- Department of Obstetrics & Gynecology, National Taiwan University (NTU) Hospital & College of Medicine, NTU, Taipei, Taiwan, Republic of China
| | - Ko-Jiunn Liu
- National Institute of Cancer Research, National Health Research Institutes (NHRI), Tainan, Taiwan, Republic of China
| | - Huey-Kang Sytwu
- National Institute of Infectious Diseases & Vaccinology, NHRI, Zhunan, Taiwan, Republic of China.,Department & Graduate Institute of Microbiology & Immunology, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Men-Luh Yen
- Department of Obstetrics & Gynecology, National Taiwan University (NTU) Hospital & College of Medicine, NTU, Taipei, Taiwan, Republic of China
| | - B Linju Yen
- Regenerative Medicine Research Group, Institute of Cellular & System Medicine, NHRI, Zhunan, Taiwan, Republic of China
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8
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El-Yamany MF, Zaki ES, Shaltout SA, Saad MA. Bone marrow mononuclear cells boosts anti-cytogentical aberration effect of N-acetylcysteine and α-lipoic acid in rat's liver and bone marrow: implication of oxidative and inflammatory pathways. Toxicol Mech Methods 2021; 31:437-449. [PMID: 33775218 DOI: 10.1080/15376516.2021.1906370] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
This study investigates the hepatoprotective effect of bone marrow mononuclear cells (BM-MNCs) transplantation, N-acetylcysteine (NAC) and α-lipoic acid (ALA). Rats were administrated carbon tetrachloride (CCl4) (1 mg/kg, i.p.) twice/week for 8 weeks for the induction of hepatotoxicity. 7 groups of rats were used as follows: Normal control, CCl4, CCl4 co-administered with BM-MNCs (1 × 106 in 0.1 ml PBS, i.v.), or NAC (300 mg/kg, p.o) or ALA (100 mg/kg, p.o) single or combination. Liver function was tested by measuring serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and albumin as well as interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), total antioxidant capacity (TAC), glutathione peroxidase (Gpx), superoxide dismutase (SOD) and catalase (CAT) activities in liver homogenates. Besides that, estimation of DNA damage was performed. In addition to Micronucleus test and histopathological investigation. CCl4 treated rats showed elevation in ALT, AST, TNF-α, IL-6 and MDA accompanied by reduction in ALB, IL-10, SOD, CAT, GPx and TAC and increased the number of DNA breaks in liver tissue, showed many micronucleated polychromatic erythrocytes (MnPCEs) in bone marrow. NAC, ALA, BM-MNCs and their combination caused a reduction of ALT, AST, while, increase albumin, CAT, TAC, GPx, SOD as compared to CCl4 treated groups. Also decrease in MDA, IL-6 and TNF-α concurrently with an increase in IL-10. Moreover, BM-MNCs, NAC, ALA, and their combination decreased DNA tail %, and the count of MnPCEs. BM-MNCs combination with NAC or ALA exerted significant antioxidant, anti-inflammatory and anti-cytogenetical aberrations effect compared to each of them alone.HighlightsCCl4 elevated ALT, AST, TNF-α, IL-6 and MDACCl4 reduced ALB, IL-10, SOD, CAT, GPx and TACCCl4 increased the number of DNA breaks in liverNAC, ALA and BM-MNCs reduced ALT, AST, while, increase albumin, CAT, TAC, GPx, SODNAC, ALA and BM-MNCs decreased in MDA, IL-6 and TNF-α and increased IL-10 [Figure: see text].
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Affiliation(s)
- Muhammed F El-Yamany
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Eman S Zaki
- General Authority for Hospitals and Educational Institutes- Ministry of Health, Cairo, Egypt
| | - Sherif A Shaltout
- Department of Pharmacology, Faculty of Medicine, Benha University, Benha, Egypt
| | - Muhammed A Saad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.,School of Pharmacy, Newgiza University, Cairo, Egypt
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Mesenchymal Stromal Cell Therapy in Novel Porcine Model of Diffuse Liver Damage Induced by Repeated Biliary Obstruction. Int J Mol Sci 2021; 22:ijms22094304. [PMID: 33919123 PMCID: PMC8122325 DOI: 10.3390/ijms22094304] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/18/2021] [Accepted: 04/19/2021] [Indexed: 12/11/2022] Open
Abstract
In liver surgery, biliary obstruction can lead to secondary biliary cirrhosis, a life-threatening disease with liver transplantation as the only curative treatment option. Mesenchymal stromal cells (MSC) have been shown to improve liver function in both acute and chronic liver disease models. This study evaluated the effect of allogenic MSC transplantation in a large animal model of repeated biliary obstruction followed by partial hepatectomy. MSC transplantation supported the growth of regenerated liver tissue after 14 days (MSC group, n = 10: from 1087 ± 108 (0 h) to 1243 ± 92 mL (14 days); control group, n = 11: from 1080 ± 95 (0 h) to 1100 ± 105 mL (14 days), p = 0.016), with a lower volume fraction of hepatocytes in regenerated liver tissue compared to resected liver tissue (59.5 ± 10.2% vs. 70.2 ± 5.6%, p < 0.05). Volume fraction of connective tissue, blood vessels and bile vessels in regenerated liver tissue, serum levels of liver enzymes (AST, ALT, ALP and GGT) and liver metabolites (albumin, bilirubin, urea and creatinine), as well as plasma levels of IL-6, IL-8, TNF-α and TGF-β, were not affected by MSC transplantation. In our novel, large animal (pig) model of repeated biliary obstruction followed by partial hepatectomy, MSC transplantation promoted growth of liver tissue without any effect on liver function. This study underscores the importance of translating results between small and large animal models as well as the careful translation of results from animal model into human medicine.
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10
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Choi JS, Park YJ, Kim SW. Three-dimensional Differentiated Human Mesenchymal Stem Cells Exhibit Robust Antifibrotic Potential and Ameliorates Mouse Liver Fibrosis. Cell Transplant 2021; 30:963689720987525. [PMID: 33555212 PMCID: PMC7876751 DOI: 10.1177/0963689720987525] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Recently, three-dimensional (3D)-cultured adipose mesenchymal stem cells (ASCs)
have provided an effective therapy for liver fibrosis. This study aimed to
enhance the potential of human ASCs for antifibrosis or hepatocyte regeneration
using a 3D culture system and investigate their therapeutic mechanism in
experimental liver fibrosis. ASC-3Dc were generated in a 3D culture system and
stimulated with four growth factors, namely epidermal growth factor,
insulin-like growth factor (IGF)-1, fibroblast growth factor-2, and vascular
endothelial growth factor-A. The expression levels of antifibrotic or hepatic
regeneration factors were then measured using quantitative real-time polymerase
chain reaction and enzyme-linked immunosorbent assay. The therapeutic effects of
ASC-3Dc were determined using a liver fibrosis model induced by thioacetamide.
Histological analysis was performed to elucidate the therapeutic mechanism.
ASC-3Dc exhibited high levels of hepatocyte growth factor (HGF), IGF-1, stromal
cell-derived factor (SDF)-1 genes, and protein expression. In addition,
injecting ASC-3Dc significantly prevented hepatic fibrosis and improved liver
function in vivo. Moreover, high numbers of ki-67-expressing hepatocytes were
detected in the ASC-3Dc-injected livers. Albumin-expressing ASC-3Dc engrafted in
fibrotic livers augmented HGF expression. Thus, short-term 3D-cultured ASCs may
be a novel alternative to the conventional treatment for liver damage in
clinical settings.
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Affiliation(s)
- Ja Sung Choi
- Department of Internal Medicine, Catholic Kwandong University College of Medicine, International St. Mary's Hospital, Incheon, Republic of Korea.,Both the authors contributed equally to this article
| | - Young-Jin Park
- Department of Family Medicine, Dong-A University College of Medicine, Dong-A University Medical Center, Busan, Republic of Korea.,Both the authors contributed equally to this article
| | - Sung-Whan Kim
- Department of Medicine, College of Medicine, Catholic Kwandong University, Gangneung, Republic of Korea
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Abstract
Hepatic fibrosis is a complex mechanism defined by the net deposition of the extracellular matrix (ECM) owing to liver injury caused by multiple etiologies such as viral hepatitis and nonalcoholic fatty liver disease. Many cell types are implicated in liver fibrosis development and progression. In general, liver fibrosis starts with the recruitment of inflammatory immune cells to generate cytokines, growth factors, and other activator molecules. Such chemical mediators drive the hepatic stellate cells (HSCs) to activate the production of the ECM component. The activation of HSC is thus a crucial event in the fibrosis initiation, and a significant contributor to collagen deposition (specifically type I). This review explores the causes and mechanisms of hepatic fibrosis and focuses on the roles of key molecules involved in liver fibro genesis, some of which are potential targets for therapeutics to hamper liver fibro genesis.
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Affiliation(s)
- Reham M Dawood
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
| | - Mai A El-Meguid
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
| | - Ghada Maher Salum
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
| | - Mostafa K El Awady
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
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12
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Khalil MR, El-Demerdash RS, Elminshawy HH, Mehanna ET, Mesbah NM, Abo-Elmatty DM. Therapeutic effect of bone marrow mesenchymal stem cells in a rat model of carbon tetrachloride induced liver fibrosis. Biomed J 2020; 44:598-610. [PMID: 32389821 PMCID: PMC8640564 DOI: 10.1016/j.bj.2020.04.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 10/30/2019] [Accepted: 04/29/2020] [Indexed: 02/07/2023] Open
Abstract
Background Liver fibrosis is a major medical problem with high mortality and morbidity rates where the formation of regenerative nodules and cirrhosis leads to loss of liver function and may result in the development of hepatocellular carcinoma. bone marrow mesenchymal stem cells (BM-MSCs) have drawn attention as a novel approach for treatment of liver fibrosis. This study aimed to evaluate the therapeutic effect of BM-MSCs on the liver structure in carbon tetrachloride (CCl4) induced liver fibrosis in male rats relative to resveratrol and Silybum marianum as standard drugs derived from herbal plants. Methods Fifty adult male albino rats (Sprague Dawley strain; 180–220 g mean body weight) were purchased from the Laboratory Animal Unit in the Nile Center of Experimental Research, Mansoura, Egypt. Liver function were determined, isolation and preparation of BM- MSCs and detection of cell-surface markers by flow cytometry. Results Animals exposed to CCl4 developed liver injury characterized by significant increase of liver enzymes, malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), and CYP450, inhibition of antioxidant enzymes, and decreased albumin. Treatment with stem cells enhanced liver state more effectively than resveratrol and S. marianum. It significantly decreased AST, ALT, ALP, MDA, TNF-α, and CYP450 and increased albumin, SOD, GSH, GST, and CAT. Histopathological study and atomic force microscope results confirmed the therapeutic effects of MSCs. Conclusions BM-MSCs could restore liver structure and function in CCL4 induced liver fibrosis rat model, ameliorating the toxicity of CCl4 and improving liver function tests.
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Affiliation(s)
- Mohammed R Khalil
- Department of Biochemistry, Faculty of Pharmacy, Delta University, Damietta, Egypt
| | - Reda S El-Demerdash
- Department of Clinical Pathology, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
| | - Hazem H Elminshawy
- Department of Internal Medicine, Specialized Medical Hospital, Mansoura University, Mansoura, Egypt
| | - Eman T Mehanna
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.
| | - Noha M Mesbah
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt
| | - Dina M Abo-Elmatty
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt
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13
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Zheng W, Yang Y, Sequeira RC, Bishop CE, Atala A, Gu Z, Zhao W. Effects of Extracellular Vesicles Derived from Mesenchymal Stem/Stromal Cells on Liver Diseases. Curr Stem Cell Res Ther 2019; 14:442-452. [PMID: 30854976 DOI: 10.2174/1574888x14666190308123714] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 12/17/2018] [Accepted: 02/13/2019] [Indexed: 12/18/2022]
Abstract
Therapeutic effects of Mesenchymal Stem/Stromal Cells (MSCs) transplantation have been observed in various disease models. However, it is thought that MSCs-mediated effects largely depend on the paracrine manner of secreting cytokines, growth factors, and Extracellular Vesicles (EVs). Similarly, MSCs-derived EVs also showed therapeutic benefits in various liver diseases through alleviating fibrosis, improving regeneration of hepatocytes, and regulating immune activity. This review provides an overview of the MSCs, their EVs, and their therapeutic potential in treating various liver diseases including liver fibrosis, acute and chronic liver injury, and Hepatocellular Carcinoma (HCC). More specifically, the mechanisms by which MSC-EVs induce therapeutic benefits in liver diseases will be covered. In addition, comparisons between MSCs and their EVs were also evaluated as regenerative medicine against liver diseases. While the mechanisms of action and clinical efficacy must continue to be evaluated and verified, MSCs-derived EVs currently show tremendous potential and promise as a regenerative medicine treatment for liver disease in the future.
