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Abd Rahman F, Azwa FN. Comparative Dental Pulp Stem Cells (DPSCs) and Periodontal Ligament Stem Cells (PDLSCs): Difference in effect of aspirin on osteoblast potential of PDLSCs and DPSCs. Tissue Cell 2025; 94:102776. [PMID: 40022908 DOI: 10.1016/j.tice.2025.102776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 01/27/2025] [Accepted: 02/01/2025] [Indexed: 03/04/2025]
Abstract
Periodontal Ligament Stem Cells (PDLSCs) and Dental Pulp Stem Cells (DPSCs) are mesenchymal stem cells with the ability to self-renew and differentiate into three lineages. One significant advantage of dental stem cells, such as PDLSCs and DPSCs, is their ease of harvest compared to other types of mesenchymal stem cells (MSCs). While MSCs are highly valued in bone tissue engineering, MSCs sourced from dental tissues, such as PDLSCs and DPSCs, offer promising options for periodontal regeneration because they are more easily accessible and can be collected through minimally invasive methods. Currently, PDLSCs and DPSCs exhibit a strong ability to undergo osteogenic differentiation when stimulated by factors such as growth factors, chemicals, and paracrine signaling. It has been shown that aspirin (ASA) can enhance the osteoblastic potential of PDLSCs and DPSCs, although the exact mechanism remains unclear. This article examines the origin and features of mesenchymal stem cells, the bone regeneration potential of DPSCs and PDLSCs, the factors that enhance their osteogenic differentiation, and a comparison of PDLSCs and DPSCs regarding their proliferation and differentiation abilities. Additionally, we will examine the effects of aspirin on PDLSCs and DPSCs. In conclusion, PDLSCs show a greater effect on osteoblast differentiation.
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Affiliation(s)
- Fazliny Abd Rahman
- School of Dentistry (SoD), Management & Science University (MSU), University Drive, Off Persiaran Olahraga, 40100 Shah Alam, Selangor.
| | - Fatin Nur Azwa
- Faculty of Dentistry, Oral Cancer Research Centre (ORCC), University of Malaya (UM), Wilayah Persekutuan, Kuala Lumpur 50603, Malaysia
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Lu W, Yan L, Peng L, Wang X, Tang X, Du J, Lin J, Zou Z, Li L, Ye J, Zhou L. Efficacy and safety of mesenchymal stem cell therapy in acute on chronic liver failure: a systematic review and meta-analysis of randomized controlled clinical trials. Stem Cell Res Ther 2025; 16:197. [PMID: 40254564 PMCID: PMC12010635 DOI: 10.1186/s13287-025-04303-8] [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: 12/27/2024] [Accepted: 04/01/2025] [Indexed: 04/22/2025] Open
Abstract
BACKGROUND Acute-on-chronic liver failure has become a serious global health burden, which is characterized by an acute deterioration of liver function, rapidly evolving organ failure, and high short-term mortality in patients with chronic liver disease. The pathogenesis includes extensive hepatic necrosis, which is related to intense systemic inflammation and subsequently causes the inflammatory cytokine storm, resulting in portal hypertension, organ dysfunction, and organ failure. Mesenchymal stem cells can function as seed cells to remodel and repair damaged liver tissues, thus showing potential therapeutic alternatives for patients with chronic liver disease. However, standard treatment protocols for mesenchymal stem cells in acute-on-chronic liver failure patients have not been established. METHODS We conducted a detailed search from PubMed/Medline, Web of Science, EMBASE, and Cochrane Library to find randomized controlled trials published before October 23, 2021. We formulated criteria for the literature screening according to the PICOS principle (Population, Intervention, Comparison, Outcome, Study design). Subsequently, the bias risk assessment tool was used to assess the quality of all enrolled studies. Finally, outcome measurements including the model of end-stage liver disease score, albumin, total bilirubin, coagulation function, and aminotransferase were extracted for statistical analysis. RESULTS A total of 7 clinical trials were included. The results of enrolled studies indicated that patients with acute-on-chronic liver failure who received mesenchymal stem cells inoculation showed a decreased MELD score in 4 weeks and 24 weeks, compared with counterparts who received conventional treatment. Reciprocally, mesenchymal stem cells inoculation improved the ALB levels in 4 weeks and 24 weeks. For secondary indicators, mesenchymal stem cells treatment significantly reduced INR levels and ALT levels, compared with the control group. Our results showed no significant differences in the incidence of adverse reactions or serious adverse events monitored in patients after mesenchymal stem cells inoculation. CONCLUSION This meta-analysis indicated that mesenchymal stem cell infusion is effective and safe in the treatment of patients with acute-on-chronic liver failure. Without increasing the incidence of adverse events or serious adverse events, MSC treatment improved liver function including a decrease in MELD score and an increase in ALB levels in patients with acute-on-chronic liver failure. However, large-cohort randomized controlled trials with longer follow-up periods are required to further confirm our conclusions.
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Affiliation(s)
- Wenming Lu
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- School of Rehabilitation Medicine, Gannan Medical University, GanZhou City, Jiangxi, 341000, PR China
- The First Clinical College of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
| | - Longxiang Yan
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- School of Rehabilitation Medicine, Gannan Medical University, GanZhou City, Jiangxi, 341000, PR China
- The First Clinical College of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
| | - Lulu Peng
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- The First Clinical College of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
| | - Xuesong Wang
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- School of Rehabilitation Medicine, Gannan Medical University, GanZhou City, Jiangxi, 341000, PR China
| | - Xingkun Tang
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- School of Rehabilitation Medicine, Gannan Medical University, GanZhou City, Jiangxi, 341000, PR China
| | - Jing Du
- School of Rehabilitation Medicine, Gannan Medical University, GanZhou City, Jiangxi, 341000, PR China
| | - Jing Lin
- The First Clinical College of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
| | - Zhengwei Zou
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, Jiangxi, 341000, PR China
| | - Lincai Li
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, Jiangxi, 341000, PR China
| | - Junsong Ye
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, Jiangxi, 341000, PR China
- Key Laboratory of Prevention and treatment of cardiovascular and cerebrovascular diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- Key Laboratory for Tissue Engineering of Jiangxi Province, Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
| | - Lin Zhou
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China.
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, Jiangxi, 341000, PR China.
- Key Laboratory of Prevention and treatment of cardiovascular and cerebrovascular diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China.
- Key Laboratory for Tissue Engineering of Jiangxi Province, Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China.
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Zhou G, You Y, Wang B, Wang S, Feng T, Lai C, Xiang G, Yang K, Yao Y. A comprehensive evaluation system for ultrasound-guided infusion of human umbilical cord-derived MSCs in liver cirrhosis patients. Stem Cells Transl Med 2025; 14:szae081. [PMID: 39520328 PMCID: PMC11821905 DOI: 10.1093/stcltm/szae081] [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: 11/19/2023] [Accepted: 09/26/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Infusion of mesenchymal stem cells (MSCs) via portal vein is one of the main ways for MSCs transplantation to treat liver cirrhosis (LC). As the tissue of LC showed diffuse fibrosis and thickened Glission sheath, the soft pig-tail catheter, or central venous catheter can not successfully insert the portal vein. Thus, our study used an improved method and performed a relatively comprehensive system to evaluate the effect for human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) transplantation. METHOD Fifteen patients with hepatitis B-related cirrhosis were enrolled in the study, and we performed hUC-MSCs transplantation via portal vein by using an 16-G needle and 0.035-inch guide wire combined with 7FR "retentional metal stiffner trocar" of pig-tail catheter under the guidance of contrast-enhanced ultrasound. Serum liver function, fibrotic indicators, tissue stiffness, coagulation function, and hemodynamics were measured at weeks 4, 12, and 24 after MSCs transplantation. Liver biopsy was performed before and 24 weeks after hUC-MSCs transplantation. RESULT After hUC-MSCs transplantation, the prothrombin time was lower than before. The levels of hyaluronic acid and IV-C(Type IV collagen) in fibrotic indicators were significantly reduced, and the Young's modulus was also decreased. Moreover, liver biopsy showed that the lytic necrosis of hepatocyte was decreased. In liver hemodynamics, the portal vein diameter was decreased after hUC-MSCs transplantation. CONCLUSION hUC-MSCs transplantation can alleviate liver damage caused by LC. The improved "retentional metal stiffner trocar" of pig-tail catheter was safe and effective in the infusion of hUC-MSCs transplantation, which is worth promoting in clinical practice.
