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Colli A, Fraquelli M, Prati D, Casazza G. Granulocyte colony-stimulating factor with or without stem or progenitor cell or growth factors infusion for people with compensated or decompensated advanced chronic liver disease. Cochrane Database Syst Rev 2023; 6:CD013532. [PMID: 37278488 PMCID: PMC10243114 DOI: 10.1002/14651858.cd013532.pub2] [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] [Indexed: 06/07/2023]
Abstract
BACKGROUND Advanced chronic liver disease is characterised by a long compensated phase followed by a rapidly progressive 'decompensated' phase, which is marked by the development of complications of portal hypertension and liver dysfunction. Advanced chronic liver disease is considered responsible for more than one million deaths annually worldwide. No treatment is available to specifically target fibrosis and cirrhosis; liver transplantation remains the only curative option. Researchers are investigating strategies to restore liver functionality to avoid or slow progression towards end-stage liver disease. Cytokine mobilisation of stem cells from the bone marrow to the liver could improve liver function. Granulocyte colony-stimulating factor (G-CSF) is a 175-amino-acid protein currently available for mobilisation of haematopoietic stem cells from the bone marrow. Multiple courses of G-CSF, with or without stem or progenitor cell or growth factors (erythropoietin or growth hormone) infusion, might be associated with accelerated hepatic regeneration, improved liver function, and survival. OBJECTIVES To evaluate the benefits and harms of G-CSF with or without stem or progenitor cell or growth factors (erythropoietin or growth hormone) infusion, compared with no intervention or placebo in people with compensated or decompensated advanced chronic liver disease. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, three other databases, and two trial registers (October 2022) together with reference-checking and web-searching to identify additional studies. We applied no restrictions on language and document type. SELECTION CRITERIA We only included randomised clinical trials comparing G-CSF, independent of the schedule of administration, as a single treatment or combined with stem or progenitor cell infusion, or with other medical co-interventions, with no intervention or placebo, in adults with chronic compensated or decompensated advanced chronic liver disease or acute-on-chronic liver failure. We included trials irrespective of publication type, publication status, outcomes reported, or language. DATA COLLECTION AND ANALYSIS We followed standard Cochrane procedures. All-cause mortality, serious adverse events, and health-related quality of life were our primary outcomes, and liver disease-related morbidity, non-serious adverse events, and no improvement of liver function scores were our secondary outcomes. We undertook meta-analyses, based on intention-to-treat, and presented results using risk ratios (RR) for dichotomous outcomes and the mean difference (MD) for continuous outcomes, with 95% confidence intervals (CI) and I2 statistic values as a marker of heterogeneity. We assessed all outcomes at maximum follow-up. We determined the certainty of evidence using GRADE, evaluated the risk of small-study effects in regression analyses, and conducted subgroup and sensitivity analyses. MAIN RESULTS We included 20 trials (1419 participants; sample size ranged from 28 to 259), which lasted between 11 and 57 months. Nineteen trials included only participants with decompensated cirrhosis; in one trial, 30% had compensated cirrhosis. The included trials were conducted in Asia (15), Europe (four), and the USA (one). Not all trials provided data for our outcomes. All trials reported data allowing intention-to-treat analyses. The experimental intervention consisted of G-CSF alone or G-CSF plus any of the following: growth hormone, erythropoietin, N-acetyl cysteine, infusion of CD133-positive haemopoietic stem cells, or infusion of autologous bone marrow mononuclear cells. The control group consisted of no intervention in 15 trials and placebo (normal saline) in five trials. Standard medical therapy (antivirals, alcohol abstinence, nutrition, diuretics, β-blockers, selective intestinal decontamination, pentoxifylline, prednisolone, and other supportive measures depending on the clinical status and requirement) was administered equally to the trial groups. Very low-certainty evidence suggested a decrease in mortality with G-CSF, administered alone or in combination with any of the above, versus placebo (RR 0.53, 95% CI 0.38 to 0.72; I2 = 75%; 1419 participants; 20 trials). Very low-certainty evidence suggested no difference in serious adverse events (G-CSF alone