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Affiliation(s)
- Wenjie Zheng
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China.,Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences, Medical Center Blvd, Winston-Salem, NC 27157, United States
| | - Yumin Yang
- Co-Innovation Center of Neuro-regeneration, Nantong University, Nantong, Jiangsu 226001, China
| | - Russel Clive Sequeira
- Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences, Medical Center Blvd, Winston-Salem, NC 27157, United States
| | - Colin E Bishop
- Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences, Medical Center Blvd, Winston-Salem, NC 27157, United States
| | - Anthony Atala
- Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences, Medical Center Blvd, Winston-Salem, NC 27157, United States
| | - Zhifeng Gu
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China
| | - Weixin Zhao
- Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences, Medical Center Blvd, Winston-Salem, NC 27157, United States
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14
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Kuse Y, Taniguchi H. Present and Future Perspectives of Using Human-Induced Pluripotent Stem Cells and Organoid Against Liver Failure. Cell Transplant 2019; 28:160S-165S. [PMID: 31838891 PMCID: PMC7016460 DOI: 10.1177/0963689719888459] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Organ failure manifests severe symptoms affecting the whole body that may cause death. However, the number of organ donors is not enough for patients requiring transplantation worldwide. Illegal transplantation is also sometimes conducted. To help address this concern, primary hepatocytes are clinically transplanted in the liver. However, donor shortage and host rejection via instant blood-mediated inflammatory reactions are worrisome. Induced pluripotent stem cell-derived hepatocyte-like cells have been developed as an alternative treatment. Recently, organoid technology has been developed to investigate the pathology and mechanism of organoids in cultures. Organoids can be transplanted with vascularization and connected to host blood vessels, and functionally mature better in vivo than in vitro. Hepatic organoids improve pathology in liver disease models. In this review, we introduce induced pluripotent stem cell- and organoid-based therapies against liver diseases considering present and future perspectives.
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Affiliation(s)
- Yoshiki Kuse
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Japan
| | - Hideki Taniguchi
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Japan.,Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Japan
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15
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Rockel JS, Rabani R, Viswanathan S. Anti-fibrotic mechanisms of exogenously-expanded mesenchymal stromal cells for fibrotic diseases. Semin Cell Dev Biol 2019; 101:87-103. [PMID: 31757583 DOI: 10.1016/j.semcdb.2019.10.014] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 10/11/2019] [Accepted: 10/30/2019] [Indexed: 12/17/2022]
Abstract
Most chronic diseases involving inflammation have a fibrotic component that involves remodeling and excess accumulation of extracellular matrix components. Left unchecked, fibrosis leads to organ failure and death. Mesenchymal stromal cells (MSCs) are emerging as a potent cell-based therapy for a wide spectrum of fibrotic conditions due to their immunomodulatory, anti-inflammatory and anti-fibrotic properties. This review provides an overview of known mechanisms by which MSCs mediate their anti-fibrotic actions and in relation to animal models of pulmonary, liver, renal and cardiac fibrosis. Recent MSC clinical trials results in liver, lung, skin, kidney and hearts are discussed and next steps for future MSC-based therapies including pre-activated or genetically-modified cells, or extracellular vesicles are also considered.
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Affiliation(s)
- Jason S Rockel
- Arthritis Program, University Health Network, Toronto, ON, Canada; Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON, Canada.
| | - Razieh Rabani
- Arthritis Program, University Health Network, Toronto, ON, Canada; Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Sowmya Viswanathan
- Arthritis Program, University Health Network, Toronto, ON, Canada; Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada; Division of Hematology, Department of Medicine, University of Toronto, Toronto, Canada
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16
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Zagoura D, Trohatou O, Makridakis M, Kollia A, Kokla N, Mokou M, Psaraki A, Eliopoulos AG, Vlahou A, Roubelakis MG. Functional secretome analysis reveals Annexin-A1 as important paracrine factor derived from fetal mesenchymal stem cells in hepatic regeneration. EBioMedicine 2019; 45:542-552. [PMID: 31303498 PMCID: PMC6642415 DOI: 10.1016/j.ebiom.2019.07.009] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 06/21/2019] [Accepted: 07/03/2019] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Human mesenchymal stem/stromal cells (MSCs) and their secreted molecules exert beneficial effects in injured tissues by promoting tissue regeneration and angiogenesis and by inhibiting inflammation and fibrosis. We have previously demonstrated that the therapeutic activity of fetal MSCs derived from amniotic fluid (AF-MSCs) and their hepatic progenitor-like cells (HPL) is mediated by paracrine effects in a mouse model of acute hepatic failure (AHF). METHODS Herein, we have combined proteomic profiling of the AF-MSCs and HPL cell secretome with ex vivo and in vivo functional studies to identify specific soluble factors, which underpin tissue regeneration in AHF. FINDINGS The anti-inflammatory molecule Annexin-A1 (ANXA1) was detected at high levels in both AF-MSC and HPL cell secretome. Further functional analyses revealed that the shRNA-mediated knock-down of ANXA1 in MSCs (shANXA1-MSCs) decreased their proliferative, clonogenic and migratory potential, as well as their ability to differentiate into HPL cells. Liver progenitors (oval cells) from AHF mice displayed reduced proliferation when cultured ex vivo in the presence of conditioned media from shANXA1-MSCs compared to control MSCs secretome. Intra-hepatic delivery of conditioned media from control MSCs but not shANXA1-MSCs reduced liver damage and circulating levels of pro-inflammatory cytokines in AHF. INTERPRETATION Collectively, our study uncovers secreted Annexin-A1 as a novel effector of MSCs in liver regeneration and further underscores the potential of cell-free therapeutic strategies for liver diseases. FUND: Fondation Santé, GILEAD Asklipeios Grant, Fellowships of Excellence - Siemens, IKY, Reinforcement of Postdoctoral Researchers, IKY.
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Affiliation(s)
- Dimitra Zagoura
- Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Ourania Trohatou
- Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Manousos Makridakis
- Biotechnology Laboratory, Centre of Basic Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece
| | - Antonia Kollia
- Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Nikolitsa Kokla
- Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Marika Mokou
- Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; Biotechnology Laboratory, Centre of Basic Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece
| | - Adriana Psaraki
- Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Aristides G Eliopoulos
- Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; Centre of Basic Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), Greece
| | - Antonia Vlahou
- Biotechnology Laboratory, Centre of Basic Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece
| | - Maria G Roubelakis
- Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; Centre of Basic Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), Greece.
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17
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Mesenchymal Stem Cells for Liver Regeneration in Liver Failure: From Experimental Models to Clinical Trials. Stem Cells Int 2019; 2019:3945672. [PMID: 31191671 PMCID: PMC6525815 DOI: 10.1155/2019/3945672] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 03/05/2019] [Accepted: 03/20/2019] [Indexed: 02/07/2023] Open
Abstract
The liver centralizes the systemic metabolism and thus controls and modulates the functions of the central and peripheral nervous systems, the immune system, and the endocrine system. In addition, the liver intervenes between the splanchnic and systemic venous circulation, determining an abdominal portal circulatory system. The liver displays a powerful regenerative potential that rebuilds the parenchyma after an injury. This regenerative mission is mainly carried out by resident liver cells. However, in many cases this regenerative capacity is insufficient and organ failure occurs. In normal livers, if the size of the liver is at least 30% of the original volume, hepatectomy can be performed safely. In cirrhotic livers, the threshold is 50% based on current practice and available data. Typically, portal vein embolization of the part of the liver that is going to be resected is employed to allow liver regeneration in two-stage liver resection after portal vein occlusion (PVO). However, hepatic resection often cannot be performed due to advanced disease progression or because it is not indicated in patients with cirrhosis. In such cases, liver transplantation is the only treatment possibility, and the need for transplantation is the common outcome of progressive liver disease. It is the only effective treatment and has high survival rates of 83% after the first year. However, donated organs are becoming less available, and mortality and the waiting lists have increased, leading to the initiation of living donor liver transplantations. This type of transplant has overall complications of 38%. In order to improve the treatment of hepatic injury, much research has been devoted to stem cells, in particular mesenchymal stem cells (MSCs), to promote liver regeneration. In this review, we will focus on the advances made using MSCs in animal models, human patients, ongoing clinical trials, and new strategies using 3D organoids.
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18
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Aithal AP, Bairy LK, Seetharam RN, Rao MK. Human bone marrow-derived mesenchymal stromal cells in combination with silymarin regulate hepatocyte growth factor expression and genotoxicity in carbon tetrachloride induced hepatotoxicity in Wistar rats. J Cell Biochem 2019; 120:13026-13036. [PMID: 30873677 DOI: 10.1002/jcb.28573] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 01/23/2019] [Accepted: 01/24/2019] [Indexed: 12/31/2022]
Abstract
BACKGROUND To evaluate the antimutagenic potential of combination treatment of human bone marrow-derived mesenchymal stromal cells (BM-MSCs) and silymarin and its effect on hepatocyte growth factor levels in CCl4 induced hepatotoxicity in Wistar rats. METHODS Hepatotoxicity was induced in adult female Wistar rats using carbon tetrachloride (CCl4 ). Thirty-six rats were randomly divided into six groups with six rats in each group: Group 1 (normal control group), Group 2 (received only CCl 4 ), Group 3 (CCl 4 +low dose BM-MSCs), Group 4 (CCl 4 +high dose BM-MSCs), Group 5 (CCl 4 + silymarin), Group 6 (CCl 4 +silymarin+high dose BM-MSCs). Thirty days after the treatment, blood samples were collected for hepatocyte growth factor estimation. The rats were then killed, bone marrow was extracted for chromosomal aberration assay. Liver tissue was processed for evaluating the DNA fragmentation assay, histopathology, and scanning electron microscopy study. RESULTS Combination treatment of silymarin and high dose BM-MSCs significantly (P < 0.05) restored the plasma hepatocyte growth factor levels which were comparable with normal levels and exhibited significant antimutagenic and antiapoptotic activity by decreasing the frequency of structural chromosomal aberrations and suppressing the DNA fragmentation in liver tissue samples. The combination treatment produced significant hepatoprotective effect which was supported by histopathology and scanning electron microscopy study. CONCLUSION Results indicate that the treatment of BM-MSCs in combination with silymarin had a better hepatoprotective and antimutagenic effect and represents a novel strategy for the treatment of hepatotoxicity.
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Affiliation(s)
- Ashwini P Aithal
- Department of Anatomy, Melaka Manipal Medical College (Manipal Campus), Manipal Academy of Higher Education, Manipal, India
| | - Laxminarayana K Bairy
- Department of Pharmacology, RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras Al Khaimah, UAE
| | | | - Mohandas Kg Rao
- Department of Anatomy, Melaka Manipal Medical College (Manipal Campus), Manipal Academy of Higher Education, Manipal, India
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19
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Salehi-pourmehr H, Rahbarghazi R, Mahmoudi J, Roshangar L, Chapple CR, Hajebrahimi S, Abolhasanpour N, Azghani MR. Intra-bladder wall transplantation of bone marrow mesenchymal stem cells improved urinary bladder dysfunction following spinal cord injury. Life Sci 2019; 221:20-28. [PMID: 30735734 DOI: 10.1016/j.lfs.2019.02.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 01/25/2019] [Accepted: 02/04/2019] [Indexed: 12/14/2022]
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20
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Choi JS, Jeong IS, Han JH, Cheon SH, Kim SW. IL-10-secreting human MSCs generated by TALEN gene editing ameliorate liver fibrosis through enhanced anti-fibrotic activity. Biomater Sci 2019; 7:1078-1087. [DOI: 10.1039/c8bm01347k] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Interleukin 10 secreting genome-edited MSCs inhibited liver fibrosis and ameliorated abnormal liver function.