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Affiliation(s)
- Guo Zhou
- Department of Ultrasound, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, People’s Republic of China
| | - Yijuan You
- Department of Ultrasound, Wenjiang Hospital of Sichuan Provincial People’s Hospital, Chengdu 611100, People’s Republic of China
| | - Binghua Wang
- Department of Ultrasound, Wenjiang Hospital of Sichuan Provincial People’s Hospital, Chengdu 611100, People’s Republic of China
| | - Simin Wang
- Department of Ultrasound, Wenjiang Hospital of Sichuan Provincial People’s Hospital, Chengdu 611100, People’s Republic of China
| | - Tianhang Feng
- Department of Hepatobiliary and Pancreatic Surgery Center, Cell Transplantation Center, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, People’s Republic of China
| | - Chunyou Lai
- Department of Hepatobiliary and Pancreatic Surgery Center, Cell Transplantation Center, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, People’s Republic of China
| | - Guangming Xiang
- Department of Hepatobiliary and Pancreatic Surgery Center, Cell Transplantation Center, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, People’s Republic of China
| | - Ke Yang
- Department of Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, Chengdu 610072, People’s Republic of China
| | - Yutong Yao
- Department of Hepatobiliary and Pancreatic Surgery Center, Cell Transplantation Center, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, People’s Republic of China
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Gunardi H, Alatas FS, Antarianto RD, Rahayatri TH. The Effect of Intrahepatic and Intrasplenic Administration of Mesenchymal Stem Cell to Liver Function and Degree of Liver Fibrosis in Common Bile Duct Ligation Model in Rabbit. J Pediatr Surg 2024; 59:634-639. [PMID: 38160190 DOI: 10.1016/j.jpedsurg.2023.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 12/03/2023] [Indexed: 01/03/2024]
Abstract
BACKGROUND Mesenchymal stem cells (MSC) is a promising alternative method in liver cirrhosis management. Several administration routes of MSC have been studied, but few studies compared one to another. The purpose of this study is to compare the intrahepatic and intrasplenic route of MSC administration in terms of liver function and degree of liver fibrosis in the bile duct ligation model in rabbits. METHOD Experimental study was conducted using rabbits (Oryctolagus cuniculus) model undergoing bile duct ligation (BDL). The subjects were randomized into 4 groups: sham surgery; bile duct ligation; bile duct ligation followed by intrahepatic route of MSC (BDL + IH MSC), and bile duct ligation followed by intrasplenic route of MSC (BDL + IS MSC). Umbilical cord mesenchymal stem cell (UC MSC) was administered on the fifth day after bile duct ligation, and the subjects were observed until the fourteenth day after bile duct ligation. The liver function was evaluated with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total and direct bilirubin. The degree of fibrosis was evaluated with Laennec score, fibrosis area fraction, the number of viable and necrosis hepatocytes, and the number of hepatic progenitor cells. RESULT The subjects were randomized into 4 groups: 2 in sham surgery group, and 7 in each of the following groups: BDL, BDL + IH MSC and BDL + IS MSC groups. The mortality rate in BDL group was 57.1 %, while mortality in BDL + IH MSC and BDL + IS MSC groups were 14.3 % and 28.6 % respectively. No significant difference was found regarding liver function in each group, such as AST, ALT, total, and direct bilirubin. Histopathology examination in almost every subject undergone bile duct ligation (regardless of MSC administration) showed degree of fibrosis of Laennec 4B. Fibrosis area fraction, the number of viable and necrotic hepatocytes, and progenitor cells were analyzed; no significant difference was found between BDL + IH MSC and BDL + IS MSC groups, but the groups administered with MSC showed a larger number of viable hepatocytes compared to BDL group. No difference was found between BDL + IH MSC and BDL + IS MSC groups in terms of liver function and histologic parameters. CONCLUSION Administration of MSC increases the number of viable hepatocytes, but no difference was found in terms of liver function and degree of liver fibrosis between the intrahepatic route and intrasplenic route of administration. TYPE OF STUDY Animal Research, Randomized Controlled Study. LEVEL OF EVIDENCE Level I? (animal research is not indicated in the levels of evidence table in the journal website).
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Affiliation(s)
- Hardian Gunardi
- Pediatric Surgery Division, Department of Surgery, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo General Hospital, Jakarta, Indonesia.
| | - Fatima Safira Alatas
- Department of Pediatric and Adolescent Health, Faculty of Medicine Universitas Indonesia, Cipto Mangunkusumo General Hospital, Jakarta, Indonesia
| | | | - Tri Hening Rahayatri
- Pediatric Surgery Division, Department of Surgery, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo General Hospital, Jakarta, Indonesia
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Raoufinia R, Arabnezhad A, Keyhanvar N, Abdyazdani N, Saburi E, Naseri N, Niazi F, Niazi F, Namdar AB, Rahimi HR. Leveraging stem cells to combat hepatitis: a comprehensive review of recent studies. Mol Biol Rep 2024; 51:459. [PMID: 38551743 DOI: 10.1007/s11033-024-09391-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Accepted: 02/27/2024] [Indexed: 04/02/2024]
Abstract
Hepatitis is a significant global public health concern, with viral infections being the most common cause of liver inflammation. Antiviral medications are the primary treatments used to suppress the virus and prevent liver damage. However, the high cost of these drugs and the lack of awareness and stigma surrounding the disease create challenges in managing hepatitis. Stem cell therapy has arisen as a promising therapeutic strategy for hepatitis by virtue of its regenerative and immunomodulatory characteristics. Stem cells have the exceptional capacity to develop into numerous cell types and facilitate tissue regeneration, rendering them a highly promising therapeutic avenue for hepatitis. In animal models, stem cell therapy has demonstrated worthy results by reducing liver inflammation and improving liver function. Furthermore, clinical trials have been undertaken to assess the safety and effectiveness of stem cell therapy in individuals with hepatitis. This review aims to explore the involvement of stem cells in treating hepatitis and highlight the findings from studies conducted on both animals and humans. The objective of this review is to primarily concentrate on the ongoing and future clinical trials that assess the application of stem cell therapy in the context of hepatitis, including the transplantation of autologous bone marrow-derived stem cells, human induced pluripotent stem cells, and other mesenchymal stem cells. In addition, this review will explore the potential merits and constraints linked to stem cell therapy for hepatitis, as well as its prospective implications in the management of this disease.
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Affiliation(s)
- Ramin Raoufinia
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Ali Arabnezhad
- Department of Pharmacognosy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Neda Keyhanvar
- Department of Biochemistry & Biophysics, University of California San Francisco, San Francisco, CA, 94107, USA
| | - Nima Abdyazdani
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ehsan Saburi
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nima Naseri
- Department of Biochemistry, School of medicine, Hamadan University of medical sciences, Hamadan, Iran
| | - Fereshteh Niazi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Faezeh Niazi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Beheshti Namdar
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid Reza Rahimi
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Xu H, Huang Y, Zhang F, Shi W, Cheng Y, Yang K, Tian P, Zhou F, Wang Y, Fang X, Song Y, Liu B, Liu L. Ultrasonic microbubbles promote mesenchymal stem cell homing to the fibrotic liver via upregulation of CXCR4 expression. Cell Div 2024; 19:7. [PMID: 38402155 PMCID: PMC10894490 DOI: 10.1186/s13008-023-00104-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 12/02/2023] [Indexed: 02/26/2024] Open
Abstract
OBJECTIVE To investigate the mechanism of ultrasound microbubbles (UTMB) promoting stem cells homing to fibrotic liver. METHODS Bone marrow derived mesenchymal stem cells (BMSCs) were divided into 5 groups with or without ultrasound microbubbles and continuously irradiated with ultrasound conditions of frequency 1 MHZ and output power 0.6 W/cm2 for different times, and then injected into a mouse model of liver fibrosis through the tail vein with or without ultrasound microbubbles, with sound intensity. The effect of ultrasound microbubbles on MSC expression of CXC chemokine receptor 4 (CXCR4) and homing fibrotic liver was evaluated by flow cytometry (FCM), western blot (WB) and immunohistochemistry (IHC) analysis. RESULTS The level of CXCR4 expression was significantly higher in the ultrasound microbubble group than in the non-intervention group (P < 0.05), and the number of MSC and the rate of CXCR4 receptor positivity in the ultrasound microbubble-treated liver tissues were significantly higher than in the non-intervention group (P < 0.01). CONCLUSION Ultrasonic microbubbles can promote the expression of CXCR4 on the surface of MSCs, thus improving the homing rate of MSCs in fibrotic liver.
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Affiliation(s)
- Heming Xu
- Department of Infectious Diseases, Tongling People's Hospital, Tongling, 244000, Anhui, China
| | - Yize Huang
- Department of Infectious Diseases, Tongling People's Hospital, Tongling, 244000, Anhui, China
| | - Fasu Zhang
- College of Medical Technology, Anhui Medical College, Hefei, Anhui, China
| | - Wei Shi
- College of Medical Technology, Anhui Medical College, Hefei, Anhui, China
| | - Yan Cheng
- Department of Infectious Diseases, The 901th Hospital of PLA Joint Logistic Support Force, Hefei, 230031, Anhui, China
| | - Kai Yang
- College of Medical Technology, Anhui Medical College, Hefei, Anhui, China
| | - Pingping Tian
- College of Medical Technology, Anhui Medical College, Hefei, Anhui, China
| | - Fei Zhou
- College of Medical Technology, Anhui Medical College, Hefei, Anhui, China
| | - Yuan Wang
- College of Medical Technology, Anhui Medical College, Hefei, Anhui, China
| | - Xueqing Fang
- Department of Infectious Diseases, Tongling People's Hospital, Tongling, 244000, Anhui, China
| | - Youliang Song
- Department of Infectious Diseases, Tongling People's Hospital, Tongling, 244000, Anhui, China
| | - Bo Liu
- Department of Infectious Diseases, The 901th Hospital of PLA Joint Logistic Support Force, Hefei, 230031, Anhui, China.
| | - Liwei Liu
- College of Medical Technology, Anhui Medical College, Hefei, Anhui, China.
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Li H, Ji XQ, Zhang SM, Bi RH. Hypoxia and inflammatory factor preconditioning enhances the immunosuppressive properties of human umbilical cord mesenchymal stem cells. World J Stem Cells 2023; 15:999-1016. [PMID: 38058960 PMCID: PMC10696190 DOI: 10.4252/wjsc.v15.i11.999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/28/2023] [Accepted: 10/30/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have great potential for the treatment of various immune diseases due to their unique immunomodulatory properties. However, MSCs exposed to the harsh inflammatory environment of damaged tissue after intravenous transplantation cannot exert their biological effects, and therefore, their therapeutic efficacy is reduced. In this challenging context, an in vitro preconditioning method is necessary for the development of MSC-based therapies with increased immunomodulatory capacity and transplantation efficacy. AIM To determine whether hypoxia and inflammatory factor preconditioning increases the immunosuppressive properties of MSCs without affecting their biological characteristics. METHODS Umbilical cord MSCs (UC-MSCs) were pretreated with hypoxia (2% O2) exposure and inflammatory factors (interleukin-1β, tumor necrosis factor-α, interferon-γ) for 24 h. Flow cytometry, polymerase chain reaction, enzyme-linked immunosorbent assay and other experimental methods were used to evaluate the biological characteristics of pretreated UC-MSCs and to determine whether pretreatment affected the immunosuppressive ability of UC-MSCs in coculture with immune cells. RESULTS Pretreatment with hypoxia and inflammatory factors caused UC-MSCs to be elongated but did not affect their viability, proliferation or size. In addition, pretreatment significantly decreased the expression of coagulation-related tissue factors but did not affect the expression of other surface markers. Similarly, mitochondrial function and integrity were retained. Although pretreatment promoted UC-MSC apoptosis and senescence, it increased the expression of genes and proteins related to immune regulation. Pretreatment increased peripheral blood mononuclear cell and natural killer (NK) cell proliferation rates and inhibited NK cell-induced toxicity to varying degrees. CONCLUSION In summary, hypoxia and inflammatory factor preconditioning led to higher immunosuppressive effects of MSCs without damaging their biological characteristics.