or in combination versus placebo: RR 1.03, 95% CI 0.66 to 1.61; I2 = 66%; 315 participants; three trials). Eight trials, with 518 participants, reported no serious adverse events. Two trials, with 165 participants, used two components of the quality of life score for assessment, with ranges from 0 to 100, where higher scores indicate better quality of life, with a mean increase from baseline of the physical component summary of 20.7 (95% CI 17.4 to 24.0; very low-certainty evidence) and a mean increase from baseline of the mental component summary of 27.8 (95% CI 12.3 to 43.3; very low-certainty evidence). G-CSF, alone or in combination, suggested a beneficial effect on the proportion of participants who developed one or more liver disease-related complications (RR 0.40, 95% CI 0.17 to 0.92; I2 = 62%; 195 participants; four trials; very low-certainty evidence). When we analysed the occurrences of single complications, there was no suggestion of a difference between G-CSF, alone or in combination, versus control, in participants in need of liver transplantation (RR 0.85, 95% CI 0.39 to 1.85; 692 participants; five trials), in the development of hepatorenal syndrome (RR 0.65, 95% CI 0.33 to 1.30; 520 participants; six trials), in the occurrence of variceal bleeding (RR 0.68, 95% CI 0.37 to 1.23; 614 participants; eight trials), and in the development of encephalopathy (RR 0.56, 95% CI 0.31 to 1.01; 605 participants; seven trials) (very low-certainty evidence). The same comparison suggested that G-CSF reduces the development of infections (including sepsis) (RR 0.50, 95% CI 0.29 to 0.84; 583 participants; eight trials) and does not improve liver function scores (RR 0.67, 95% CI 0.53 to 0.86; 319 participants; two trials) (very low-certainty evidence). AUTHORS' CONCLUSIONS G-CSF, alone or in combination, seems to decrease mortality in people with decompensated advanced chronic liver disease of whatever aetiology and with or without acute-on-chronic liver failure, but the certainty of evidence is very low because of high risk of bias, inconsistency, and imprecision. The results of trials conducted in Asia and Europe were discrepant; this could not be explained by differences in participant selection, intervention, and outcome measurement. Data on serious adverse events and health-related quality of life were few and inconsistently reported. The evidence is also very uncertain regarding the occurrence of one or more liver disease-related complications. We lack high-quality, global randomised clinical trials assessing the effect of G-CSF on clinically relevant outcomes.
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Affiliation(s)
- Agostino Colli
- Department of Transfusion Medicine and Haematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Mirella Fraquelli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Daniele Prati
- Department of Transfusion Medicine and Haematology, Ospedale Alessandro Manzoni, Lecco, Italy
| | - Giovanni Casazza
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
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Jindal A, Jagdish RK, Kumar A. Hepatic Regeneration in Cirrhosis. J Clin Exp Hepatol 2022; 12:603-616. [PMID: 35535091 PMCID: PMC9077225 DOI: 10.1016/j.jceh.2021.08.029] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 08/31/2021] [Indexed: 01/03/2023] Open
Abstract
End-stage liver disease is characterized by massive hepatocyte death resulting in clinical decompensation and organ failures. Clinical consequences in cirrhosis are the results of the loss of functional hepatocytes and excessive scarring. The only curative therapy in advanced cirrhosis is orthotropic liver transplantation, but the clinical demand outweighs the availability of acceptable donor organs. Moreover, this also necessitates lifelong immunosuppression and carries associated risks. The liver has a huge capability for regeneration. Self-replication of quiescent differentiated hepatocytes and cholangiocytes occurs in patients with acute liver injury. Due to limited hepatocyte self-renewal capacity in advanced cirrhosis, great interest has therefore been shown in characterizing the possible role of hepatic progenitor cells and bone marrow-derived stem cells to therapeutically aid this process. Transplantation of cells from various sources that can be properly differentiated into functional liver cells or use of growth factors for ex-vivo expansion of progenitor cells is needed at utmost priority. Multiple researches over the last two decades have aided researchers in refining proliferation, differentiation, and storage techniques and understand the functionality of these cells for use in clinical practice. However, these cell-based therapies are still experimental and have to be used in trial settings.