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Affiliation(s)
- Ja Sung Choi
- Department of Internal Medicine
- Catholic Kwandong University College of Medicine
- International St. Mary's Hospital
- Incheon
- Republic of Korea
| | - In Sil Jeong
- Department Medicine
- Catholic Kwandong University College of Medicine
- Gangneung
- Republic of Korea
| | - Ju Hye Han
- Department Medicine
- Catholic Kwandong University College of Medicine
- Gangneung
- Republic of Korea
| | - Sae Hee Cheon
- Department of Dental Hygiene
- Masan University
- Masan
- Korea
| | - Sung-Whan Kim
- Department Medicine
- Catholic Kwandong University College of Medicine
- Gangneung
- Republic of Korea
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21
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Yanagawa T, Sumiyoshi H, Higashi K, Nakao S, Higashiyama R, Fukumitsu H, Minakawa K, Chiba Y, Suzuki Y, Sumida K, Saito K, Kamiya A, Inagaki Y. Identification of a Novel Bone Marrow Cell-Derived Accelerator of Fibrotic Liver Regeneration Through Mobilization of Hepatic Progenitor Cells in Mice. Stem Cells 2018; 37:89-101. [PMID: 30270488 DOI: 10.1002/stem.2916] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 08/21/2018] [Accepted: 09/01/2018] [Indexed: 12/14/2022]
Abstract
Granulocyte colony stimulating factor (G-CSF) has been reported to ameliorate impaired liver function in patients with advanced liver diseases through mobilization and proliferation of hepatic progenitor cells (HPCs). However, the underlying mechanisms remain unknown. We previously showed that G-CSF treatment increased the number of bone marrow (BM)-derived cells migrating to the fibrotic liver following repeated carbon tetrachloride (CCl4 ) injections into mice. In this study, we identified opioid growth factor receptor-like 1 (OGFRL1) as a novel BM cell-derived accelerator of fibrotic liver regeneration in response to G-CSF treatment. Endogenous Ogfrl1 was highly expressed in the hematopoietic organs such as the BM and spleen, whereas the liver contained a relatively small amount of Ogfrl1 mRNA. Among the peripheral blood cells, monocytes were the major sources of OGFRL1. Endogenous Ogfrl1 expression in both the peripheral blood monocytes and the liver was decreased following repeated CCl4 injections. An intrasplenic injection of cells overexpressing OGFRL1 into CCl4 -treated fibrotic mice increased the number of HPC and stimulated proliferation of hepatic parenchymal cells after partial resection of the fibrotic liver. Furthermore, overexpression of OGFRL1 in cultured HPC accelerated their differentiation as estimated by increased expression of liver-specific genes such as hepatocyte nuclear factor 4α, cytochrome P450, and fatty acid binding protein 1, although it did not affect the colony forming ability of HPC. These results indicate a critical role of OGFRL1 in the mobilization and differentiation of HPC in the fibrotic liver, and administration of OGFRL1-expressing cells may serve as a potential regenerative therapy for advanced liver fibrosis. Stem Cells 2019;37:89-101.
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Affiliation(s)
- Takayo Yanagawa
- Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Japan.,Department of Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Hideaki Sumiyoshi
- Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Japan.,Department of Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Kiyoshi Higashi
- Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd., Osaka, Japan
| | - Sachie Nakao
- Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Japan.,Department of Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Reiichi Higashiyama
- Department of Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Hiroshi Fukumitsu
- Department of Surgery, Tokai University School of Medicine, Isehara, Japan
| | - Kaori Minakawa
- Department of Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Yosuke Chiba
- Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Japan
| | - Yuhei Suzuki
- Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Japan
| | - Kayo Sumida
- Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd., Osaka, Japan
| | - Koichi Saito
- Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd., Osaka, Japan
| | - Akihide Kamiya
- Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Japan.,Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Japan
| | - Yutaka Inagaki
- Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Japan.,Department of Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan.,Institute of Medical Sciences, Tokai University, Isehara, Japan
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22
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Farouk S, Sabet S, Abu Zahra FA, El-Ghor AA. Bone marrow derived-mesenchymal stem cells downregulate IL17A dependent IL6/STAT3 signaling pathway in CCl4-induced rat liver fibrosis. PLoS One 2018; 13:e0206130. [PMID: 30346985 PMCID: PMC6197688 DOI: 10.1371/journal.pone.0206130] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Accepted: 10/08/2018] [Indexed: 12/20/2022] Open
Abstract
Therapeutic potential of bone marrow–derived mesenchymal stem cells (BM-MSCs) has been reported in several animal models of liver fibrosis. Interleukin (IL) 17A, IL6 and Stat3 have been described to play crucial roles in chronic liver injury. However, the modulatory effect of MSCs on these markers was controversial in different diseases. BM-MSCs might activate the IL6/STAT3 signaling pathway and promote cell invasion in hepatocellular carcinoma, but the immunomodulatory role of BM-MSCs on IL17A/IL6/STAT3 was not fully elucidated in liver fibrosis. In the present study, we evaluated the capacity of the BM-MSCs in the modulation of cytokines milieu and signal transducers, based on unique inflammatory genes Il17a and Il17f and their receptors Il17rc and their effect on the IL6/STAT3 pathway in CCl4-induced liver fibrosis in rats. A single dose of BM-MSCs was administered to the group with induced liver fibrosis, and the genes and proteins of interest were evaluated along six weeks after treatment. Our results showed a significant downregulation of Il17a, Il17ra, il17f and Il17rc genes. In accordance, BM-MSCs administration declined IL17, IL2 and IL6 serum proteins and downregulated IL17A and IL17RA proteins in liver tissue. Interestingly, BM-MSCs downregulated both Stat3 mRNA expression and p-STAT3, while Stat5a gene was downregulated and p-STAT5 protein was elevated. Also P-SMAD3 and TGFβR2 proteins were downregulated in response to BM-MSCs treatment. Collectively, we suggest that BM-MSCs might play an immunomodulatory role in the treatment of liver fibrosis through downregulation of IL17A affecting IL6/STAT3 signaling pathway.
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Affiliation(s)
- Shimaa Farouk
- Department of Biology and Biotechnologies, Faculty of Science & Technology, AL-Neelain University, Khartoum, Sudan
| | - Salwa Sabet
- Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt
- * E-mail:
| | - Fatma A. Abu Zahra
- Medical Research Center, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Akmal A. El-Ghor
- Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt
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23
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Hegab MH, Abd-Allah SH, Badawey MS, Saleh AA, Metwally AS, Fathy GM, Nada SM, Abdel-Rahman SA, Saleh AA, Fawzy A, El-Magd MA. Therapeutic potential effect of bone marrow-derived mesenchymal stem cells on chronic liver disease in murine Schistosomiasis Mansoni. J Parasit Dis 2018; 42:277-286. [PMID: 29844633 DOI: 10.1007/s12639-018-0997-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 04/11/2018] [Indexed: 12/11/2022] Open
Abstract
Some reports have shown that mesenchymal stem cells (MSCs) therapy could ameliorate chemically-induced hepatic fibrosis. This research assesses the therapeutic action of bone marrow mesenchymal stem cells (BM-MSCs) on chronic diseased liver in Schistosoma mansoni infected mice. All infected female mice divided into three groups, one group (15 mice) treated with oral praziquantel (PZQ), second group (15 mice) received intravenous injection of BM-MSCs and third group (15 mice) treated with both MSCs + PZQ. Two control groups (15 mice each) subdivided into one infected and second healthy one. BM-MSCs were obtained from bones of both femur and tibia of male mice (30 mice), then cultured and characterized morphologically by detection of CD105 by flow cytometer. Liver tissues for all groups were examined histopathologically. Measuring of the collagen 1 gene expression was done by real-time PCR and immunohistochemical study to detect stem cells differentiation for detection of MSCs engraftments in liver tissue. MSCs treatment caused marked improvement and regression of fibrosis, and prevents deposition of collagen and reduced the expression of collagen 1 gene in infected mice on their liver tissues, especially when used with PZQ in mice treatment. It can be concluded that, MSCs is a good therapeutic method for liver fibrosis caused by S. mansoni infection.
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Affiliation(s)
- Mohamed H Hegab
- 1Department of Parasitology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Somia H Abd-Allah
- 2Department of Biochemistry, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Maha S Badawey
- 1Department of Parasitology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Ayman A Saleh
- 3Department of Animal Wealth Development, Genetics & Genetic Engineering, of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Ashraf S Metwally
- 1Department of Parasitology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Ghada M Fathy
- 1Department of Parasitology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Soad M Nada
- 1Department of Parasitology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Sara A Abdel-Rahman
- 1Department of Parasitology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Amira A Saleh
- 1Department of Parasitology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Amal Fawzy
- 2Department of Biochemistry, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Mohammed Abu El-Magd
- 4Department of Anatomy & Embryology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh, Egypt
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Proceedings of the signature series event of the international society for cellular therapy: "Advancements in cellular therapies and regenerative medicine in digestive diseases," London, United Kingdom, May 3, 2017. Cytotherapy 2018; 20:461-476. [PMID: 29398624 DOI: 10.1016/j.jcyt.2017.12.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Accepted: 12/01/2017] [Indexed: 12/18/2022]
Abstract
A summary of the First Signature Series Event, "Advancements in Cellular Therapies and Regenerative Medicine for Digestive Diseases," held on May 3, 2017, in London, United Kingdom, is presented. Twelve speakers from three continents covered major topics in the areas of cellular therapy and regenerative medicine applied to liver and gastrointestinal medicine as well as to diabetes mellitus. Highlights from their presentations, together with an overview of the global impact of digestive diseases and a proposal for a shared online collection and data-monitoring platform tool, are included in this proceedings. Although growing evidence demonstrate the feasibility and safety of exploiting cell-based technologies for the treatment of digestive diseases, regulatory and methodological obstacles will need to be overcome before the successful implementation in the clinic of these novel attractive therapeutic strategies.
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Current Perspectives Regarding Stem Cell-Based Therapy for Liver Cirrhosis. Can J Gastroenterol Hepatol 2018; 2018:4197857. [PMID: 29670867 PMCID: PMC5833156 DOI: 10.1155/2018/4197857] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 01/16/2018] [Indexed: 12/12/2022] Open
Abstract
Liver cirrhosis is a major cause of mortality and a common end of various progressive liver diseases. Since the effective treatment is currently limited to liver transplantation, stem cell-based therapy as an alternative has attracted interest due to promising results from preclinical and clinical studies. However, there is still much to be understood regarding the precise mechanisms of action. A number of stem cells from different origins have been employed for hepatic regeneration with different degrees of success. The present review presents a synopsis of stem cell research for the treatment of patients with liver cirrhosis according to the stem cell type. Clinical trials to date are summarized briefly. Finally, issues to be resolved and future perspectives are discussed with regard to clinical applications.
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Reversal of Experimental Liver Damage after Transplantation of Stem-Derived Cells Detected by FTIR Spectroscopy. Stem Cells Int 2017; 2017:4585169. [PMID: 29445403 PMCID: PMC5763141 DOI: 10.1155/2017/4585169] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 08/23/2017] [Accepted: 09/10/2017] [Indexed: 01/09/2023] Open
Abstract
The transplantation of autologous BM-MSCs holds great potential for treating end-stage liver diseases. The aim of this study was to compare the efficiency of transplanted rBM-MSCs and rBM-MSC-derived differentiated stem cells (rBM-MSC-DSCs) for suppression of dimethylnitrosamine-injured liver damage in rat model. Synchrotron radiation Fourier-transform infrared (SR-FTIR) microspectroscopy was applied to investigate changes in the macromolecular composition. Transplantation of rBM-MSC-DSCs into liver-injured rats restored their serum albumin level and significantly suppressed transaminase activity as well as the morphological manifestations of liver disease. The regenerative effects of rBM-MSC-DSCs were corroborated unequivocally by the phenotypic difference analysis between liver tissues revealed by infrared spectroscopy. Spectroscopic changes in the spectral region from 1190–970 cm−1 (bands with absorbance maxima at 1150 cm−1, 1081 cm−1, and 1026 cm−1) indicated decreased levels of carbohydrates, in rBM-MSC-DSC-transplanted livers, compared with untreated and rBM-MSC--transplanted animals. Principal component analysis (PCA) of spectra acquired from liver tissue could readily discriminate rBM-MSC-DSC-transplanted animals from the untreated and rBM-MSC-transplanted animals. We conclude that the transplantation of rBM-MSC-DSCs effectively treats liver disease in rats and SR-FTIR microspectroscopy provides important insights into the fundamental biochemical alterations induced by the stem-derived cell transplantation, including an objective “signature” of the regenerative effects of stem cell therapy upon liver injury.