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Affiliation(s)
- Hang Li
- Department of Histology and Embryology, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Xiao-Qing Ji
- School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Shu-Ming Zhang
- School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Ri-Hui Bi
- Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Hospital Affiliated to Shanxi Medical University, The Third Hospital of Shanxi Medical University, Taiyuan 030002, Shanxi Province, China.
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Lu W, Qu J, Yan L, Tang X, Wang X, Ye A, Zou Z, Li L, Ye J, Zhou L. Efficacy and safety of mesenchymal stem cell therapy in liver cirrhosis: a systematic review and meta-analysis. Stem Cell Res Ther 2023; 14:301. [PMID: 37864199 PMCID: PMC10590028 DOI: 10.1186/s13287-023-03518-x] [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: 07/04/2023] [Accepted: 09/22/2023] [Indexed: 10/22/2023] Open
Abstract
AIM Although the efficacy and safety of mesenchymal stem cell therapy for liver cirrhosis have been demonstrated in several studies. Clinical cases of mesenchymal stem cell therapy for patients with liver cirrhosis are limited and these studies lack the consistency of treatment effects. This article aimed to systematically investigate the efficacy and safety of mesenchymal stem cells in the treatment of liver cirrhosis. METHOD The data source included PubMed/Medline, Web of Science, EMBASE, and Cochrane Library, from inception to May 2023. Literature was screened by the PICOS principle, followed by literature quality evaluation to assess the risk of bias. Finally, the data from each study's outcome indicators were extracted for a combined analysis. Outcome indicators of the assessment included liver functions and adverse events. Statistical analysis was performed using Review Manager 5.4. RESULTS A total of 11 clinical trials met the selection criteria. The pooled analysis' findings demonstrated that both primary and secondary indicators had improved. Compared to the control group, infusion of mesenchymal stem cells significantly increased ALB levels in 2 weeks, 1 month, 3 months, and 6 months, and significantly decreased MELD score in 1 month, 2 months, and 6 months, according to a subgroup analysis using a random-effects model. Additionally, the hepatic arterial injection favored improvements in MELD score and ALB levels. Importantly, none of the included studies indicated any severe adverse effects. CONCLUSION The results showed that mesenchymal stem cell was effective and safe in the treatment of liver cirrhosis, improving liver function (such as a decrease in MELD score and an increase in ALB levels) in patients with liver cirrhosis and exerting protective effects on complications of liver cirrhosis and the incidence of hepatocellular carcinoma. Although the results of the subgroup analysis were informative for the selection of mesenchymal stem cells for clinical treatment, a large number of high-quality randomized controlled trials validations are still needed.
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Affiliation(s)
- Wenming Lu
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
- The First Clinical College of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
| | - Jiayang Qu
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
- The First Clinical College of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
| | - Longxiang Yan
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
- The First Clinical College of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
| | - Xingkun Tang
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
| | - Xuesong Wang
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
| | - Anqi Ye
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
| | - Zhengwei Zou
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, 341000, Jiangxi, People's Republic of China
| | - Lincai Li
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, 341000, Jiangxi, People's Republic of China
| | - Junsong Ye
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China.
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, 341000, Jiangxi, People's Republic of China.
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China.
- Key Laboratory of Biomaterials and Biofabrication in Tissue Engineering of Jiangxi Province, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China.
| | - Lin Zhou
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China.
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, 341000, Jiangxi, People's Republic of China.
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China.
- Key Laboratory of Biomaterials and Biofabrication in Tissue Engineering of Jiangxi Province, Gannan Medical University, Ganzhou, 341000, Jiangxi, People's Republic of China.
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9
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Wang YH, Wang ML, Tao YC, Wu DB, Chen EQ, Tang H. The high level of IL-1β in the serum of ACLF patients induces increased IL-8 expression in hUC-MSCs and reduces the efficacy of hUC-MSCs in liver failure. Stem Cell Res Ther 2023; 14:231. [PMID: 37649110 PMCID: PMC10468895 DOI: 10.1186/s13287-023-03455-9] [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: 07/24/2022] [Accepted: 08/17/2023] [Indexed: 09/01/2023] Open
Abstract
BACKGROUND Stem cells play a therapeutic role mainly through immunoregulation. However, the immunomodulatory function of stem cells may be affected by inflammation-related factors in patients' serum. Therefore, this study aims to investigate the possible mechanism by which acute-on-chronic liver failure (ACLF) patient serum influences the efficacy of hUC-MSCs. METHODS The serum of surviving and dead ACLF patients was collected to culture hUC-MSCs in vitro, and the hUC-MSCs cultured in the serum of ACLF patients were used to treat acute liver failure (ALF) rats. The therapeutic effect on the rats was evaluated by a survival curve, the transaminase level and liver histopathology. The expression of cytokines in hUC-MSCs was detected by Q-PCR and ELISA. RESULTS Serum pretreatment reduced the therapeutic effect of hUC-MSCs on ALF, especially pretreatment in the serum from dead ACLF patients. After hUC-MSCs were cultured in the serum of surviving or dead ACLF patients, the most differentially expressed factor was IL-8. Interfering with the expression of IL-8 in hUC-MSCs can improve the therapeutic effect of hUC-MSCs on ALF. The high level of IL-1β in the serum of dead ACLF patients causes the increased expression of IL-8 in hUC-MSCs through the activation of the NF-κB signaling pathway. Meanwhile, we found that the neutralizing IL-1β in serum from dead ACLF patients can improve the therapeutic effect of hUC-MSCs on ALF. CONCLUSION The high level of IL-1β in ACLF serum can promote the expression of IL-8 in hUC-MSCs through the NF-κB signaling pathway, thus reducing the effect of hUC-MSCs on ALF.
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Affiliation(s)
- Yong-Hong Wang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Meng-Lan Wang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Ya-Chao Tao
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Dong-Bo Wu
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - En-Qiang Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China.
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China.
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.
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10
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Mendiratta M, Mendiratta M, Mohanty S, Sahoo RK, Prakash H. Breaking the graft-versus-host-disease barrier: Mesenchymal stromal/stem cells as precision healers. Int Rev Immunol 2023; 43:95-112. [PMID: 37639700 DOI: 10.1080/08830185.2023.2252007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 08/08/2023] [Accepted: 08/21/2023] [Indexed: 08/31/2023]
Abstract
Mesenchymal Stromal/Stem Cells (MSCs) are multipotent, non-hematopoietic progenitor cells with a wide range of immune modulation and regenerative potential which qualify them as a potential component of cell-based therapy for various autoimmune/chronic inflammatory ailments. Their immunomodulatory properties include the secretion of immunosuppressive cytokines, the ability to suppress T-cell activation and differentiation, and the induction of regulatory T-cells. Considering this and our interest, we here discuss the significance of MSC for the management of Graft-versus-Host-Disease (GvHD), one of the autoimmune manifestations in human. In pre-clinical models, MSCs have been shown to reduce the severity of GvHD symptoms, including skin and gut damage, which are the most common and debilitating manifestations of this disease. While initial clinical studies of MSCs in GvHD cases were promising, the results were variable in randomized studies. So, further studies are warranted to fully understand their potential benefits, safety profile, and optimal dosing regimens. Owing to these inevitable issues, here we discuss various mechanisms, and how MSCs can be employed in managing GvHD, as a cellular therapeutic approach for this disease.
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Affiliation(s)
- Mohini Mendiratta
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | | | - Sujata Mohanty
- Stem Cell Facility, All India Institute of Medical Sciences, New Delhi, India
| | - Ranjit Kumar Sahoo
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Hridayesh Prakash
- Amity Centre for Translational Research, Amity University, Noida, India
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11
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Liu P, Mao Y, Xie Y, Wei J, Yao J. Stem cells for treatment of liver fibrosis/cirrhosis: clinical progress and therapeutic potential. Stem Cell Res Ther 2022; 13:356. [PMID: 35883127 PMCID: PMC9327386 DOI: 10.1186/s13287-022-03041-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 07/06/2022] [Indexed: 02/06/2023] Open
Abstract
Cost-effective treatment strategies for liver fibrosis or cirrhosis are limited. Many clinical trials of stem cells for liver disease shown that stem cells might be a potential therapeutic approach. This review will summarize the published clinical trials of stem cells for the treatment of liver fibrosis/cirrhosis and provide the latest overview of various cell sources, cell doses, and delivery methods. We also describe the limitations and strengths of various stem cells in clinical applications. Furthermore, to clarify how stem cells play a therapeutic role in liver fibrosis, we discuss the molecular mechanisms of stem cells for treatment of liver fibrosis, including liver regeneration, immunoregulation, resistance to injury, myofibroblast repression, and extracellular matrix degradation. We provide a perspective for the prospects of future clinical implementation of stem cells.
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Affiliation(s)
- Pinyan Liu
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Yongcui Mao
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Ye Xie
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Jiayun Wei
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Jia Yao
- The First Clinical Medical College of Lanzhou University, Lanzhou, China. .,Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China.