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Key Words
- Ang2, angiopoietin 2
- BM, Bone marrow
- BM-MNCs, bone marrow mononuclear cells
- BMSC, bone marrow stem cells
- DAMPs, Damage associated molecular patterns
- EPCs, endothelial progenitor cells
- ESRP2, epithelial splicing regulatory protein 2
- GCSF
- HGF, hepatocyte growth factor
- HPC, Hepatocyte progenitor cells
- HSCs, hematopoietic stem cells
- Hh, Hedgehog
- HybHP, hybrid periportal hepatocytes
- MMP, matrix metalloprotease
- MSCs, mesenchymal stromal cells
- OLT, Orthotropic liver transplantation
- PAMPs, Pathogen associated molecular patterns
- SAH, severe alcoholic hepatitis
- SDF1, stromal-derived factor 1
- TNFSF12, tumor necrosis factor ligand superfamily member 12
- Terthigh, high Telomerase reverse transcriptase
- [Hnf4a], Hepatocyte Nuclear Factor 4 Alpha
- [Mfsd2a], Major Facilitator Superfamily Domain containing 2A
- acute liver failure
- chronic liver diseases
- hepatocyte transplant
- liver regeneration
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Affiliation(s)
- Ankur Jindal
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi 110070, India
| | | | - Anupam Kumar
- Department of Research, Institute of Liver and Biliary Sciences, New Delhi 110070, India
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Ichinohe N, Ishii M, Tanimizu N, Mizuguchi T, Yoshioka Y, Ochiya T, Suzuki H, Mitaka T. Extracellular vesicles containing miR-146a-5p secreted by bone marrow mesenchymal cells activate hepatocytic progenitors in regenerating rat livers. Stem Cell Res Ther 2021; 12:312. [PMID: 34051870 PMCID: PMC8164814 DOI: 10.1186/s13287-021-02387-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 05/13/2021] [Indexed: 02/06/2023] Open
Abstract
Background Small hepatocyte-like progenitor cells (SHPCs) appear to form transient clusters in rat livers treated with retrorsine (Ret) and 70% partial hepatectomy (PH). We previously reported that the expansion of SHPCs was amplified in Ret/PH-treated rat livers transplanted with Thy1+ cells derived from d-galactosamine-treated injured livers. Extracellular vesicles (EVs) produced by hepatic Thy1+ donor cells activated SHPCs via interleukin (IL)-17 receptor B signaling. As bone marrow-derived mesenchymal cells (BM-MCs) also express Thy1, we aimed to determine whether BM-MCs could also promote the growth of SHPCs. Methods BM-MCs were isolated from dipeptidyl-peptidase IV (DPPIV)-positive rats. BM-MCs or BM-MC-derived EVs were administered to DPPIV-negative Ret/PH rat livers, and the growth and the characteristics of SHPC clusters were evaluated 14 days post-treatment. miRNA microarrays and cytokine arrays examined soluble factors within EVs. Small hepatocytes (SHs) isolated from an adult rat liver were used to identify factors enhancing hepatocytic progenitor cells growth. Results The recipient’s livers were enlarged at 2 weeks post-BM-MC transplantation. The number and the size of SHPCs increased remarkably in livers transplanted with BM-MCs. BM-MC-derived EVs also stimulated SHPC growth. Comprehensive analyses revealed that BM-MC-derived EVs contained miR-146a-5p, interleukin-6, and stem cell factor, which could enhance SHs’ proliferation. Administration of EVs derived from the miR-146a-5p-transfected BM-MCs to Ret/PH rat livers remarkably enhanced the expansion of SHPCs. Conclusions miR-146a-5p involved in EVs produced by BM-MCs may play a major role in accelerating liver regeneration by activating the intrinsic hepatocytic progenitor cells. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02387-6.
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Affiliation(s)
- Norihisa Ichinohe
- Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo, 060-8556, Japan.
| | - Masayuki Ishii
- Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo, 060-8556, Japan.,Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Naoki Tanimizu
- Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo, 060-8556, Japan
| | - Toru Mizuguchi
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Nursing, Sapporo Medical University School of Health Science, Sapporo, Japan
| | - Yusuke Yoshioka
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.,Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
| | - Takahiro Ochiya
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.,Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Toshihiro Mitaka
- Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo, 060-8556, Japan.
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De A, Kumari S, Singh A, Kaur A, Sharma R, Bhalla A, Sharma N, Kalra N, Singh V. Multiple Cycles of Granulocyte Colony-Stimulating Factor Increase Survival Times of Patients With Decompensated Cirrhosis in a Randomized Trial. Clin Gastroenterol Hepatol 2021; 19:375-383.e5. [PMID: 32088302 DOI: 10.1016/j.cgh.2020.02.022] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 02/01/2020] [Accepted: 02/07/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS There is controversy regarding the inclusion of granulocyte colony stimulating factor (G-CSF) in the treatment of decompensated cirrhosis. Previous studies tested only a single cycle of G-CSF administration or were underpowered to detect changes in survival time. We performed an adequately powered study to determine whether multiple cycles of G-CSF increased the survival of patients 1 year after the start of therapy. METHODS We conducted an open-label trial of 100 patients with decompensated cirrhosis without acute-on-chronic liver failure at a tertiary center from July 2016 through June 2018. The patients were assigned randomly to a group given 5 days of G-CSF every 3 months, with standard medical therapy, in 4 cycles (group A, n = 50), or standard medical therapy alone (group B, n = 50). The primary outcome was survival for 12 months after treatment began. Secondary outcomes were an increase in the number of CD34+ cells at day 6 compared with day 0, along with reductions in Child-Turcotte-Pugh and model for end-stage liver disease scores, increased control of ascites, reduced decompensation and episodes of infection, fewer hospitalizations, lower liver stiffness measurements, increased quality of life and nutrition, fulfilment of liver transplant criteria, and fewer adverse events at 12 months after the start of treatment. RESULTS Groups A and B were comparable at baseline. Survival at 12 months after initiation of treatment was significantly higher in group A (74%) than in group B (42%) (P < .001). Blood samples from patients in group A had significantly more CD34+ cells on day 6 than on day 0 (P < .001); there was no significant change in group B. Compared with patients in group B, patients in group A had significant reductions in Child-Turcotte-Pugh and model for end-stage liver disease scores, increased ascites control, fewer infections and hospitalizations, lower liver stiffness measurements, an increased quality of life, and a lower number fulfilled the liver transplant criteria (P < .05). There was no improvement in nutrition in either group compared with baseline. G-CSF was safe and well tolerated. CONCLUSIONS Administration of multiple cycles of G-CSF increases the numbers of hematopoietic stem cells and survival of patients with decompensated cirrhosis receiving standard medical treatment. The addition of G-CSF to medical treatment might provide a bridge to liver transplantation for these patients. ClincialTrials.gov no: NCT03415698.