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Wang H, Zhang H, Huang B, Miao G, Yan X, Gao G, Luo Y, Chen H, Chen W, Yang L. Mesenchymal stem cells reverse high‑fat diet‑induced non‑alcoholic fatty liver disease through suppression of CD4+ T lymphocytes in mice. Mol Med Rep 2017; 17:3769-3774. [PMID: 29286155 DOI: 10.3892/mmr.2017.8326] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 03/27/2017] [Indexed: 12/14/2022] Open
Abstract
Although the multipotency of mesenchymal stem cells (MSCs) makes them an attractive choice for clinical applications, immune modulation is an important factor affecting MSC transplantation. At present, the effect of treatment with MSCs on non‑alcoholic fatty liver disease (NAFLD) has received little attention. In the present study, a compact bone‑derived method was used to isolate mouse MSCs (mMSCs) and a high‑fat diet was used to establish a mouse model of NAFLD. Immunophenotypic features of mMSCs were analyzed using flow cytometry. Paraffin sections were stained with hematoxylin and eosin to assess inflammation and steatosis, and with picrosirius red to assess fibrosis. Spleen leukocytes were analyzed by flow cytometry. The results demonstrated that compact bone‑derived MSC transplantation decreased high‑fat diet‑induced weight gain, expansion of subcutaneous adipose tissue, steatosis, lobular inflammation and liver fibrogenesis. Flow cytometry analysis of spleen leukocytes demonstrated that compact bone‑derived MSC transplantation suppressed the proliferation of cluster of differentiation (CD) 4+ T lymphocytes in the spleen, which had been induced by the high‑fat diet. In conclusion, compact bone‑derived MSCs may exhibit clinical value in the treatment of NAFLD through their capacity to suppress the activation of CD4+ T cells.
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Affiliation(s)
- Huafeng Wang
- Modern College of Arts and Science and School of Life Science, Shanxi Normal University, Linfen, Shanxi 041004, P.R. China
| | - Huan Zhang
- Clinical Laboratory, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin 300120, P.R. China
| | - Biao Huang
- Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Guolin Miao
- Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Xiaoyan Yan
- Modern College of Arts and Science and School of Life Science, Shanxi Normal University, Linfen, Shanxi 041004, P.R. China
| | - Gang Gao
- Modern College of Arts and Science and School of Life Science, Shanxi Normal University, Linfen, Shanxi 041004, P.R. China
| | - Yongping Luo
- Modern College of Arts and Science and School of Life Science, Shanxi Normal University, Linfen, Shanxi 041004, P.R. China
| | - Huize Chen
- Modern College of Arts and Science and School of Life Science, Shanxi Normal University, Linfen, Shanxi 041004, P.R. China
| | - Wei Chen
- Modern College of Arts and Science and School of Life Science, Shanxi Normal University, Linfen, Shanxi 041004, P.R. China
| | - Luhong Yang
- Modern College of Arts and Science and School of Life Science, Shanxi Normal University, Linfen, Shanxi 041004, P.R. China
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Brückner S, Zipprich A, Hempel M, Thonig A, Schwill F, Roderfeld M, Roeb E, Christ B. Improvement of portal venous pressure in cirrhotic rat livers by systemic treatment with adipose tissue–derived mesenchymal stromal cells. Cytotherapy 2017; 19:1462-1473. [DOI: 10.1016/j.jcyt.2017.09.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 09/01/2017] [Accepted: 09/05/2017] [Indexed: 02/07/2023]
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Gazdic M, Arsenijevic A, Markovic BS, Volarevic A, Dimova I, Djonov V, Arsenijevic N, Stojkovic M, Volarevic V. Mesenchymal Stem Cell-Dependent Modulation of Liver Diseases. Int J Biol Sci 2017; 13:1109-1117. [PMID: 29104502 PMCID: PMC5666326 DOI: 10.7150/ijbs.20240] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 05/27/2017] [Indexed: 12/14/2022] Open
Abstract
Acute liver failure and cirrhosis display sequential and overlapping severe pathogenic processes that include inflammation, hepatocyte necrosis, and fibrosis, carrying a high mortality rate. Mesenchymal stem cells (MSCs) are a heterogeneous subset of stromal stem cells with immunonodulatory characteristics. MSCs are considered to act through multiple mechanisms to coordinate a dynamic, integrated response to liver inflammation and fibrosis, which prevents the progressive distortion of hepatic architecture. Accordingly, MSCs as well as their products have been investigated as a novel therapeutic approach for the treatment of inflammatory and fibrotic liver diseases. In this review, we highlight the current findings on the MSC-based modulation of liver inflammation and fibrosis, and the possible use of MSCs in the therapy of immune-mediated liver pathology. We briefly describe the cellular and molecular mechanisms involved in MSC-dependent modulation of cytokine production, phenotype and function of liver infiltrated inflammatory cells and compare effects of engrafted MSCs versus MSC-generated conditioned medium (MSC-CM) in the therapy of acute liver injury. In order to elucidate therapeutic potential of MSCs and their products in modulation of chronic liver inflammation and fibrosis, we present the current findings regarding pathogenic role of immune cells in liver fibrosis and describe mechanisms involved in MSC-dependent modulation of chronic liver inflammation with the brief overview of on-going and already published clinical trials that used MSCs for the treatment of immune mediated chronic liver diseases. The accumulating evidence shows that MSCs had a significant beneficial effect in the treatment of immune-mediated liver diseases.
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Affiliation(s)
- Marina Gazdic
- University of Kragujevac, Serbia, Faculty of Medical Sciences, Department of Genetics
| | - Aleksandar Arsenijevic
- University of Kragujevac, Serbia, Faculty of Medical Sciences, Department of Microbiology and immunology, Center for Molecular Medicine and Stem Cell Research
| | - Bojana Simovic Markovic
- University of Kragujevac, Serbia, Faculty of Medical Sciences, Department of Microbiology and immunology, Center for Molecular Medicine and Stem Cell Research
| | - Ana Volarevic
- University of Kragujevac, Serbia, Faculty of Medical Sciences, Department of Microbiology and immunology, Center for Molecular Medicine and Stem Cell Research
| | - Ivanka Dimova
- Department of medical genetics, Medical University Sofia, Sofia, Bulgaria
| | | | - Nebojsa Arsenijevic
- University of Kragujevac, Serbia, Faculty of Medical Sciences, Department of Microbiology and immunology, Center for Molecular Medicine and Stem Cell Research
| | - Miodrag Stojkovic
- University of Kragujevac, Serbia, Faculty of Medical Sciences, Department of Genetics.,Spebo Medical, Leskovac, Serbia
| | - Vladislav Volarevic
- University of Kragujevac, Serbia, Faculty of Medical Sciences, Department of Microbiology and immunology, Center for Molecular Medicine and Stem Cell Research
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30
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Almasry SM, Elfayomy AK, El-Sherbiny MH. Regeneration of the Fallopian Tube Mucosa Using Bone Marrow Mesenchymal Stem Cell Transplantation After Induced Chemical Injury in a Rat Model. Reprod Sci 2017; 25:773-781. [PMID: 28826366 DOI: 10.1177/1933719117725824] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In this study, we describe a novel insight about the use of bone marrow-derived mesenchymal stem cells (BM-MSCs) for fallopian tube (FT) regeneration. Seventy rats' tubes were involved in this study and divided into 4 groups: control (15), ethanol injured (20), mesenchymal stem cell (MSC)-recipient without injury (15), and MSC recipient after injury (20). The BM-MSCs were isolated from male rats, and their incorporation into the tissues was confirmed by the detection of Sry gene in MSC-recipient rats using RT-PCR. Histological and immunohistological sections of the 4 groups were comparably evaluated. We found that direct injection of ethanol into FT caused structural impairment, which was restored largely after receiving MSCs. We have revealed for the first time that prominin 1 (Prom1, stem cell marker) was expressed in the fimbriated distal tubal end. The MSC transplantation caused (1) significant increase in the tissue level and immunoexpresstion of Prom1 ( P < .001 and P = .017, respectively) and vascular endothelial growth factor (VEGF; vasculogenic marker; P < .001 and P = .004, respectively), (2) significant increase in the immunoexpresstion of proliferating cell nuclear antigen (PCNA; proliferation marker; P < .001), and (3) significant decrease in the immunoexpresstion of caspase 3 (CASP-3; apoptotic marker; P < .001) compared to the injured tissues. In conclusion, MSCs could exhibit its restorative effect on FT through their ability to (1) activate the resident stem cells in the distal tubal end, (2) mediate the expression of VEGF and PCNA, and (3) influence tissue apoptosis. This study laid the foundation for assessing the contribution of stem cells in the distal tubal end in direct repair of the tube when required to assist reproduction.
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Affiliation(s)
- Shaima M Almasry
- 1 Department of Anatomy, Almansoura University, Egypt.,2 Department of Anatomy, Almadinah Almunawarah, Taibah University, Saudi Arabia
| | - Amr K Elfayomy
- 3 Department of Obstetrics and Gynecology, Zagazig University, Zagazig, Egypt.,4 Department of Obstetrics and Gynecology, Almadinah Almunawarah, Taibah University, Saudi Arabia
| | - Mohamed H El-Sherbiny
- 2 Department of Anatomy, Almadinah Almunawarah, Taibah University, Saudi Arabia.,5 Department of Anatomy, Amaarefa College of Medicine, Riyadh, Saudi Arabia
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31
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Rengasamy M, Singh G, Fakharuzi NA, Siddikuzzaman, Balasubramanian S, Swamynathan P, Thej C, Sasidharan G, Gupta PK, Das AK, Rahman AZA, Fakiruddin KS, Nian LM, Zakaria Z, Majumdar AS. Transplantation of human bone marrow mesenchymal stromal cells reduces liver fibrosis more effectively than Wharton's jelly mesenchymal stromal cells. Stem Cell Res Ther 2017; 8:143. [PMID: 28610623 PMCID: PMC5470281 DOI: 10.1186/s13287-017-0595-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Revised: 03/23/2017] [Accepted: 05/22/2017] [Indexed: 12/17/2022] Open
Abstract
Background Mesenchymal stromal cells (MSCs) from various tissues have shown moderate therapeutic efficacy in reversing liver fibrosis in preclinical models. Here, we compared the relative therapeutic potential of pooled, adult human bone marrow (BM)- and neonatal Wharton’s jelly (WJ)-derived MSCs to treat CCl4-induced liver fibrosis in rats. Methods Sprague-Dawley rats were injected with CCl4 for 8 weeks to induce irreversible liver fibrosis. Ex-vivo expanded, pooled human MSCs obtained from BM and WJ were intravenously administered into rats with liver fibrosis at a dose of 10 × 106 cells/animal. Sham control and vehicle-treated animals served as negative and disease controls, respectively. The animals were sacrificed at 30 and 70 days after cell transplantation and hepatic-hydroxyproline content, histopathological, and immunohistochemical analyses were performed. Results BM-MSCs treatment showed a marked reduction in liver fibrosis as determined by Masson’s trichrome and Sirius red staining as compared to those treated with the vehicle. Furthermore, hepatic-hydroxyproline content and percentage collagen proportionate area were found to be significantly lower in the BM-MSCs-treated group. In contrast, WJ-MSCs treatment showed less reduction of fibrosis at both time points. Immunohistochemical analysis of BM-MSCs-treated liver samples showed a reduction in α-SMA+ myofibroblasts and increased number of EpCAM+ hepatic progenitor cells, along with Ki-67+ and human matrix metalloprotease-1+ (MMP-1+) cells as compared to WJ-MSCs-treated rat livers. Conclusions Our findings suggest that BM-MSCs are more effective than WJ-MSCs in treating liver fibrosis in a CCl4-induced model in rats. The superior therapeutic activity of BM-MSCs may be attributed to their expression of certain MMPs and angiogenic factors.