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12
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Zhou Q, Rong C, Gu T, Li H, Wu L, Zhuansun X, Zhao X, Xiao Z, Kuang Y, Xu S, Wang S. Mesenchymal stem cells improve liver fibrosis and protect hepatocytes by promoting microRNA-148a-5p-mediated inhibition of Notch signaling pathway. Stem Cell Res Ther 2022; 13:354. [PMID: 35883205 PMCID: PMC9327397 DOI: 10.1186/s13287-022-03030-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 07/04/2022] [Indexed: 11/11/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) are considered to be a potential therapeutic tool for liver fibrosis. Inhibiting the activation of hepatic stellate cells (HSCs) and protecting hepatocytes are important mechanisms for the anti-fibrotic effect of MSCs. However, how MSCs inhibit liver fibrosis by regulating the expression of microRNAs (miRNAs) has not been fully clarified. Methods Transforming growth factor-β1 (TGF-β1)-activated HSCs LX-2 were single cultured or co-cultured with human umbilical cord mesenchymal stem cells (HUC-MSCs). High-throughput sequencing was used to evaluate the differentially expressed microRNAs (DEMs) between the two groups. Quantitative real-time PCR (qRT-PCR), Western blot, and transfection experiments were used to investigate and screen the most significantly up-regulated DEM. Bioinformatics analysis was used to predict the target mRNAs and the potential functions of the DEM. The possible mechanism of HUC-MSCs against liver fibrosis was analyzed by co-culture experiment of HUC-MSCs with LX-2 cells, and HUC-MSCs treatment of Bile duct ligation (BDL)-induced liver fibrosis in mice. Finally, the mechanism of the DEM regulating liver fibrosis was confirmed in human liver fibrosis specimens. Results MicroRNA-148a-5p (miR-148a-5p) was the most significantly up-regulated DEM in activated LX-2 cells co-cultured with HUC-MSCs compared with LX-2 cells single cultured. Up-regulation of the expression of miR-148a-5p in activated LX-2 cells could significantly inhibit the expression of hepatic fibrosis markers α-SMA and Col1α1. Notch2 was one target gene of miR-148a-5p. Co-cultured with HUC-MSCs could inhibit the activation of LX-2 cells by inhibiting the expression of the Notch2 and the Notch signaling pathway. In addition, HUC-MSCs treatment could up-regulate the expression of miR-148a-5p in liver tissue and hepatocytes, promote the proliferation and avoid the apoptosis of hepatocytes, and reduce the degree of fibrosis by inhibiting expression of the Notch2 and the Notch signaling pathway in BDL-induced liver fibrosis mice. Moreover, miR-148a-5p was down-regulated and Notch2 was up-regulated in fibrotic human liver tissues compared with the normal livers. Conclusions HUC-MSCs treatment could inhibit HSCs activation, protect hepatocytes, and alleviate BDL-induced liver fibrosis in mice by up-regulating the expression of miR-148-5p and inhibiting the Notch signaling pathway. The down-regulation of miR-148-5p and up-regulation of Notch2 could be used as biomarkers to monitor the progression of liver fibrosis. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03030-8.
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Affiliation(s)
- Qing Zhou
- Department of Pathology, School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, 215123, China.,Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Chao Rong
- Department of Pathology, School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, 215123, China
| | - Tengfei Gu
- Department of Anesthesiology, People's Hospital of Lianshui County, Huaian, 223400, China
| | - Hongda Li
- Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Lei Wu
- Department of Pathology, School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, 215123, China
| | - Xuemei Zhuansun
- Department of Pathology, School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, 215123, China
| | - Xin Zhao
- Department of Pathology, School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, 215123, China
| | - Zuorun Xiao
- Department of Pathology, School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, 215123, China
| | - Yuting Kuang
- Department of General Surgery, First Affiliated Hospital of Soochow University, Suzhou, 215008, China
| | - Sanrong Xu
- Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China.
| | - Shouli Wang
- Department of Pathology, School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, 215123, China.
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13
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Yao L, Hu X, Dai K, Yuan M, Liu P, Zhang Q, Jiang Y. Mesenchymal stromal cells: promising treatment for liver cirrhosis. Stem Cell Res Ther 2022; 13:308. [PMID: 35841079 PMCID: PMC9284869 DOI: 10.1186/s13287-022-03001-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 05/13/2022] [Indexed: 11/11/2022] Open
Abstract
Liver fibrosis is a wound-healing process that occurs in response to severe injuries and is hallmarked by the excessive accumulation of extracellular matrix or scar tissues within the liver. Liver fibrosis can be either acute or chronic and is induced by a variety of hepatotoxic causes, including lipid deposition, drugs, viruses, and autoimmune reactions. In advanced fibrosis, liver cirrhosis develops, a condition for which there is no successful therapy other than liver transplantation. Although liver transplantation is still a viable option, numerous limitations limit its application, including a lack of donor organs, immune rejection, and postoperative complications. As a result, there is an immediate need for a different kind of therapeutic approach. Recent research has shown that the administration of mesenchymal stromal cells (MSCs) is an attractive treatment modality for repairing liver injury and enhancing liver regeneration. This is accomplished through the cell migration into liver sites, immunoregulation, hepatogenic differentiation, as well as paracrine mechanisms. MSCs can also release a huge variety of molecules into the extracellular environment. These molecules, which include extracellular vesicles, lipids, free nucleic acids, and soluble proteins, exert crucial roles in repairing damaged tissue. In this review, we summarize the characteristics of MSCs, representative clinical study data, and the potential mechanisms of MSCs-based strategies for attenuating liver cirrhosis. Additionally, we examine the processes that are involved in the MSCs-dependent modulation of the immune milieu in liver cirrhosis. As a result, our findings lend credence to the concept of developing a cell therapy treatment for liver cirrhosis that is premised on MSCs. MSCs can be used as a candidate therapeutic agent to lengthen the survival duration of patients with liver cirrhosis or possibly reverse the condition in the near future.
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Affiliation(s)
- Lichao Yao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Xue Hu
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Kai Dai
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Mengqin Yuan
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Pingji Liu
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Qiuling Zhang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Yingan Jiang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China.
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14
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Yuan M, Hu X, Yao L, Jiang Y, Li L. Mesenchymal stem cell homing to improve therapeutic efficacy in liver disease. Stem Cell Res Ther 2022; 13:179. [PMID: 35505419 PMCID: PMC9066724 DOI: 10.1186/s13287-022-02858-4] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 02/21/2022] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stem cell (MSC) transplantation, as an alternative strategy to orthotopic liver transplantation, has been evaluated for treating end-stage liver disease. Although the therapeutic mechanism of MSC transplantation remains unclear, accumulating evidence has demonstrated that MSCs can regenerate tissues and self-renew to repair the liver through differentiation into hepatocyte-like cells, immune regulation, and anti-fibrotic mechanisms. Multiple clinical trials have confirmed that MSC transplantation restores liver function and alleviates liver damage. A sufficient number of MSCs must be home to the target tissues after administration for successful application. However, inefficient homing of MSCs after systemic administration is a major limitation in MSC therapy. Here, we review the mechanisms and clinical application status of MSCs in the treatment of liver disease and comprehensively summarize the molecular mechanisms of MSC homing, and various strategies for promoting MSC homing to improve the treatment of liver disease.
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Affiliation(s)
- Mengqin Yuan
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xue Hu
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lichao Yao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yingan Jiang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China.
| | - Lanjuan Li
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China. .,State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
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15
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Sun X, Guo S. Effectiveness of cell- and colony stimulating factor-based therapy for liver cirrhosis: a network meta-analysis of randomized controlled trials. Cytotherapy 2022; 24:516-525. [PMID: 35227600 DOI: 10.1016/j.jcyt.2021.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 11/01/2021] [Accepted: 11/15/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND AIMS Cirrhosis is the 11th leading cause of death worldwide. Because of the limitations of liver transplantation, cell- and granulocyte colony-stimulating factor (G-CSF)-based therapies are considered potential treatment methods. This work analyzes the effectiveness of cell- and G-CSF-based therapies by network meta-analysis. METHODS A literature search was performed in four databases from inception to September 10, 2021. Registered randomized controlled trials (RCTs) evaluating cell-based therapies and/or G-CSF-based therapies for cirrhosis patients were included. Traditional and network meta-analyses were analyzed in terms of survival, model for end-stage liver disease (MELD) score, Child-Turcotte-Pugh (CTP) score, alanine aminotransferase levels and aspartate aminotransferase levels. RESULTS Twenty-four studies were included in this analysis. The results showed that G-CSF-based therapies (odds ratio [OR], 2.38, 95% confidence interval [CI], 1.49-3.79, P < 0.01) and cell-based therapies (OR, 1.54, 95% CI, 1.00-2.40, P = 0.048) improved the transplantation-free survival rate compared with standard medical treatment. Network analysis results showed that G-CSF combined with erythropoietin (EPO) and growth hormone (GH) had a therapeutic advantage, and cell-based therapy with mononuclear cell (MNC) hepatic artery injection and intravenous mesenchymal stem cells (MSCs) combined with G-CSF also had a relative advantage in terms of survival outcome. For the MELD score, G-CSF plus GH and MSC portal vein injection had relative advantages. G-CSF plus GH and G-CSF plus EPO had advantages in terms of CTP scores. The included strategies demonstrated no obvious improvement in liver injury indicators. CONCLUSIONS Cell-based therapy has potential therapeutic effects for liver cirrhosis. Among cell-based therapies, intravenous MSCs and hepatic artery injection of MNCs have advantageous therapeutic effects. The use of G-CSF was also noted in regimens that improved survival outcomes. However, more well-designed, large-scale RCTs are needed to confirm this conclusion.
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Affiliation(s)
- Xiaojun Sun
- Inpatients Department, Nanjing Qi-xia Xi-gang Community Health Service Centers, Nanjing, China
| | - Shilei Guo
- Research and Development Department, Nanjing Regenerative Medicine Engineering and Technology Research Center, Nanjing, China.
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16
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Feng Y, Luo J, Cheng J, Xu A, Qiu D, He S, Zheng D, Jia C, Zhang Q, Lin N. A Small-Molecule Cocktails-Based Strategy in Culture of Mesenchymal Stem Cells. Front Bioeng Biotechnol 2022; 10:819148. [PMID: 35360405 PMCID: PMC8963903 DOI: 10.3389/fbioe.2022.819148] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 02/11/2022] [Indexed: 12/28/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have a variety of unique properties, such as stem cell multipotency and immune regulation, making them attractive for use in cell therapy. Before infusion therapy, MSCs are required to undergo tissue separation, purification, and expansion in vitro for a certain duration. During the process of in vitro expansion of MSCs, the influence of culture time and environment can lead to cell senescence, increased heterogeneity, and function attenuation, which limits their clinical applications. We used a cocktail of three small-molecule compounds, ACY (A-83-01, CHIR99021, and Y-27632), to increase the proliferation activity of MSCs in vitro and reduce cell senescence. ACY inhibited the increase in heterogeneity of MSCs and conserved their differentiation potential. Additionally, ACY maintained the phenotype of MSCs and upregulated the expression of immunomodulatory factors. These results suggest that ACY can effectively improve the quantity and quality of MSCs.