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Affiliation(s)
- Mathiyazhagan Rengasamy
- Stempeutics Research Pvt Ltd, Akshay Tech Park, EPIP Zone, Phase-1, Whitefield, Bangalore, 560066, Karnataka, India
| | - Gurbind Singh
- Stempeutics Research Pvt Ltd, Akshay Tech Park, EPIP Zone, Phase-1, Whitefield, Bangalore, 560066, Karnataka, India.,Department of Life Sciences, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
| | - Noor Atiqah Fakharuzi
- Hematology Unit, Cancer Research Centre, Institute for Medical Research, Jalan Pahang, 50588, Kuala Lumpur, Malaysia
| | - Siddikuzzaman
- Stempeutics Research Pvt Ltd, Akshay Tech Park, EPIP Zone, Phase-1, Whitefield, Bangalore, 560066, Karnataka, India
| | - Sudha Balasubramanian
- Stempeutics Research Pvt Ltd, Akshay Tech Park, EPIP Zone, Phase-1, Whitefield, Bangalore, 560066, Karnataka, India
| | - Priyanka Swamynathan
- Stempeutics Research Pvt Ltd, Akshay Tech Park, EPIP Zone, Phase-1, Whitefield, Bangalore, 560066, Karnataka, India
| | - Charan Thej
- Stempeutics Research Pvt Ltd, Akshay Tech Park, EPIP Zone, Phase-1, Whitefield, Bangalore, 560066, Karnataka, India.,Manipal University, Manipal, Karnataka, India
| | - Gopinath Sasidharan
- Stempeutics Research Pvt Ltd, Akshay Tech Park, EPIP Zone, Phase-1, Whitefield, Bangalore, 560066, Karnataka, India
| | - Pawan Kumar Gupta
- Stempeutics Research Pvt Ltd, Akshay Tech Park, EPIP Zone, Phase-1, Whitefield, Bangalore, 560066, Karnataka, India
| | - Anjan Kumar Das
- Stempeutics Research Pvt Ltd, Akshay Tech Park, EPIP Zone, Phase-1, Whitefield, Bangalore, 560066, Karnataka, India.,Department of Surgery, Taylor's University School of Medicine, Selangor, Subang Jaya, Malaysia
| | - Ahmad Zuhairi Abd Rahman
- Hematology Unit, Cancer Research Centre, Institute for Medical Research, Jalan Pahang, 50588, Kuala Lumpur, Malaysia
| | - Kamal Shaik Fakiruddin
- Hematology Unit, Cancer Research Centre, Institute for Medical Research, Jalan Pahang, 50588, Kuala Lumpur, Malaysia
| | - Lim Moon Nian
- Hematology Unit, Cancer Research Centre, Institute for Medical Research, Jalan Pahang, 50588, Kuala Lumpur, Malaysia
| | - Zubaidah Zakaria
- Hematology Unit, Cancer Research Centre, Institute for Medical Research, Jalan Pahang, 50588, Kuala Lumpur, Malaysia
| | - Anish S Majumdar
- Stempeutics Research Pvt Ltd, Akshay Tech Park, EPIP Zone, Phase-1, Whitefield, Bangalore, 560066, Karnataka, India.
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32
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Lou G, Yang Y, Liu F, Ye B, Chen Z, Zheng M, Liu Y. MiR-122 modification enhances the therapeutic efficacy of adipose tissue-derived mesenchymal stem cells against liver fibrosis. J Cell Mol Med 2017; 21:2963-2973. [PMID: 28544786 PMCID: PMC5661245 DOI: 10.1111/jcmm.13208] [Citation(s) in RCA: 169] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 03/11/2017] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cell (MSC) transplantation alone may be insufficient for treatment of liver fibrosis because of complicated histopathological changes in the liver. Given that miR‐122 plays an essential role in liver fibrosis by negatively regulating the proliferation and transactivation of hepatic stellate cells (HSCs), this study investigated whether miR‐122 modification can improve the therapeutic efficacy of adipose tissue‐derived MSCs in treating liver fibrosis. MiR‐122‐modified AMSCs (AMSC‐122) were constructed through lentivirus‐mediated transfer of pre‐miR‐122. MiR‐122‐modified AMSCs expressed high level of miR‐122, while they retained their phenotype and differentiation potential as naïve AMSCs. AMSC‐122 more effectively suppressed the proliferation of and collagen maturation in HSCs than scramble miRNA‐modified AMSCs. In addition, AMSC‐derived exosomes mediated the miR‐122 communication between AMSCs and HSCs, further affecting the expression levels of miR‐122 target genes, such as insulin‐like growth factor receptor 1 (IGF1R), Cyclin G(1) (CCNG1) and prolyl‐4‐hydroxylase α1 (P4HA1), which are involved in proliferation of and collagen maturation in HSCs. Moreover, miR‐122 modification enhanced the therapeutic efficacy of AMSCs in the treatment of carbon tetrachloride (CCl4)‐induced liver fibrosis by suppressing the activation of HSCs and alleviating collagen deposition. Results demonstrate that miR‐122 modification improves the therapeutic efficacy of AMSCs through exosome‐mediated miR‐122 communication; thus, miR‐122 modification is a new potential strategy for treatment of liver fibrosis.
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Affiliation(s)
- Guohua Lou
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ying Yang
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Feifei Liu
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Bingjue Ye
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhi Chen
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Min Zheng
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yanning Liu
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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Gilsanz C, Aller MA, Fuentes-Julian S, Prieto I, Blázquez-Martinez A, Argudo S, Fernández-Delgado J, Beleña J, Arias J, De Miguel MP. Adipose-derived mesenchymal stem cells slow disease progression of acute-on-chronic liver failure. Biomed Pharmacother 2017; 91:776-787. [PMID: 28501004 DOI: 10.1016/j.biopha.2017.04.117] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 04/11/2017] [Accepted: 04/13/2017] [Indexed: 12/21/2022] Open
Abstract
A serious complication of chronic hepatic insufficiency is acute-on-chronic liver failure, a recognized syndrome characterized by acute decompensation of cirrhosis and organ/system failure. We investigated the use of adipose-derived mesenchymal stem cells (AD-MSCs) in an experimental model of acute-on-chronic liver failure, developed by microsurgical extrahepatic cholestasis in rats. Rats undergoing microsurgical extrahepatic cholestasis were treated by intraparenchymal liver injection of human or rat AD-MSCs, undifferentiated or previously differentiated in vitro toward the hepatocyte lineage. The groups treated with rat AD-MSCs showed less ascites, lower hepato- and splenomegaly, less testicular atrophy, and an improvement in serum biochemical hepatic parameters. There was also an improvement in histological liver changes, in which the area of fibrosis and bile duct proliferation were significantly decreased in the group treated with predifferentiated rat AD-MSCs. In conclusion, an isograft of hepatocyte-predifferentiated AD-MSCs injected intraparenchymally 2 weeks after microsurgery in extrahepatic cholestatic rats prevents secondary complications of acute-on-chronic hepatic failure. These data support the potential use of autologous AD-MSCs in the treatment of human cholestasis, and specifically of newborn biliary atresia, which could be beneficial for patients awaiting transplant.
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Affiliation(s)
- Carlos Gilsanz
- Department of General and Digestive Surgery, Sureste Hospital, Arganda del Rey, Madrid, Spain
| | - Maria-Angeles Aller
- Department of Surgery, School of Medicine, Complutense University of Madrid, Madrid, Spain
| | - Sherezade Fuentes-Julian
- Cell Engineering Laboratory, La Paz University Hospital Biomedical Research Institute, IDiPAZ, Madrid, Spain
| | - Isabel Prieto
- Department of General and Digestive Surgery, La Paz University Hospital, Autonomous University of Madrid, Madrid, Spain
| | - Alejandro Blázquez-Martinez
- Cell Engineering Laboratory, La Paz University Hospital Biomedical Research Institute, IDiPAZ, Madrid, Spain
| | - Salvador Argudo
- Department of Surgery, School of Medicine, Complutense University of Madrid, Madrid, Spain
| | - Jorge Fernández-Delgado
- Department of Plastic and Reconstructive Surgery, Santa Cristina Hospital and Centrocim, Madrid, Spain
| | - Jose Beleña
- Department of Anesthesia and Resuscitation, Sureste Hospital, Arganda del Rey, Madrid, Spain
| | - Jaime Arias
- Department of Surgery, School of Medicine, Complutense University of Madrid, Madrid, Spain
| | - María P De Miguel
- Cell Engineering Laboratory, La Paz University Hospital Biomedical Research Institute, IDiPAZ, Madrid, Spain.
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Mesenchymal Stem Cells Transplantation following Partial Hepatectomy: A New Concept to Promote Liver Regeneration-Systematic Review of the Literature Focused on Experimental Studies in Rodent Models. Stem Cells Int 2017; 2017:7567958. [PMID: 28386285 PMCID: PMC5366767 DOI: 10.1155/2017/7567958] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2016] [Revised: 02/09/2017] [Accepted: 02/14/2017] [Indexed: 02/08/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are an attractive source for regenerative medicine because they are easily accessible through minimally invasive methods and have the potential to enhance liver regeneration (LG) and improve liver function, following partial hepatectomy (PH) and acute or chronic liver injury. A systematic review of the literature was conducted for articles published up to September 1st, 2016, using the MEDLINE database. The keywords that were used in various combinations were as follows: “Mesenchymal stem cells”, “transplantation”, “stem cells”, “adipose tissue derived stem cells”, “bone marrow-derived stem cells”, “partial hepatectomy”, “acute liver failure”, “chronic liver failure”, “liver fibrosis”, “liver cirrhosis”, “rats”, “mice”, and “liver regeneration”. All introduced keywords were searched for separately in MeSH Database to control relevance and terminological accuracy and validity. A total of 41 articles were identified for potential inclusion and reviewed in detail. After a strict selection process, a total of 28 articles were excluded, leaving 13 articles to form the basis of this systematic review. MSCs transplantation promoted LG and improved liver function. Furthermore, MSCs had the ability to differentiate in hepatocyte-like cells, increase survival, and protect hepatocytes by paracrine mechanisms. MSCs transplantation may provide beneficial effects in the process of LG after PH and acute or chronic liver injury. They may represent a new therapeutic option to treat posthepatectomy acute liver failure.
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35
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Ezquer F, Bahamonde J, Huang YL, Ezquer M. Administration of multipotent mesenchymal stromal cells restores liver regeneration and improves liver function in obese mice with hepatic steatosis after partial hepatectomy. Stem Cell Res Ther 2017; 8:20. [PMID: 28129776 PMCID: PMC5273822 DOI: 10.1186/s13287-016-0469-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 11/11/2016] [Accepted: 12/31/2016] [Indexed: 02/06/2023] Open
Abstract
Background The liver has the remarkable capacity to regenerate in order to compensate for lost or damaged hepatic tissue. However, pre-existing pathological abnormalities, such as hepatic steatosis (HS), inhibits the endogenous regenerative process, becoming an obstacle for liver surgery and living donor transplantation. Recent evidence indicates that multipotent mesenchymal stromal cells (MSCs) administration can improve hepatic function and increase the potential for liver regeneration in patients with liver damage. Since HS is the most common form of chronic hepatic illness, in this study we evaluated the role of MSCs in liver regeneration in an animal model of severe HS with impaired liver regeneration. Methods C57BL/6 mice were fed with a regular diet (normal mice) or with a high-fat diet (obese mice) to induce HS. After 30 weeks of diet exposure, 70% hepatectomy (Hpx) was performed and normal and obese mice were divided into two groups that received 5 × 105 MSCs or vehicle via the tail vein immediately after Hpx. Results We confirmed a significant inhibition of hepatic regeneration when liver steatosis was present, while the hepatic regenerative response was promoted by infusion of MSCs. Specifically, MSC administration improved the hepatocyte proliferative response, PCNA-labeling index, DNA synthesis, liver function, and also reduced the number of apoptotic hepatocytes. These effects may be associated to the paracrine secretion of trophic factors by MSCs and the hepatic upregulation of key cytokines and growth factors relevant for cell proliferation, which ultimately improves the survival rate of the mice. Conclusions MSCs represent a promising therapeutic strategy to improve liver regeneration in patients with HS as well as for increasing the number of donor organs available for transplantation. Electronic supplementary material The online version of this article (doi:10.1186/s13287-016-0469-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Fernando Ezquer
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Av. Las Condes 12.438, Lo Barnechea, 7710162, Santiago, Chile
| | - Javiera Bahamonde
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Av. Las Condes 12.438, Lo Barnechea, 7710162, Santiago, Chile.,Departamento de Fomento de la Producción Animal, Facultad de Ciencias Veterinarias y Pecuarias, Universidad de Chile, Av. Santa Rosa 11735, La Pintana, Santiago, Chile
| | - Ya-Lin Huang
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Av. Las Condes 12.438, Lo Barnechea, 7710162, Santiago, Chile
| | - Marcelo Ezquer
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Av. Las Condes 12.438, Lo Barnechea, 7710162, Santiago, Chile.
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Wang H, Wang D, Yang L, Wang Y, Jia J, Na D, Chen H, Luo Y, Liu C. Compact bone-derived mesenchymal stem cells attenuate nonalcoholic steatohepatitis in a mouse model by modulation of CD4 cells differentiation. Int Immunopharmacol 2016; 42:67-73. [PMID: 27889556 DOI: 10.1016/j.intimp.2016.11.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 11/03/2016] [Accepted: 11/14/2016] [Indexed: 12/29/2022]
Abstract
Increasing evidence has accrued which indicates that mesenchymal stem cells (MSCs) have a potential clinical value in the treatment of certain diseases. Globally, nonalcoholic steatohepatitis (NASH) is a widespread disorder. In the present study, MSCs were isolated successfully from compact bone and a mouse model of NASH was established as achieved with use of a methionine-choline deficient (MCD) diet. Compact bone-derived MSCs transplantation reduced MCD diet-induced weight loss, hepatic lipid peroxidation, steatosis, ballooning, lobular inflammation and fibrogenesis. It was shown that MSCs treatment hampered MCD diet-induced proliferation of CD4+ IFN-γ+ and CD4+IL-6+ T spleen cells. In addition, CD4+IL-17+ lymphocytes that associated with anti-inflammation show little change in MCD as well as in MCD+MSCs splenocytes. We conclude that MSCs may have a potential clinical value upon NASH, through their capacity to suppress activation of CD4+ IFN-γ+ and CD4+IL-6+ lymphocytes.
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Affiliation(s)
- Huafeng Wang
- Modern College of Arts and Science, or School of Life Science, Shanxi Normal University, Linfen, China.
| | - Dong Wang
- Central Blood Station of Tianjin, Tianjin, China
| | - Luhong Yang
- Modern College of Arts and Science, or School of Life Science, Shanxi Normal University, Linfen, China
| | - Yanxia Wang
- Modern College of Arts and Science, or School of Life Science, Shanxi Normal University, Linfen, China
| | - Junli Jia
- Modern College of Arts and Science, or School of Life Science, Shanxi Normal University, Linfen, China
| | - Dongchen Na
- Modern College of Arts and Science, or School of Life Science, Shanxi Normal University, Linfen, China
| | - Huize Chen
- Modern College of Arts and Science, or School of Life Science, Shanxi Normal University, Linfen, China
| | - Yongping Luo
- Modern College of Arts and Science, or School of Life Science, Shanxi Normal University, Linfen, China
| | - Chengfang Liu
- Department of Human anatomy, Shanxi Medical University, Taiyuan, China; Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
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The Comparative Effects of Human Mesenchymal Stem Cell and Platelet Extract on CCl4-Induced Liver Toxicity in Rats. Jundishapur J Nat Pharm Prod 2016. [DOI: 10.5812/jjnpp.36818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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38
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Hesami Z, Jamshidzadeh A, Ayatollahi M, Gramizadeh B, Vahdati A. The Comparative Effects of Human Mesenchymal Stem Cell and Platelet Extract on CCl4-Induced Liver Toxicity in Rats. Jundishapur J Nat Pharm Prod 2016. [DOI: 10.17795/jjnpp-36818] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
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Iseki M, Kushida Y, Wakao S, Akimoto T, Mizuma M, Motoi F, Asada R, Shimizu S, Unno M, Chazenbalk G, Dezawa M. Muse Cells, Nontumorigenic Pluripotent-Like Stem Cells, Have Liver Regeneration Capacity Through Specific Homing and Cell Replacement in a Mouse Model of Liver Fibrosis. Cell Transplant 2016; 26:821-840. [PMID: 27938474 DOI: 10.3727/096368916x693662] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Muse cells, a novel type of nontumorigenic pluripotent-like stem cells, reside in the bone marrow, skin, and adipose tissue and are collectable as cells positive for pluripotent surface marker SSEA-3. They are able to differentiate into cells representative of all three germ layers. The capacity of intravenously injected human bone marrow-derived Muse cells to repair an immunodeficient mouse model of liver fibrosis was evaluated in this study. The cells exhibited the ability to spontaneously differentiate into hepatoblast/hepatocyte lineage cells in vitro. They demonstrated a high migration capacity toward the serum and liver section of carbon tetrachloride-treated mice in vitro. In vivo, they specifically accumulated in the liver, but not in other organs except, to a lesser extent, in the lungs at 2 weeks after intravenous injection in the liver fibrosis model. After homing, Muse cells spontaneously differentiated in vivo into HepPar-1 (71.1 ± 15.2%), human albumin (54.3 ± 8.2%), and anti-trypsin (47.9 ± 4.6%)-positive cells without fusing with host hepatocytes, and expressed mature functional markers such as human CYP1A2 and human Glc-6-Pase at 8 weeks after injection. Recovery in serum, total bilirubin, and albumin and significant attenuation of fibrosis were recognized with statistical differences between the Muse cell-transplanted group and the control groups, which received the vehicle or the same number of a non-Muse cell population of MSCs (MSCs in which Muse cells were eliminated). Thus, unlike ESCs and iPSCs, Muse cells are unique in their efficient migration and integration into the damaged liver after intravenous injection, nontumorigenicity, and spontaneous differentiation into hepatocytes, rendering induction into hepatocytes prior to transplantation unnecessary. They may repair liver fibrosis by two simple steps: expansion after collection from the bone marrow and intravenous injection. A therapeutic strategy such as this is feasible and may provide significant advancements toward liver regeneration in patients with liver disease.
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Yun JW, Ahn JH, Kwon E, Kim SH, Kim H, Jang JJ, Kim WH, Kim JH, Han SY, Kim JT, Kim JH, Kim W, Ku SY, Do BR, Kang BC. Human umbilical cord-derived mesenchymal stem cells in acute liver injury: Hepatoprotective efficacy, subchronic toxicity, tumorigenicity, and biodistribution. Regul Toxicol Pharmacol 2016; 81:437-447. [PMID: 27693706 DOI: 10.1016/j.yrtph.2016.09.029] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 09/26/2016] [Accepted: 09/27/2016] [Indexed: 12/21/2022]
Abstract
Umbilical cord-derived mesenchymal stem cells (UC-MSCs) therapy might be an alternative to liver transplantation for acute or chronic liver injury. The aim of this study was to evaluate the efficacy of human UC-MSCs on carbon tetrachloride (CCl4)-induced acute liver injury. In addition, its toxicity, tumorigenicity, and biodistribution were determined. Significant hepatoprotective effects of hUC-MSCs with decreased levels of hepatocellular necrosis and lobular neutrophilic infiltration were found. Regarding the safety of hUC-MSCs, no serious hUC-MSCs-related changes (body weight, food/water consumption, clinical symptom, urinalysis, hematology, clinical chemistry, organ weight, and histopathology) were observed in a 13-week subchronic toxicity study. In a 26-week tumorigenicity study, no mice developed tumor related to hUC-MSCs transplantation up to 1 × 108 cells/kg. In particular, human mitochondrial sequence detection revealed that most hUC-MSCs were cleared from the major organs of the mice at 13 weeks after transplantation. There was no systemic toxicity or neoplastic finding either. Taken together, these results suggested that hUC-MSCs have great potential for future clinical treatment of acute liver disease.
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Affiliation(s)
- Jun-Won Yun
- Department of Experimental Animal Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Jae Hun Ahn
- Graduate School of Translational Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Euna Kwon
- Department of Experimental Animal Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Seung-Hyun Kim
- Department of Experimental Animal Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Hanna Kim
- Department of Experimental Animal Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Ja-June Jang
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Woo Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ji Hyang Kim
- Biotechnology Research Institute, Hurim BioCell Co. Ltd., Seoul, Republic of Korea
| | - Su-Youne Han
- Biotechnology Research Institute, Hurim BioCell Co. Ltd., Seoul, Republic of Korea
| | - Jin Tac Kim
- Biotechnology Research Institute, Hurim BioCell Co. Ltd., Seoul, Republic of Korea
| | - Jong-Hoon Kim
- Laboratory of Stem Cell Biology, Division of Biotechnology, Department of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Wookhwan Kim
- Department of General Surgery, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Seung-Yup Ku
- Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Byung-Rok Do
- Biotechnology Research Institute, Hurim BioCell Co. Ltd., Seoul, Republic of Korea.
| | - Byeong-Cheol Kang
- Department of Experimental Animal Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea; Graduate School of Translational Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Biomedical Center for Animal Resource and Development, Seoul National University College of Medicine, Seoul, Republic of Korea; Designed Animal and Transplantation Research Institute, Institute of GreenBio Science Technology, Seoul National University, Pyeongchang-gun, Gangwon-do, Republic of Korea.
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41
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Haldar D, Henderson NC, Hirschfield G, Newsome PN. Mesenchymal stromal cells and liver fibrosis: a complicated relationship. FASEB J 2016; 30:3905-3928. [DOI: 10.1096/fj.201600433r] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 08/15/2016] [Indexed: 12/17/2022]
Affiliation(s)
- Debashis Haldar
- National Institute for Health ResearchBirmingham Liver Biomedical Research Unit and Centre for Liver Research University of Birmingham Birmingham United Kingdom
- Liver UnitUniversity Hospital Birmingham National Health Service (NHS) Foundation Trust Birmingham United Kingdom
| | - Neil C. Henderson
- Medical Research Council (MRC) Centre for Inflammation ResearchQueens Medical Research Institute University of Edinburgh Edinburgh United Kingdom
| | - Gideon Hirschfield
- National Institute for Health ResearchBirmingham Liver Biomedical Research Unit and Centre for Liver Research University of Birmingham Birmingham United Kingdom
- Liver UnitUniversity Hospital Birmingham National Health Service (NHS) Foundation Trust Birmingham United Kingdom
| | - Philip N. Newsome
- National Institute for Health ResearchBirmingham Liver Biomedical Research Unit and Centre for Liver Research University of Birmingham Birmingham United Kingdom
- Liver UnitUniversity Hospital Birmingham National Health Service (NHS) Foundation Trust Birmingham United Kingdom
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Fikry H, Gawad SA, Baher W. Therapeutic Potential of Bone Marrow-Derived Mesenchymal Stem Cells on Experimental Liver Injury Induced by Schistosoma mansoni: A Histological Study. Int J Stem Cells 2016; 9:96-106. [PMID: 27426091 PMCID: PMC4961109 DOI: 10.15283/ijsc.2016.9.1.96] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/23/2015] [Indexed: 12/13/2022] Open
Abstract
Background and Objectives Bone marrow derived mesenchymal stem cells (BM-MSCs) have been proposed as effective treatment of many diseases owing to their unique ability to differentiate into other cell types in vivo. Schistosoma mansoni (S. mansoni) infection is characterized by hepatic granuloma formation around schistosome eggs at acute stage of infection, followed by hepatic fibrosis at chronic and advanced stages. Whether BM-MSCs have an ameliorative effect on hepatic tissue injury caused by S. mansoni infection or not, was inspected in the current study. Materials and Results Female Swiss Albino mice were divided into a control group and an experimental group. Half of control animals served as donors for bone marrow stem cells, and the other half was used to collect liver samples. Experimental group was injected with circariae of S. mansoni, and then subdivided into three subgroups; Subgroup B1, sacrificed after eight weeks of infection without treatment, subgroup B2, received BM-MSCs at the eighth week and sacrificed four weeks later, and subgroup B3, was untreated till the twelfth week of infection. Histological examination of liver samples showed the formation of granulomas and liver fibrosis which were extensive in subgroup B3. However, treated subgroup illustrated improvement of liver histology, signs of hepatocytes regeneration, and possible contribution of oval cell in the process of hepatic and biliary regeneration. Conclusion BM-MSCs decreased liver fibrosis and contributed to an increase in oval cells, generation of new hepatocytes and/or to the improvement of resident hepatocytes in S. mansoni infected mice.