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Affiliation(s)
- Yuan Feng
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jing Luo
- Department of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jintao Cheng
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Aimin Xu
- The First People’s Hospital of Kashi Prefecture, Kashi, China
| | - Dongbo Qiu
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Sixiao He
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Dayong Zheng
- The First People’s Hospital of Kashi Prefecture, Kashi, China
| | - Changchang Jia
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Qi Zhang
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Nan Lin
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
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17
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Wen C, Xie L, Hu C. Roles of mesenchymal stem cells and exosomes in interstitial cystitis/bladder pain syndrome. J Cell Mol Med 2021; 26:624-635. [PMID: 34953040 PMCID: PMC8817120 DOI: 10.1111/jcmm.17132] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/24/2021] [Accepted: 11/27/2021] [Indexed: 12/13/2022] Open
Abstract
Interstitial cystitis/bladder pain syndrome (IC/BPS) is characterized by several symptoms of higher sensitivity of the lower urinary tract, such as bladder pain/discomfort, urgency, urinary frequency, pelvic pain and nocturia. Although the pathophysiology of IC/BPS is not fully understood, the hypothesis suggests that mast cell activation, glycosaminoglycan (GAG) layer defects, urothelium permeability disruption, inflammation, autoimmune disorder and infection are potential mechanisms. Mesenchymal stem cells (MSCs) have been proven to protect against tissue injury in IC/BPS by migrating into bladders, differentiating into key bladder cells, inhibiting mast cell accumulation and cellular apoptosis, inhibiting inflammation and oxidative stress, alleviating collagen fibre accumulation and enhancing tissue regeneration in bladder tissues. In addition, MSCs can protect against tissue injury in IC/BPS by secreting various soluble factors, including exosomes and other soluble factors, with antiapoptotic, anti-inflammatory, angiogenic and immunomodulatory properties in a cell-to-cell independent manner. In this review, we comprehensively summarized the current potential pathophysiological mechanisms and standard treatments of IC/BPS, and we discussed the potential mechanisms and therapeutic effects of MSCs and MSC-derived exosomes in alleviating tissue injury in IC/BPS models.
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Affiliation(s)
- Chao Wen
- Department of Urology, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Liping Xie
- Department of Urology, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Chenxia Hu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,National Clinical Research Center for Infectious Diseases, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
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18
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Deng Y, Xia B, Chen Z, Wang F, Lv Y, Chen G. Stem Cell-based Therapy Strategy for Hepatic Fibrosis by Targeting Intrahepatic Cells. Stem Cell Rev Rep 2021; 18:77-93. [PMID: 34668120 DOI: 10.1007/s12015-021-10286-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/14/2021] [Indexed: 12/11/2022]
Abstract
The whole liver transplantation is the most effective treatment for end-stage fibrosis. However, the lack of available donors, immune rejection and total cost of surgery remain as the key challenges in advancing liver fibrosis therapeutics. Due to the multi-differentiation and low immunogenicity of stem cells, treatment of liver fibrosis with stem cells has been considered as a valuable new therapeutic modality. The pathological progression of liver fibrosis is closely related to the changes in the activities of intrahepatic cells. Damaged hepatocytes, activated Kupffer cells and other inflammatory cells lead to hepatic stellate cells (HSCs) activation, further promoting apoptosis of damaged hepatocytes, while stem cells can work on fibrosis-related intrahepatic cells through relevant transduction pathways. Herein, this article elucidates the phenomena and the mechanisms of the crosstalk between various types of stem cells and intrahepatic cells including HSCs and hepatocytes in the treatment of liver fibrosis. Then, the important influences of chemical compositions, mechanical properties and blood flow on liver fibrosis models with stem cell treatment are emphasized. Clinical trials on stem cell-based therapy for liver fibrosis are also briefly summarized. Finally, continuing challenges and future directions of stem cell-based therapy for hepatic fibrosis are discussed. In short, stem cells play an important advantage and have a great potential in treating liver fibrosis by interacting with intrahepatic cells. Clarifying how stem cells interact with intrahepatic cells to change the progression of liver fibrosis is of great significance for a deeper understanding of liver fibrosis mechanisms and targeted therapy.
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Affiliation(s)
- Yaxin Deng
- School of Pharmacy and Bioengineering, Chongqing University of Technology, No. 69 Hongguang Avenue, Banan District, Chongqing, 400054, People's Republic of China.,Chongqing Key Laboratory of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing, 400054, People's Republic of China
| | - Bin Xia
- Engineering Research Center for Waste Oil Recovery Technology and Equipment, Ministry of Education, Chongqing Technology and Business University, Chongqing, 400067, People's Republic of China
| | - Zhongmin Chen
- School of Pharmacy and Bioengineering, Chongqing University of Technology, No. 69 Hongguang Avenue, Banan District, Chongqing, 400054, People's Republic of China.,Chongqing Key Laboratory of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing, 400054, People's Republic of China
| | - Fuping Wang
- School of Pharmacy and Bioengineering, Chongqing University of Technology, No. 69 Hongguang Avenue, Banan District, Chongqing, 400054, People's Republic of China.,Chongqing Key Laboratory of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing, 400054, People's Republic of China
| | - Yonggang Lv
- Mechanobiology and Regenerative Medicine Laboratory, Bioengineering College, Chongqing University, Chongqing, 400044, People's Republic of China.,State Key Laboratory of New Textile Materials and Advanced Processing Technologies, Wuhan Textile University, Wuhan, 430200, People's Republic of China
| | - Guobao Chen
- School of Pharmacy and Bioengineering, Chongqing University of Technology, No. 69 Hongguang Avenue, Banan District, Chongqing, 400054, People's Republic of China. .,Chongqing Key Laboratory of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing, 400054, People's Republic of China.
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19
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Neshat SY, Quiroz VM, Wang Y, Tamayo S, Doloff JC. Liver Disease: Induction, Progression, Immunological Mechanisms, and Therapeutic Interventions. Int J Mol Sci 2021; 22:ijms22136777. [PMID: 34202537 PMCID: PMC8267746 DOI: 10.3390/ijms22136777] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/18/2021] [Accepted: 06/21/2021] [Indexed: 02/06/2023] Open
Abstract
The liver is an organ with impressive regenerative potential and has been shown to heal sizable portions after their removal. However, certain diseases can overstimulate its potential to self-heal and cause excessive cellular matrix and collagen buildup. Decompensation of liver fibrosis leads to cirrhosis, a buildup of fibrotic ECM that impedes the liver’s ability to efficiently exchange fluid. This review summarizes the complex immunological activities in different liver diseases, and how failure to maintain liver homeostasis leads to progressive fibrotic tissue development. We also discuss a variety of pathologies that lead to liver cirrhosis, such as alcoholic liver disease and chronic hepatitis B virus (HBV). Mesenchymal stem cells are widely studied for their potential in tissue replacement and engineering. Herein, we discuss the potential of MSCs to regulate immune response and alter the disease state. Substantial efforts have been performed in preclinical animal testing, showing promising results following inhibition of host immunity. Finally, we outline the current state of clinical trials with mesenchymal stem cells and other cellular and non-cellular therapies as they relate to the detection and treatment of liver cirrhosis.
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Affiliation(s)
- Sarah Y. Neshat
- Department of Biomedical Engineering, Translational Tissue Engineering Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (S.Y.N.); (V.M.Q.); (Y.W.); (S.T.)
| | - Victor M. Quiroz
- Department of Biomedical Engineering, Translational Tissue Engineering Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (S.Y.N.); (V.M.Q.); (Y.W.); (S.T.)
| | - Yuanjia Wang
- Department of Biomedical Engineering, Translational Tissue Engineering Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (S.Y.N.); (V.M.Q.); (Y.W.); (S.T.)
| | - Sebastian Tamayo
- Department of Biomedical Engineering, Translational Tissue Engineering Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (S.Y.N.); (V.M.Q.); (Y.W.); (S.T.)
| | - Joshua C. Doloff
- Department of Biomedical Engineering, Translational Tissue Engineering Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (S.Y.N.); (V.M.Q.); (Y.W.); (S.T.)
- Department of Materials Science and Engineering, Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA
- Sidney Kimmel Comprehensive Cancer Center, Oncology-Cancer Immunology Sidney Kimmel Comprehensive Cancer Center and the Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
- Correspondence:
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20
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El-Derany MO, AbdelHamid SG. Upregulation of miR-96-5p by bone marrow mesenchymal stem cells and their exosomes alleviate non-alcoholic steatohepatitis: Emphasis on caspase-2 signaling inhibition. Biochem Pharmacol 2021; 190:114624. [PMID: 34052187 DOI: 10.1016/j.bcp.2021.114624] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/23/2021] [Accepted: 05/25/2021] [Indexed: 11/29/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) has evolved as the most common and devastating chronic liver disease. This study aimed to explore the underlined mechanism for the therapeutic potentials of bone marrow mesenchymal stem cells (BM-MSCs) and their derived exosomes (BM-MSCs-Exo) in an experimental model of high fat diet (HFD) induced NASH. Rats were fed with HFD for 12 weeks. At the seventh week, BM-MSCs were given at a dose of 1x106 cell i.v., per rat. A total of three doses of BM-MSCs were given per each rat in six weeks. BM-MSCs-Exo were given at a dose of 15, 30 and 120 µg/kg i.v., twice per week for six weeks. Perfect homing to the liver was detected. Beneficial effects were reported to BM-MSCs or BM-MSCs-Exo cotreatment; where the highest anti-steatotic effects were attributed to BM-MSCs-Exo (120 µg/kg) showing significant downregulation of fatty acid synthesis (SREB1, 2, ACC), downregulation in lipid uptake (CD36); accompanied by significant upregulation in fatty acid oxidation (PPARα, CPT1). These events were associated with abrogation of hepatic steatosis and ballooning in HFD-induced NASH. BM-MSCs or BM-MSCs-Exo cotreatment exerted significant anti-apoptotic effects mediated by significant decrease in Bax/Bcl2 ratio. Besides, significant increase in mitochondrial mitophagy genes (Parkin, PINK1, ULK1, BNIP3L, ATG5, ATG7, ATG12) were detected in BM-MSCs or BM-MSCs-Exo cotreated groups. These findings are thought to be modulated through upregulation of miRNA-96-5p which leads to downregulation of its downstream target caspase-2. Being a critical player in NASH development, caspase-2 targeting by miRNA-96-5p could be a promising therapeutic modality to treat NASH.