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Affiliation(s)
- Heba Fikry
- Department of Histology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Sara Abdel Gawad
- Department of Histology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Walaa Baher
- Department of Histology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Gao L, Zhang Y, Hu B, Liu J, Kong P, Lou S, Su Y, Yang T, Li H, Liu Y, Zhang C, Gao L, Zhu L, Wen Q, Wang P, Chen X, Zhong J, Zhang X. Phase II Multicenter, Randomized, Double-Blind Controlled Study of Efficacy and Safety of Umbilical Cord-Derived Mesenchymal Stromal Cells in the Prophylaxis of Chronic Graft-Versus-Host Disease After HLA-Haploidentical Stem-Cell Transplantation. J Clin Oncol 2016; 34:2843-50. [PMID: 27400949 DOI: 10.1200/jco.2015.65.3642] [Citation(s) in RCA: 136] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
PURPOSE Although mesenchymal stromal cells (MSCs) possess immunomodulatory properties and exhibit promising efficacy against chronic graft-versus-host disease (cGVHD), little is known about the efficacy of MSCs in the prophylaxis of cGVHD after HLA-haploidentical hematopoietic stem-cell transplantation (HLA-haplo HSCT). PATIENTS AND METHODS In this multicenter, double-blind, randomized controlled trial, we investigated the incidence and severity of cGVHD among patients, and the changes in T, B, and natural killer (NK) cells after the repeated infusion of MSCs. RESULTS The 2-year cumulative incidence of cGVHD in the MSCs group was 27.4% (95% CI, 16.2% to 38.6%), compared with 49.0% (95% CI, 36.5% to 61.5%) in the non-MSCs control group (P = .021). Seven patients in the non-MSCs control group had severe lung cGVHD, but no patients in the MSCs group developed typical lung cGVHD (P = .047). After the MSC infusions, increasing memory B lymphocytes and regulatory T cells, as well as the ratio of type 1 T helper to type 2 T helper cells, were observed, whereas the number of NK cells decreased. CONCLUSION Our findings suggest that the repeated infusion of MSCs might inhibit cGVHD symptoms in patients after HLA-haplo HSCT, accompanied by changes in the numbers and subtypes of T, B, and NK cells, leading to the acquisition of immune tolerance.
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Affiliation(s)
- Lei Gao
- Lei Gao, Yanqi Zhang, Jia Liu, Peiyan Kong, Yao Liu, Li Gao, Cheng Zhang, Lidan Zhu, Qin Wen, Ping Wang, Xinghua Chen, Jiangfan Zhong, and Xi Zhang, Third Military Medical University, Chongqing; Baoyang Hu, Chinese Academy of Sciences, Beijing; Shifeng Lou, Second Affiliated Hospital of Chongqing Medical University, Chongqing; Yi Su, General Hospital of Chengdu Military Region of People's Liberation Army, Chengdu; Tonghua Yang, Yunnan Provincial People's Hospital; Huimin Li, Affiliated Hospital of Kunming Medical College, Kunming, China; and Jiangfan Zhong, University of Southern California, Los Angeles, CA
| | - Yanqi Zhang
- Lei Gao, Yanqi Zhang, Jia Liu, Peiyan Kong, Yao Liu, Li Gao, Cheng Zhang, Lidan Zhu, Qin Wen, Ping Wang, Xinghua Chen, Jiangfan Zhong, and Xi Zhang, Third Military Medical University, Chongqing; Baoyang Hu, Chinese Academy of Sciences, Beijing; Shifeng Lou, Second Affiliated Hospital of Chongqing Medical University, Chongqing; Yi Su, General Hospital of Chengdu Military Region of People's Liberation Army, Chengdu; Tonghua Yang, Yunnan Provincial People's Hospital; Huimin Li, Affiliated Hospital of Kunming Medical College, Kunming, China; and Jiangfan Zhong, University of Southern California, Los Angeles, CA
| | - Baoyang Hu
- Lei Gao, Yanqi Zhang, Jia Liu, Peiyan Kong, Yao Liu, Li Gao, Cheng Zhang, Lidan Zhu, Qin Wen, Ping Wang, Xinghua Chen, Jiangfan Zhong, and Xi Zhang, Third Military Medical University, Chongqing; Baoyang Hu, Chinese Academy of Sciences, Beijing; Shifeng Lou, Second Affiliated Hospital of Chongqing Medical University, Chongqing; Yi Su, General Hospital of Chengdu Military Region of People's Liberation Army, Chengdu; Tonghua Yang, Yunnan Provincial People's Hospital; Huimin Li, Affiliated Hospital of Kunming Medical College, Kunming, China; and Jiangfan Zhong, University of Southern California, Los Angeles, CA
| | - Jia Liu
- Lei Gao, Yanqi Zhang, Jia Liu, Peiyan Kong, Yao Liu, Li Gao, Cheng Zhang, Lidan Zhu, Qin Wen, Ping Wang, Xinghua Chen, Jiangfan Zhong, and Xi Zhang, Third Military Medical University, Chongqing; Baoyang Hu, Chinese Academy of Sciences, Beijing; Shifeng Lou, Second Affiliated Hospital of Chongqing Medical University, Chongqing; Yi Su, General Hospital of Chengdu Military Region of People's Liberation Army, Chengdu; Tonghua Yang, Yunnan Provincial People's Hospital; Huimin Li, Affiliated Hospital of Kunming Medical College, Kunming, China; and Jiangfan Zhong, University of Southern California, Los Angeles, CA
| | - Peiyan Kong
- Lei Gao, Yanqi Zhang, Jia Liu, Peiyan Kong, Yao Liu, Li Gao, Cheng Zhang, Lidan Zhu, Qin Wen, Ping Wang, Xinghua Chen, Jiangfan Zhong, and Xi Zhang, Third Military Medical University, Chongqing; Baoyang Hu, Chinese Academy of Sciences, Beijing; Shifeng Lou, Second Affiliated Hospital of Chongqing Medical University, Chongqing; Yi Su, General Hospital of Chengdu Military Region of People's Liberation Army, Chengdu; Tonghua Yang, Yunnan Provincial People's Hospital; Huimin Li, Affiliated Hospital of Kunming Medical College, Kunming, China; and Jiangfan Zhong, University of Southern California, Los Angeles, CA
| | - Shifeng Lou
- Lei Gao, Yanqi Zhang, Jia Liu, Peiyan Kong, Yao Liu, Li Gao, Cheng Zhang, Lidan Zhu, Qin Wen, Ping Wang, Xinghua Chen, Jiangfan Zhong, and Xi Zhang, Third Military Medical University, Chongqing; Baoyang Hu, Chinese Academy of Sciences, Beijing; Shifeng Lou, Second Affiliated Hospital of Chongqing Medical University, Chongqing; Yi Su, General Hospital of Chengdu Military Region of People's Liberation Army, Chengdu; Tonghua Yang, Yunnan Provincial People's Hospital; Huimin Li, Affiliated Hospital of Kunming Medical College, Kunming, China; and Jiangfan Zhong, University of Southern California, Los Angeles, CA
| | - Yi Su
- Lei Gao, Yanqi Zhang, Jia Liu, Peiyan Kong, Yao Liu, Li Gao, Cheng Zhang, Lidan Zhu, Qin Wen, Ping Wang, Xinghua Chen, Jiangfan Zhong, and Xi Zhang, Third Military Medical University, Chongqing; Baoyang Hu, Chinese Academy of Sciences, Beijing; Shifeng Lou, Second Affiliated Hospital of Chongqing Medical University, Chongqing; Yi Su, General Hospital of Chengdu Military Region of People's Liberation Army, Chengdu; Tonghua Yang, Yunnan Provincial People's Hospital; Huimin Li, Affiliated Hospital of Kunming Medical College, Kunming, China; and Jiangfan Zhong, University of Southern California, Los Angeles, CA
| | - Tonghua Yang
- Lei Gao, Yanqi Zhang, Jia Liu, Peiyan Kong, Yao Liu, Li Gao, Cheng Zhang, Lidan Zhu, Qin Wen, Ping Wang, Xinghua Chen, Jiangfan Zhong, and Xi Zhang, Third Military Medical University, Chongqing; Baoyang Hu, Chinese Academy of Sciences, Beijing; Shifeng Lou, Second Affiliated Hospital of Chongqing Medical University, Chongqing; Yi Su, General Hospital of Chengdu Military Region of People's Liberation Army, Chengdu; Tonghua Yang, Yunnan Provincial People's Hospital; Huimin Li, Affiliated Hospital of Kunming Medical College, Kunming, China; and Jiangfan Zhong, University of Southern California, Los Angeles, CA
| | - Huimin Li
- Lei Gao, Yanqi Zhang, Jia Liu, Peiyan Kong, Yao Liu, Li Gao, Cheng Zhang, Lidan Zhu, Qin Wen, Ping Wang, Xinghua Chen, Jiangfan Zhong, and Xi Zhang, Third Military Medical University, Chongqing; Baoyang Hu, Chinese Academy of Sciences, Beijing; Shifeng Lou, Second Affiliated Hospital of Chongqing Medical University, Chongqing; Yi Su, General Hospital of Chengdu Military Region of People's Liberation Army, Chengdu; Tonghua Yang, Yunnan Provincial People's Hospital; Huimin Li, Affiliated Hospital of Kunming Medical College, Kunming, China; and Jiangfan Zhong, University of Southern California, Los Angeles, CA
| | - Yao Liu
- Lei Gao, Yanqi Zhang, Jia Liu, Peiyan Kong, Yao Liu, Li Gao, Cheng Zhang, Lidan Zhu, Qin Wen, Ping Wang, Xinghua Chen, Jiangfan Zhong, and Xi Zhang, Third Military Medical University, Chongqing; Baoyang Hu, Chinese Academy of Sciences, Beijing; Shifeng Lou, Second Affiliated Hospital of Chongqing Medical University, Chongqing; Yi Su, General Hospital of Chengdu Military Region of People's Liberation Army, Chengdu; Tonghua Yang, Yunnan Provincial People's Hospital; Huimin Li, Affiliated Hospital of Kunming Medical College, Kunming, China; and Jiangfan Zhong, University of Southern California, Los Angeles, CA
| | - Cheng Zhang
- Lei Gao, Yanqi Zhang, Jia Liu, Peiyan Kong, Yao Liu, Li Gao, Cheng Zhang, Lidan Zhu, Qin Wen, Ping Wang, Xinghua Chen, Jiangfan Zhong, and Xi Zhang, Third Military Medical University, Chongqing; Baoyang Hu, Chinese Academy of Sciences, Beijing; Shifeng Lou, Second Affiliated Hospital of Chongqing Medical University, Chongqing; Yi Su, General Hospital of Chengdu Military Region of People's Liberation Army, Chengdu; Tonghua Yang, Yunnan Provincial People's Hospital; Huimin Li, Affiliated Hospital of Kunming Medical College, Kunming, China; and Jiangfan Zhong, University of Southern California, Los Angeles, CA
| | - Li Gao
- Lei Gao, Yanqi Zhang, Jia Liu, Peiyan Kong, Yao Liu, Li Gao, Cheng Zhang, Lidan Zhu, Qin Wen, Ping Wang, Xinghua Chen, Jiangfan Zhong, and Xi Zhang, Third Military Medical University, Chongqing; Baoyang Hu, Chinese Academy of Sciences, Beijing; Shifeng Lou, Second Affiliated Hospital of Chongqing Medical University, Chongqing; Yi Su, General Hospital of Chengdu Military Region of People's Liberation Army, Chengdu; Tonghua Yang, Yunnan Provincial People's Hospital; Huimin Li, Affiliated Hospital of Kunming Medical College, Kunming, China; and Jiangfan Zhong, University of Southern California, Los Angeles, CA
| | - Lidan Zhu
- Lei Gao, Yanqi Zhang, Jia Liu, Peiyan Kong, Yao Liu, Li Gao, Cheng Zhang, Lidan Zhu, Qin Wen, Ping Wang, Xinghua Chen, Jiangfan Zhong, and Xi Zhang, Third Military Medical University, Chongqing; Baoyang Hu, Chinese Academy of Sciences, Beijing; Shifeng Lou, Second Affiliated Hospital of Chongqing Medical University, Chongqing; Yi Su, General Hospital of Chengdu Military Region of People's Liberation Army, Chengdu; Tonghua Yang, Yunnan Provincial People's Hospital; Huimin Li, Affiliated Hospital of Kunming Medical College, Kunming, China; and Jiangfan Zhong, University of Southern California, Los Angeles, CA
| | - Qin Wen
- Lei Gao, Yanqi Zhang, Jia Liu, Peiyan Kong, Yao Liu, Li Gao, Cheng Zhang, Lidan Zhu, Qin Wen, Ping Wang, Xinghua Chen, Jiangfan Zhong, and Xi Zhang, Third Military Medical University, Chongqing; Baoyang Hu, Chinese Academy of Sciences, Beijing; Shifeng Lou, Second Affiliated Hospital of Chongqing Medical University, Chongqing; Yi Su, General Hospital of Chengdu Military Region of People's Liberation Army, Chengdu; Tonghua Yang, Yunnan Provincial People's Hospital; Huimin Li, Affiliated Hospital of Kunming Medical College, Kunming, China; and Jiangfan Zhong, University of Southern California, Los Angeles, CA
| | - Ping Wang
- Lei Gao, Yanqi Zhang, Jia Liu, Peiyan Kong, Yao Liu, Li Gao, Cheng Zhang, Lidan Zhu, Qin Wen, Ping Wang, Xinghua Chen, Jiangfan Zhong, and Xi Zhang, Third Military Medical University, Chongqing; Baoyang Hu, Chinese Academy of Sciences, Beijing; Shifeng Lou, Second Affiliated Hospital of Chongqing Medical University, Chongqing; Yi Su, General Hospital of Chengdu Military Region of People's Liberation Army, Chengdu; Tonghua Yang, Yunnan Provincial People's Hospital; Huimin Li, Affiliated Hospital of Kunming Medical College, Kunming, China; and Jiangfan Zhong, University of Southern California, Los Angeles, CA
| | - Xinghua Chen
- Lei Gao, Yanqi Zhang, Jia Liu, Peiyan Kong, Yao Liu, Li Gao, Cheng Zhang, Lidan Zhu, Qin Wen, Ping Wang, Xinghua Chen, Jiangfan Zhong, and Xi Zhang, Third Military Medical University, Chongqing; Baoyang Hu, Chinese Academy of Sciences, Beijing; Shifeng Lou, Second Affiliated Hospital of Chongqing Medical University, Chongqing; Yi Su, General Hospital of Chengdu Military Region of People's Liberation Army, Chengdu; Tonghua Yang, Yunnan Provincial People's Hospital; Huimin Li, Affiliated Hospital of Kunming Medical College, Kunming, China; and Jiangfan Zhong, University of Southern California, Los Angeles, CA
| | - Jiangfan Zhong
- Lei Gao, Yanqi Zhang, Jia Liu, Peiyan Kong, Yao Liu, Li Gao, Cheng Zhang, Lidan Zhu, Qin Wen, Ping Wang, Xinghua Chen, Jiangfan Zhong, and Xi Zhang, Third Military Medical University, Chongqing; Baoyang Hu, Chinese Academy of Sciences, Beijing; Shifeng Lou, Second Affiliated Hospital of Chongqing Medical University, Chongqing; Yi Su, General Hospital of Chengdu Military Region of People's Liberation Army, Chengdu; Tonghua Yang, Yunnan Provincial People's Hospital; Huimin Li, Affiliated Hospital of Kunming Medical College, Kunming, China; and Jiangfan Zhong, University of Southern California, Los Angeles, CA
| | - Xi Zhang
- Lei Gao, Yanqi Zhang, Jia Liu, Peiyan Kong, Yao Liu, Li Gao, Cheng Zhang, Lidan Zhu, Qin Wen, Ping Wang, Xinghua Chen, Jiangfan Zhong, and Xi Zhang, Third Military Medical University, Chongqing; Baoyang Hu, Chinese Academy of Sciences, Beijing; Shifeng Lou, Second Affiliated Hospital of Chongqing Medical University, Chongqing; Yi Su, General Hospital of Chengdu Military Region of People's Liberation Army, Chengdu; Tonghua Yang, Yunnan Provincial People's Hospital; Huimin Li, Affiliated Hospital of Kunming Medical College, Kunming, China; and Jiangfan Zhong, University of Southern California, Los Angeles, CA.
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Feasibility and Safety of Endometrial Injection of Autologous Bone Marrow Mesenchymal Stem Cells in Mares. J Equine Vet Sci 2016. [DOI: 10.1016/j.jevs.2016.03.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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Li Q, Zhang C, Fu X. Will stem cells bring hope to pathological skin scar treatment? Cytotherapy 2016; 18:943-956. [PMID: 27293205 DOI: 10.1016/j.jcyt.2016.05.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 04/19/2016] [Accepted: 05/10/2016] [Indexed: 12/12/2022]
Abstract
Pathological skin scars, such as keloids, aesthetically and psychosocially affect patients. The quest for scar reduction and the increasing recognition of patient satisfaction has led to the continued exploration of scar treatment. Stem cells are a promising source for tissue repair and regeneration. The multi-potency and secretory functions of these cells could offer possible treatments for pathological scars and have been examined in recent studies. Here, we analyze the factors that influence the formation of pathological skin scars, summarize recent research on pathological scar treatment with stem cells and elaborate on the possible mechanisms of this treatment. Additionally, other effects of stem cell treatments are also presented while evaluating potential side effects of stem cell-based pathological scar treatments. Thus, this review may provide meaningful guidance in the clinic for scar treatments with stem cells.
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Affiliation(s)
- Qiankun Li
- Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Science, Chinese PLA General Hospital, Beijing, China
| | - Cuiping Zhang
- Stem Cell and Tissue Regeneration Laboratory, The First Affiliated Hospital, General Hospital of PLA, Beijing, China.
| | - Xiaobing Fu
- Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Science, Chinese PLA General Hospital, Beijing, China; Stem Cell and Tissue Regeneration Laboratory, The First Affiliated Hospital, General Hospital of PLA, Beijing, China.
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Mesenchymal Stem/Stromal Cells in Liver Fibrosis: Recent Findings, Old/New Caveats and Future Perspectives. Stem Cell Rev Rep 2016; 11:586-97. [PMID: 25820543 DOI: 10.1007/s12015-015-9585-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Mesenchymal stem/stromal cells (MSCs) are progenitors which share plastic-adherence capacity and cell surface markers but have different properties according to their cell and tissue sources and to culture conditions applied. Many recent publications suggest that MSCs can differentiate into hepatic-like cells, which can be a consequence of either a positive selection of rare in vivo pluripotent cells or of the original plasticity of some cells contributing to MSC cultures. A possible role of MSCs in hereditary transmission of obesity and/or diabetes as well as properties of MSCs regarding immunomodulation, cell fusion and exosome release capacities are discussed according to recent literature. Limitations in methods used to track MSCs in vivo especially in the context of liver cirrhosis are addressed as well as strategies explored to enhance their migratory, survival and proliferation properties, which are known to be relevant for their future clinical use. Current knowledge regarding mechanisms involved in liver cirrhosis amelioration mediated by naïve and genetically modified MSCs as well as the effects of applying preconditioning and combined strategies to improve their therapeutic effects are evaluated. Finally, first reports of GMP guidelines and biosafety issues in MSCs applications are discussed.
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Abstract
Stem cell therapy holds the potential to revolutionize the treatment of a number of chronic conditions. Stem cells ability to home in on injured sites of the body, stimulate angiogenesis, tissue regeneration, immunomodulation, anti-inflammatory, and anti-fibrotic factors have attracted their use in the treatment of many conditions. Urology has registered one of the highest experimental successes using stem cell therapy. However, the rate of clinical applications is comparatively lower. This review takes a look at our efforts so far and what needs to be done in order to maximize the clinical benefit we can derive from stem cells.
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Affiliation(s)
- Bridget Wiafe
- 3-007 Li Ka Shing Centre for Health Research Innovation, University of Alberta, Edmonton, AB, Canada, T6G 2E1.
| | | | - Adetola B Adesida
- 3-002E Li Ka Shing Centre for Health Research Innovation, University of Alberta, Edmonton, AB, Canada, T6G 2E1.
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48
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Eom YW, Kim G, Baik SK. Mesenchymal stem cell therapy for cirrhosis: Present and future perspectives. World J Gastroenterol 2015; 21:10253-10261. [PMID: 26420953 PMCID: PMC4579873 DOI: 10.3748/wjg.v21.i36.10253] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Revised: 06/01/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Cirrhosis occurs as a result of various chronic liver injuries, which may be caused by viral infections, alcohol abuse and the administration of drugs and chemicals. Recently, bone marrow cells (BMCs), hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) have been used for developing treatments for cirrhosis. Clinical trials have investigated the therapeutic potential of BMCs, HSCs and MSCs for the treatment of cirrhosis based on their potential to differentiate into hepatocytes. Although the therapeutic mechanisms of BMC, HSC and MSC treatments are still not fully characterized, the evidence thus far has indicated that the potential therapeutic mechanisms of MSCs are clearer than those of BMCs or HSCs with respect to liver regenerative medicine. MSCs suppress inflammatory responses, reduce hepatocyte apoptosis, increase hepatocyte regeneration, reverse liver fibrosis and enhance liver functionality. This paper summarizes the clinical studies that have used BMCs, HSCs and MSCs in patients with liver failure or cirrhosis. We also present the potential therapeutic mechanisms of BMCs, HSCs and MSCs for the improvement of liver function.
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Raafat N, Abdel Aal SM, Abdo FK, El Ghonaimy NM. Mesenchymal stem cells: In vivo therapeutic application ameliorates carbon tetrachloride induced liver fibrosis in rats. Int J Biochem Cell Biol 2015; 68:109-18. [PMID: 26369870 DOI: 10.1016/j.biocel.2015.09.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Revised: 08/20/2015] [Accepted: 09/09/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND Egypt has the highest prevalence of hepatitis C virus in the world with infection rate up to 60%, for which liver fibrosis or hepatic carcinoma is the final outcome. Stem cell therapy provides a new hope for hepatic repair instead of traditional treatment, liver transplantation, as it is safer, gives long term engraftment and avoid expensive immunosuppressive drugs and unexpected hazardous effects. AIM This work aimed at determining the therapeutic potential of mesenchymal stem cells (MSC) in hepatic repair as a new line of therapy for liver fibrosis. METHODS 33 female albino rats were divided into three groups: Group I: 10 rats injected subcutaneously with olive oil, Group II: 13 rats injected with carbon tetrachloride (CCl4) and Group III: 10 rats injected with CCl4 then bone marrow derived MSC from male rats. Blood and liver tissue samples were taken from all rats for biochemical and histological study. RESULTS Liver functions for group II rats showed significant deterioration in response to CCl4 in addition to significant histological changes in liver lobules and portal areas. Those parameters tend to be normal in MSC-treated group. Group III rats revealed normalized liver function and histological picture. Meanwhile, most of the pathological lesions were still detected in rats of second group. CONCLUSION Undifferentiated MSCs have the ability to ameliorate CCl4 induced liver injury in albino rats in terms of liver functions and histological features. So, stem cell therapy can be considered clinically to offer a hope for patients suffering from liver fibrosis.
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Affiliation(s)
- Nermin Raafat
- Medical Biochemistry & Molecular Biology Department, Faculty of Medicine, Zagazig University, Egypt.
| | - Sara M Abdel Aal
- Histology & Cell Biology Department, Faculty of Medicine, Zagazig University, Egypt
| | - Fadia K Abdo
- Histology & Cell Biology Department, Faculty of Medicine, Zagazig University, Egypt
| | - Nabila M El Ghonaimy
- Histology & Cell Biology Department, Faculty of Medicine, Zagazig University, Egypt
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50
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Al Ghrbawy NM, Afify RAAM, Dyaa N, El Sayed AA. Differentiation of Bone Marrow: Derived Mesenchymal Stem Cells into Hepatocyte-like Cells. Indian J Hematol Blood Transfus 2015; 32:276-83. [PMID: 27429519 DOI: 10.1007/s12288-015-0581-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Accepted: 08/17/2015] [Indexed: 02/06/2023] Open
Abstract
Cirrhosis is the end-stage liver fibrosis, whereby normal liver architecture is disrupted by fibrotic bands, parenchymal nodules and vascular distortion. Portal hypertension and hepatocyte dysfunction are the end results and give rise to major systemic complications and premature death. Mesenchymal stem cells (MSC) have the capacity of self-renew and to give rise to cells of various lineages, so MSC can be isolated from bone marrow (BM) and induced to differentiate into hepatocyte-like cells. MSC were induced to differentiate into hepatocyte-like cells by hepatotic growth factor (HGF) and fibroblast growth factor-4 (FGF-4). Differentiated cells were examined for the expression of hepatocyte-specific markers and hepatocyte functions. MSC were isolated. Flow cytometry analysis showed that they expressed the MSC-specific markers, reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated that MSC expressed the hepatocyte-specific marker cytokeratin 18 (CK-18) following hepatocyte induction. This study demonstrates that BM-derived-MSC can differentiate into functional hepatocyte-like cells following the induction of HGF and FGF-4. MSC can serve as a favorable cell source for tissue engineering in the treatment of liver disease.
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Affiliation(s)
- Nesrien M Al Ghrbawy
- Clinical Pathology Department, Faculty of Medicine, Al kaser Al Aini, Cairo University, Cairo, Egypt
| | | | - Nehal Dyaa
- Clinical Pathology Department, Faculty of Medicine, Al kaser Al Aini, Cairo University, Cairo, Egypt
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