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Affiliation(s)
- Marwa O El-Derany
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
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21
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Huang Y, Miyamoto D, Hidaka M, Adachi T, Gu WL, Eguchi S. Regenerative medicine for the hepatobiliary system: A review. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2020; 28:913-930. [PMID: 33314713 DOI: 10.1002/jhbp.882] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/05/2020] [Accepted: 11/20/2020] [Indexed: 12/16/2022]
Abstract
Liver transplantation, the only proven treatment for end-stage liver disease and acute liver failure, is hampered by the scarcity of donors. Regenerative medicine provides an alternative therapeutic approach. Tremendous efforts dedicated to liver regenerative medicine include the delivery of transplantable cells, microtissues, and bioengineered whole livers via tissue engineering and the maintenance of partial liver function via extracorporeal support. This brief review summarizes the current status of regenerative medicine for the hepatobiliary system. For liver regenerative medicine, the focus is on strategies for expansion of transplantable hepatocytes, generation of hepatocyte-like cells, and therapeutic potential of engineered tissues in liver disease models. For biliary regenerative medicine, the discussion concentrates on the methods for generation of cholangiocyte-like cells and strategies in the treatment of biliary disease. Significant advances have been made in large-scale and long-term expansion of liver cells. The development of tissue engineering and stem cell induction technology holds great promise for the future treatment of hepatobiliary diseases. The application of regenerative medicine in liver still lacks extensive animal experiments. Therefore, a large number of preclinical studies are necessary to provide sufficient evidence for their therapeutic effectiveness. Much remains to be done for the treatment of hepatobiliary diseases with regenerative medicine.
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Affiliation(s)
- Yu Huang
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.,Department of Surgery, School of Medicine, Guangzhou First People's Hospital, South China University of Technology, Guangdong, China
| | - Daisuke Miyamoto
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Masaaki Hidaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tomohiko Adachi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Wei-Li Gu
- Department of Surgery, School of Medicine, Guangzhou First People's Hospital, South China University of Technology, Guangdong, China
| | - Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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22
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Influences of Xeno-Free Media on Mesenchymal Stem Cell Expansion for Clinical Application. Tissue Eng Regen Med 2020; 18:15-23. [PMID: 33150562 DOI: 10.1007/s13770-020-00306-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 09/21/2020] [Accepted: 09/27/2020] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are multipotent somatic stem/progenitor cells that can be isolated from various tissues and have attracted increasing attention from the scientific community. This is due to MSCs showing great potential for incurable disease treatment, and most applications of MSCs involve tissue degeneration and treatment of immune- and inflammation-mediated diseases. Conventional MSC cultures contain fetal bovine serum (FBS), which is a common supplement for cell development but is also a risk factor for exposure to animal-derived pathogens. To avoid the risks resulting from the xenogeneic origin and animal-derived pathogens of FBS, xeno-free media have been developed and commercialized to satisfy MSC expansion demands for human clinical applications. This review summarized and provided an overview of xeno-free media that are currently used for MSC expansion. Additionally, we discussed the influences of different xeno-free media on MSC biology with particular regard to cell morphology, surface marker expression, proliferation, differentiation and immunomodulation. The xeno-free media can be serum-free and xeno-free media or media supplemented with some human-originating substances, such as human serum, human platelet lysates, human umbilical cord serum/plasma, or human plasma-derived supplements for cell culture medium. These media have capacity to maintain a spindle-shaped morphology, the expression of typical surface markers, and the capacity of multipotent differentiation and immunomodulation of MSCs. Xeno-free media showed potential for safe use for human clinical treatment. However, the influences of these xeno-free media on MSCs are various and any xeno-free medium should be examined prior to being used for MSC cultures.
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23
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Zhou GP, Jiang YZ, Sun LY, Zhu ZJ. Therapeutic effect and safety of stem cell therapy for chronic liver disease: a systematic review and meta-analysis of randomized controlled trials. Stem Cell Res Ther 2020; 11:419. [PMID: 32977828 PMCID: PMC7519526 DOI: 10.1186/s13287-020-01935-w] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 08/10/2020] [Accepted: 09/14/2020] [Indexed: 02/06/2023] Open
Abstract
Background Stem cell therapy is becoming an emerging therapeutic option for chronic liver disease (CLD). However, whether stem cell therapy is more effective than conventional treatment remains questionable. We performed a large-scale meta-analysis of randomized controlled trials (RCTs) to evaluate the therapeutic effects and safety of stem cell therapy for CLD. Methods We systematically searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov databases for the period from inception through March 16, 2020. Primary outcomes were all-cause mortality and adverse events related to stem cell therapy. Secondary outcomes included the model for end-stage liver disease score, total bilirubin, albumin, alanine aminotransferase, prothrombin activity, and international normalized ratio. The standardized mean difference (SMD) and odds ratio (OR) with 95% confidence interval (CI) were calculated using a random-effects model. Results Twenty-four RCTs were included and the majority of these studies showed a high risk of bias. The meta-analysis indicated that compared with conventional treatment, stem cell therapy was associated with improved survival and liver function including the model of end-stage liver disease score, total bilirubin, and albumin levels. However, it had no obvious beneficial effects on alanine aminotransferase level, prothrombin activity, and international normalized ratio. Subgroup analyses showed stem cell therapy conferred a short-term survival benefit for patients with acute-on-chronic liver failure (ACLF), a single injection was more effective than multiple injections, hepatic arterial infusion was more effective than intravenous infusion, and bone marrow-derived stem cells were more effective than those derived from the umbilical cord. Thirteen trials reported adverse events related to stem cell therapy, but no serious adverse events were reported. Conclusions Stem cell therapy is a safe and effective therapeutic option for CLD, while patients with ACLF benefit the most in terms of improved short-term survival. A single injection administration of bone marrow-derived stem cells via the hepatic artery has superior therapeutic effects.
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Affiliation(s)
- Guang-Peng Zhou
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China.,Clinical Center for Pediatric Liver Transplantation, Capital Medical University, No. 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China
| | - Yi-Zhou Jiang
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China.,Clinical Center for Pediatric Liver Transplantation, Capital Medical University, No. 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China
| | - Li-Ying Sun
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China.,Clinical Center for Pediatric Liver Transplantation, Capital Medical University, No. 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China.,Intensive Care Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Zhi-Jun Zhu
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China. .,Clinical Center for Pediatric Liver Transplantation, Capital Medical University, No. 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China.
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24
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Su DN, Wu SP, Xu SZ. Mesenchymal stem cell-based Smad7 gene therapy for experimental liver cirrhosis. Stem Cell Res Ther 2020; 11:395. [PMID: 32928296 PMCID: PMC7489041 DOI: 10.1186/s13287-020-01911-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 08/17/2020] [Accepted: 08/27/2020] [Indexed: 01/17/2023] Open
Abstract
Background Bone mesenchymal stem cells (MSCs) can promote liver regeneration and inhibit inflammation and hepatic fibrosis. MSCs also can serve as a vehicle for gene therapy. Smad7 is an essential negative regulatory gene in the TGF-β1/Smad signalling pathway. Activation of TGF-β1/Smad signalling accelerates liver inflammation and fibrosis; we therefore hypothesized that MSCs overexpressing the Smad7 gene might be a new cell therapy approach for treating liver fibrosis via the inhibition of TGF-β1/Smad signalling. Methods MSCs were isolated from 6-week-old Wistar rats and transduced with the Smad7 gene using a lentivirus vector. Liver cirrhosis was induced by subcutaneous injection of carbon tetrachloride (CCl4) for 8 weeks. The rats with established liver cirrhosis were treated with Smad7-MSCs by direct injection of cells into the main lobes of the liver. The expression of Smad7, Smad2/3 and fibrosis biomarkers or extracellular matrix proteins and histopathological change were assessed by quantitative PCR, ELISA and Western blotting and staining. Results The mRNA and protein level of Smad7 in the recipient liver and serum were increased after treating with Smad-MSCs for 7 and 21 days (P < 0.001). The serum levels of collagen I and III and collagenase I and III were significantly (P < 0.001) reduced after the treatment with Smad7-MSCs. The mRNA levels of TGF-β1, TGFBR1, α-SMA, TIMP-1, laminin and hyaluronic acid were decreased (P < 0.001), while MMP-1 increased (P < 0.001). The liver fibrosis score and liver function were significantly alleviated after the cell therapy. Conclusions The findings suggest that the MSC therapy with Smad7-MSCs is effective in the treatment of liver fibrosis in the CCl4-induced liver cirrhosis model. Inhibition of TGF-β1 signalling pathway by enhancement of Smad-7 expression could be a feasible cell therapy approach to mitigate liver cirrhosis.
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Affiliation(s)
- Dong-Na Su
- Department of Infectious Diseases, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), 1017 Dong Men Bei Road, Luo Hu District, Shenzhen, 518020, Guangdong Province, People's Republic of China
| | - Shi-Pin Wu
- Department of Infectious Diseases, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), 1017 Dong Men Bei Road, Luo Hu District, Shenzhen, 518020, Guangdong Province, People's Republic of China.
| | - Shang-Zhong Xu
- Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, University of Hull, Hull, HU6 7RX, UK.
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25
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Filho DM, de Carvalho Ribeiro P, Oliveira LF, Dos Santos ALRT, Parreira RC, Pinto MCX, Resende RR. Enhancing the Therapeutic Potential of Mesenchymal Stem Cells with the CRISPR-Cas System. Stem Cell Rev Rep 2020; 15:463-473. [PMID: 31147819 DOI: 10.1007/s12015-019-09897-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Mesenchymal stem cells (MSCs), also known as multipotent mesenchymal stromal stem cells, are found in the perivascular space of several tissues. These cells have been subject of intense research in the last decade due to their low teratogenicity, as well as their ability to differentiate into mature cells and to secrete immunomodulatory and trophic factors. However, they usually promote only a modest benefit when transplanted in experimental disease models, one of the limitations for their clinical application. The CRISPR-Cas system, in turn, is highlighted as a simple and effective tool for genetic engineering. This system was tested in clinical trials over a relatively short period of time after establishing its applicability to the edition of the mammalian cell genome. Similar to the research evolution in MSCs, the CRISPR-Cas system demonstrated inconsistencies that limited its clinical application. In this review, we outline the evolution of MSC research and its applicability, and the progress of the CRISPR-Cas system from its discovery to the most recent clinical trials. We also propose perspectives on how the CRISPR-Cas system may improve the therapeutic potential of MSCs, making it more beneficial and long lasting.
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Affiliation(s)
- Daniel Mendes Filho
- Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil
| | - Patrícia de Carvalho Ribeiro
- Laboratory of Immunology and Experimental Transplantation, São José do Rio Preto Medical School, São José do Rio Preto, São Paulo, Brazil.,Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Lucas Felipe Oliveira
- Department of Physiology, Biological and Natural Sciences Institute, Triangulo Mineiro Federal University, Uberaba, Minas Gerais, Brazil.,National Institute of Science and Technology for Regenerative Medicine (INCT-REGENERA-CNPq), Rio de Janeiro, RJ, Brazil.,Minas Gerais Network for Tissue Engineering and Cell Therapy (REMETTECFAPEMIG), Belo Horizonte, MG, Brazil
| | | | - Ricardo Cambraia Parreira
- Department of Pharmacology, Biological Sciences Institute, Goias Federal University, Goiania, Goias, Brazil.
| | - Mauro Cunha Xavier Pinto
- Department of Pharmacology, Biological Sciences Institute, Goias Federal University, Goiania, Goias, Brazil
| | - Rodrigo Ribeiro Resende
- Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
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26
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Fan XL, Zhang Y, Li X, Fu QL. Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy. Cell Mol Life Sci 2020; 77:2771-2794. [PMID: 31965214 PMCID: PMC7223321 DOI: 10.1007/s00018-020-03454-6] [Citation(s) in RCA: 332] [Impact Index Per Article: 66.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 01/02/2020] [Accepted: 01/03/2020] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem cells (MSCs) have been extensively investigated for the treatment of various diseases. The therapeutic potential of MSCs is attributed to complex cellular and molecular mechanisms of action including differentiation into multiple cell lineages and regulation of immune responses via immunomodulation. The plasticity of MSCs in immunomodulation allow these cells to exert different immune effects depending on different diseases. Understanding the biology of MSCs and their role in treatment is critical to determine their potential for various therapeutic applications and for the development of MSC-based regenerative medicine. This review summarizes the recent progress of particular mechanisms underlying the tissue regenerative properties and immunomodulatory effects of MSCs. We focused on discussing the functional roles of paracrine activities, direct cell-cell contact, mitochondrial transfer, and extracellular vesicles related to MSC-mediated effects on immune cell responses, cell survival, and regeneration. This will provide an overview of the current research on the rapid development of MSC-based therapies.
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Affiliation(s)
- Xing-Liang Fan
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Road II, Guangzhou, 510080, People's Republic of China
| | - Yuelin Zhang
- Department of Emergency, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Road II, Guangzhou, 510080, People's Republic of China
| | - Xin Li
- Department of Emergency, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Road II, Guangzhou, 510080, People's Republic of China
| | - Qing-Ling Fu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Road II, Guangzhou, 510080, People's Republic of China.
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China.
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27
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Hepatogenic Potential and Liver Regeneration Effect of Human Liver-derived Mesenchymal-Like Stem Cells. Cells 2020; 9:cells9061521. [PMID: 32580448 PMCID: PMC7348751 DOI: 10.3390/cells9061521] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 06/18/2020] [Accepted: 06/20/2020] [Indexed: 12/22/2022] Open
Abstract
Human liver-derived stem cells (hLD-SCs) have been proposed as a possible resource for stem cell therapy in patients with irreversible liver diseases. However, it is not known whether liver resident hLD-SCs can differentiate toward a hepatic fate better than mesenchymal stem cells (MSCs) obtained from other origins. In this study, we compared the differentiation ability and regeneration potency of hLD-SCs with those of human umbilical cord matrix-derived stem cells (hUC-MSCs) by inducing hepatic differentiation. Undifferentiated hLD-SCs expressed relatively high levels of endoderm-related markers (GATA4 and FOXA1). During directed hepatic differentiation supported by two small molecules (Fasudil and 5-azacytidine), hLD-SCs presented more advanced mitochondrial respiration compared to hUC-MSCs. Moreover, hLD-SCs featured higher numbers of hepatic progenitor cell markers on day 14 of differentiation (CPM and CD133) and matured into hepatocyte-like cells by day 7 through 21 with increased hepatocyte markers (ALB, HNF4A, and AFP). During in vivo cell transplantation, hLD-SCs migrated into the liver of ischemia-reperfusion injury-induced mice within 2 h and relieved liver injury. In the thioacetamide (TAA)-induced liver injury mouse model, transplanted hLD-SCs trafficked into the liver and spontaneously matured into hepatocyte-like cells within 14 days. These results collectively suggest that hLD-SCs hold greater hepatogenic potential, and hepatic differentiation-induced hLD-SCs may be a promising source of stem cells for liver regeneration.
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28
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Sameri S, Samadi P, Dehghan R, Salem E, Fayazi N, Amini R. Stem Cell Aging in Lifespan and Disease: A State-of-the-Art Review. Curr Stem Cell Res Ther 2020; 15:362-378. [DOI: 10.2174/1574888x15666200213105155] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 11/09/2019] [Accepted: 12/31/2019] [Indexed: 12/11/2022]
Abstract
Aging is considered as inevitable changes at different levels of genome, cell, and organism.
From the accumulation of DNA damages to imperfect protein homeostasis, altered cellular communication
and exhaustion of stem cells, aging is a major risk factor for many prevalent diseases, such as
cancer, cardiovascular disease, pulmonary disease, diabetes, and neurological disorders. The cells are
dynamic systems, which, through a cycle of processes such as replication, growth, and death, could
replenish the bodies’ organs and tissues, keeping an entire organism in optimal working order. In many
different tissues, adult stem cells are behind these processes, replenishing dying cells to maintain normal
tissue function and regenerating injured tissues. Therefore, adult stem cells play a vital role in preventing
the aging of organs and tissues, and can delay aging. However, during aging, these cells also
undergo some detrimental changes such as alterations in the microenvironment, a decline in the regenerative
capacity, and loss of function. This review aimed to discuss age-related changes of stem cells in
different tissues and cells, including skin, muscles, brain, heart, hair follicles, liver, and lung.
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Affiliation(s)
- Saba Sameri
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Pouria Samadi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Razieh Dehghan
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Elham Salem
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Nashmin Fayazi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Razieh Amini
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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29
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Cao Y, Ji C, Lu L. Mesenchymal stem cell therapy for liver fibrosis/cirrhosis. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:562. [PMID: 32775363 PMCID: PMC7347778 DOI: 10.21037/atm.2020.02.119] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Liver fibrosis represents a common outcome of most chronic liver diseases. Advanced fibrosis leads to cirrhosis for which no effective treatment is available except liver transplantation. Because of the limitations of liver transplantation, alternative therapeutic strategies are an urgent need to find. Recently, mesenchymal stem cells (MSCs) based therapy has been suggested as an attractive therapeutic option for liver fibrosis and cirrhosis, based on the promising results from preclinical and clinical studies. Although the precise mechanisms of MSC transplantation are still not fully understood, accumulating evidence has indicated that MSCs eliminate the progression of fibrosis due to their immune-modulatory properties. In this review, we summarise the properties of MSCs and their clinical application in the treatment of liver fibrosis and cirrhosis. We also discuss the mechanisms involved in MSC-dependent regulation of immune microenvironment in the context of liver fibrosis and cirrhosis.
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Affiliation(s)
- Yan Cao
- Nanjing Maternity and Child Health Care Institute, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing 210004, China
| | - Chenbo Ji
- Nanjing Maternity and Child Health Care Institute, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing 210004, China
| | - Ling Lu
- Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing 210029, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing 210029, China
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30
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Naji A, Eitoku M, Favier B, Deschaseaux F, Rouas-Freiss N, Suganuma N. Biological functions of mesenchymal stem cells and clinical implications. Cell Mol Life Sci 2019; 76:3323-3348. [PMID: 31055643 PMCID: PMC11105258 DOI: 10.1007/s00018-019-03125-1] [Citation(s) in RCA: 353] [Impact Index Per Article: 58.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 04/19/2019] [Accepted: 04/30/2019] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem cells (MSCs) are isolated from multiple biological tissues-adult bone marrow and adipose tissues and neonatal tissues such as umbilical cord and placenta. In vitro, MSCs show biological features of extensive proliferation ability and multipotency. Moreover, MSCs have trophic, homing/migration and immunosuppression functions that have been demonstrated both in vitro and in vivo. A number of clinical trials are using MSCs for therapeutic interventions in severe degenerative and/or inflammatory diseases, including Crohn's disease and graft-versus-host disease, alone or in combination with other drugs. MSCs are promising for therapeutic applications given the ease in obtaining them, their genetic stability, their poor immunogenicity and their curative properties for tissue repair and immunomodulation. The success of MSC therapy in degenerative and/or inflammatory diseases might depend on the robustness of the biological functions of MSCs, which should be linked to their therapeutic potency. Here, we outline the fundamental and advanced concepts of MSC biological features and underline the biological functions of MSCs in their basic and translational aspects in therapy for degenerative and/or inflammatory diseases.
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Affiliation(s)
- Abderrahim Naji
- Department of Environmental Medicine, Cooperative Medicine Unit, Research and Education Faculty, Medicine Science Cluster, Kochi Medical School, Kochi University, Kohasu, Oko-Cho, Nankoku, Kochi, 783-8505, Japan.
| | - Masamitsu Eitoku
- Department of Environmental Medicine, Cooperative Medicine Unit, Research and Education Faculty, Medicine Science Cluster, Kochi Medical School, Kochi University, Kohasu, Oko-Cho, Nankoku, Kochi, 783-8505, Japan
| | - Benoit Favier
- CEA, DRF-IBFJ, IDMIT, INSERM U1184, Immunology of Viral Infections and Autoimmune Diseases, Paris-Sud University, Fontenay-aux-Roses, France
| | - Frédéric Deschaseaux
- STROMALab, Etablissement Français du Sang Occitanie, UMR 5273 CNRS, INSERM U1031, Université de Toulouse, Toulouse, France
| | - Nathalie Rouas-Freiss
- CEA, DRF-Francois Jacob Institute, Research Division in Hematology and Immunology (SRHI), Saint-Louis Hospital, IRSL, UMRS 976, Paris, France
| | - Narufumi Suganuma
- Department of Environmental Medicine, Cooperative Medicine Unit, Research and Education Faculty, Medicine Science Cluster, Kochi Medical School, Kochi University, Kohasu, Oko-Cho, Nankoku, Kochi, 783-8505, Japan
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Feng J, Wang C, Liu T, Li J, Wu L, Yu Q, Li S, Zhou Y, Zhang J, Chen J, Ji J, Chen K, Mao Y, Wang F, Dai W, Fan X, Wu J, Guo C. Procyanidin B2 inhibits the activation of hepatic stellate cells and angiogenesis via the Hedgehog pathway during liver fibrosis. J Cell Mol Med 2019; 23:6479-6493. [PMID: 31328391 PMCID: PMC6714206 DOI: 10.1111/jcmm.14543] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 06/08/2019] [Accepted: 06/28/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Liver fibrosis is a wound-healing process of liver featured by the over-deposition of extracellular matrix (ECM) and angiogenesis. However, the effective treatment is lacking. Procyanidin B2 (PB2) is a flavonoid extract abundant in grape seeds with anti-oxidant, anti-inflammatory and anti-cancer properties. The present study aimed to determine effects of PB2 on liver fibrosis. METHOD The CCl4-induced mouse liver fibrosis model and a human hepatic stellate cell (HSC) line (LX2 cells) were used to study the activation, ECM production and angiogenesis of HSCs through Western blotting analysis, immunohistochemistry, immunofluorescence staining, flow cytometry and tubulogenesis assay. A Hedgehog (Hh) pathway inhibitor (cyclopamine) and Smoothened agonist (SAG) were used to investigate the role of PB2 on Hh pathway. RESULTS The results showed that PB2 could inhibit the proliferation and induce apoptosis of HSCs. PB2 could also down-regulate the expressions of VEGF-A, HIF-1α, α-SMA, Col-1 and TGF-β1 of HSCs in vivo and in vitro. The application of SAG and cyclopamine proved that PB2 targets on Hh pathway. CONCLUSIONS PB2 inhibited the Hh pathway to suppress the activation, ECM production and angiogenesis of HSCs, therefore reverses the progression of liver fibrosis in vivo and in vitro.
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Affiliation(s)
- Jiao Feng
- Department of Gastroenterology, Putuo People's HospitalTongji University School of MedicineShanghaiChina
- Department of Gastroenterology, Shanghai Tenth People's HospitalTongji University School of MedicineShanghaiChina
| | - Chengfen Wang
- Department of Gastroenterology, Putuo People's HospitalTongji University School of MedicineShanghaiChina
| | - Tong Liu
- Department of Gastroenterology, Shanghai Tenth People's HospitalTongji University School of MedicineShanghaiChina
| | - Jingjing Li
- Department of Gastroenterology, Putuo People's HospitalTongji University School of MedicineShanghaiChina
| | - Liwei Wu
- Department of Gastroenterology, Shanghai Tenth People's HospitalTongji University School of MedicineShanghaiChina
| | - Qiang Yu
- Department of Gastroenterology, Shanghai Tenth People's HospitalTongji University School of MedicineShanghaiChina
- Shanghai Tenth HospitalSchool of Clinical Medicine of Nanjing Medical UniversityShanghaiChina
| | - Sainan Li
- Department of Gastroenterology, Shanghai Tenth People's HospitalTongji University School of MedicineShanghaiChina
| | - Yuting Zhou
- Department of Gastroenterology, Shanghai Tenth People's HospitalTongji University School of MedicineShanghaiChina
- Shanghai Tenth HospitalSchool of Clinical Medicine of Nanjing Medical UniversityShanghaiChina
| | - Jie Zhang
- Department of Gastroenterology, Shanghai Tenth People's HospitalTongji University School of MedicineShanghaiChina
- Shanghai Tenth HospitalSchool of Clinical Medicine of Nanjing Medical UniversityShanghaiChina
| | - Jiaojiao Chen
- Department of Gastroenterology, Shanghai Tenth People's HospitalTongji University School of MedicineShanghaiChina
- Shanghai Tenth HospitalSchool of Clinical Medicine of Nanjing Medical UniversityShanghaiChina
| | - Jie Ji
- Department of Gastroenterology, Shanghai Tenth People's HospitalTongji University School of MedicineShanghaiChina
| | - Kan Chen
- Department of Gastroenterology, Shanghai Tenth People's HospitalTongji University School of MedicineShanghaiChina
| | - Yuqing Mao
- Department of Gerontology, Shanghai General HospitalShanghai Jiaotong University School of MedicineShanghaiChina
| | - Fan Wang
- Department of Oncology, Shanghai General HospitalShanghai Jiaotong University School of MedicineShanghaiChina
| | - Weiqi Dai
- Department of Gastroenterology, Putuo People's HospitalTongji University School of MedicineShanghaiChina
- Department of Gastroenterology, Shanghai Tenth People's HospitalTongji University School of MedicineShanghaiChina
- Department of GastroenterologyZhongshan Hospital of Fudan UniversityShanghaiChina
- Shanghai Institute of Liver DiseasesZhongshan Hospital of Fudan UniversityShanghaiChina
| | - Xiaoming Fan
- Department of GastroenterologyJinshan Hospital of Fudan UniversityJinshan, ShanghaiChina
| | - Jianye Wu
- Department of Gastroenterology, Putuo People's HospitalTongji University School of MedicineShanghaiChina
| | - Chuanyong Guo
- Department of Gastroenterology, Shanghai Tenth People's HospitalTongji University School of MedicineShanghaiChina
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Perucca Orfei C, Talò G, Viganò M, Perteghella S, Lugano G, Fabro Fontana F, Ragni E, Colombini A, De Luca P, Moretti M, Torre ML, de Girolamo L. Silk/Fibroin Microcarriers for Mesenchymal Stem Cell Delivery: Optimization of Cell Seeding by the Design of Experiment. Pharmaceutics 2018; 10:E200. [PMID: 30352986 PMCID: PMC6321597 DOI: 10.3390/pharmaceutics10040200] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 10/18/2018] [Accepted: 10/22/2018] [Indexed: 12/18/2022] Open
Abstract
In this methodological paper, lyophilized fibroin-coated alginate microcarriers (LFAMs) proposed as mesenchymal stem cells (MSCs) delivery systems and optimal MSCs seeding conditions for cell adhesion rate and cell arrangement, was defined by a Design of Experiment (DoE) approach. Cells were co-incubated with microcarriers in a bioreactor for different time intervals and conditions: variable stirring speed, dynamic culture intermittent or continuous, and different volumes of cells-LFAMs loaded in the bioreactor. Intermittent dynamic culture resulted as the most determinant parameter; the volume of LFAMs/cells suspension and the speed used for the dynamic culture contributed as well, whereas time was a less influencing parameter. The optimized seeding conditions were: 98 min of incubation time, 12.3 RPM of speed, and 401.5 µL volume of cells-LFAMs suspension cultured with the intermittent dynamic condition. This DoE predicted protocol was then validated on both human Adipose-derived Stem Cells (hASCs) and human Bone Marrow Stem Cells (hBMSCs), revealing a good cell adhesion rate on the surface of the carriers. In conclusion, microcarriers can be used as cell delivery systems at the target site (by injection or arthroscopic technique), to maintain MSCs and their activity at the injured site for regenerative medicine.
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Affiliation(s)
- Carlotta Perucca Orfei
- IRCCS Istituto Ortopedico Galeazzi, Orthopaedic Biotechnology Lab, Via R. Galeazzi 4, 20161 Milano, Italy.
| | - Giuseppe Talò
- IRCCS Istituto Ortopedico Galeazzi, Cells and Tissue Engineering Laboratory, Via R. Galeazzi 4, 20161 Milano, Italy.
| | - Marco Viganò
- IRCCS Istituto Ortopedico Galeazzi, Orthopaedic Biotechnology Lab, Via R. Galeazzi 4, 20161 Milano, Italy.
| | - Sara Perteghella
- Department of Drug Sciences, University of Pavia, via T. Taramelli 12, 27100 Pavia, Italy.
| | - Gaia Lugano
- IRCCS Istituto Ortopedico Galeazzi, Orthopaedic Biotechnology Lab, Via R. Galeazzi 4, 20161 Milano, Italy.
| | | | - Enrico Ragni
- IRCCS Istituto Ortopedico Galeazzi, Orthopaedic Biotechnology Lab, Via R. Galeazzi 4, 20161 Milano, Italy.
| | - Alessandra Colombini
- IRCCS Istituto Ortopedico Galeazzi, Orthopaedic Biotechnology Lab, Via R. Galeazzi 4, 20161 Milano, Italy.
| | - Paola De Luca
- IRCCS Istituto Ortopedico Galeazzi, Orthopaedic Biotechnology Lab, Via R. Galeazzi 4, 20161 Milano, Italy.
| | - Matteo Moretti
- IRCCS Istituto Ortopedico Galeazzi, Cells and Tissue Engineering Laboratory, Via R. Galeazzi 4, 20161 Milano, Italy.
| | - Maria Luisa Torre
- Department of Drug Sciences, University of Pavia, via T. Taramelli 12, 27100 Pavia, Italy.
| | - Laura de Girolamo
- IRCCS Istituto Ortopedico Galeazzi, Orthopaedic Biotechnology Lab, Via R. Galeazzi 4, 20161 Milano, Italy.
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