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Affiliation(s)
- Arka De
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Sunita Kumari
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Akash Singh
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Amritjyot Kaur
- Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Rattiram Sharma
- Department of Transfusion Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Ashish Bhalla
- Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Navneet Sharma
- Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Naveen Kalra
- Department of Radiodiagnosis and Imaging, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Virendra Singh
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
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Assis-Mendonça GR, Cunha-Silva M, Fernandes MF, Torres LD, de Almeida Verissimo MP, Okano MTN, Mazo DF, Lalli CA, Sevá-Pereira T, Stelini RF, da Costa LBE. Massive iron overload and acute-on-chronic liver failure in a patient with Diamond-Blackfan anaemia: a case report. BMC Gastroenterol 2020; 20:332. [PMID: 33045993 PMCID: PMC7552380 DOI: 10.1186/s12876-020-01468-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 09/23/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Genetic anaemias lead us to reflect on the classic 'trolley dilemma', when there are two choices but neither one is satisfactory. Either we do not treat anaemia and the patient suffers from chronic tiredness and fatigue, or we do treat it through blood transfusions, leading to iron overload, which is a quite harmful consequence. CASE PRESENTATION We present the case of a 34-year-old woman with Diamond-Blackfan anaemia (DBA). Bone marrow stem cell transplantation had not been accessible during her childhood, so she had been submitted to monthly blood transfusions throughout her life, leading to a hepatitis C virus infection (which was treated, achieving a sustained virological response when she was 18 years old), and secondary haemochromatosis. Despite chelation therapy, diffuse iron deposition was occurring in multiple organs, markedly in the heart and liver. Her serum ferritin was higher than 21,000 ng/mL and transferrin saturation reached 102%. When she faced heart decompensation, this congestive condition led to an acute liver injury overlapping pre-existing hepatic fibrosis. She progressed to haemodynamic and hepatic failure, with clinical features of acute-on-chronic liver failure (ACLF). Despite therapeutic optimisation, she died of respiratory insufficiency. An autopsy was performed and revealed the macroscopic and microscopic findings of a massive iron deposition in the liver, heart, lungs, spleen, bone marrow, thyroid and adrenal glands. We found marked advance of liver fibrosis (chronic damage), as well as necrosis of hepatocytes in zone 3 of the Rappaport acinus (acute damage), supporting the hypothesis of ACLF. The main feature responsible for acute liver decompensation seemed to be heart insufficiency. CONCLUSION This is the first case reporting the sequence: DBA, multiple blood transfusions, secondary haemochromatosis, advanced liver fibrosis, heart failure, ACLF and death. A multidisciplinary team is essential to care for DBA patients, since there is a significant emotional burden related to the disease, which might impair an effective chelation therapy and lead to severe consequences due to iron deposition.
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Affiliation(s)
- Guilherme Rossi Assis-Mendonça
- Department of Pathology, University of Campinas (UNICAMP), Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, Campinas, SP, 13.083-887, Brazil.
| | - Marlone Cunha-Silva
- Division of Gastroenterology (Gastrocentro), University of Campinas (UNICAMP), Campinas, Brazil
| | | | - Luiza Dias Torres
- Division of Gastroenterology (Gastrocentro), University of Campinas (UNICAMP), Campinas, Brazil
| | | | - Marcelo Trevisan Neves Okano
- Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil
| | - Daniel Ferraz Mazo
- Division of Gastroenterology (Gastrocentro), University of Campinas (UNICAMP), Campinas, Brazil
| | - Cristina Alba Lalli
- Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil
| | - Tiago Sevá-Pereira
- Division of Gastroenterology (Gastrocentro), University of Campinas (UNICAMP), Campinas, Brazil
| | - Rafael Fantelli Stelini
- Department of Pathology, University of Campinas (UNICAMP), Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, Campinas, SP, 13.083-887, Brazil
| | - Larissa Bastos Eloy da Costa
- Department of Pathology, University of Campinas (UNICAMP), Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, Campinas, SP, 13.083-887, Brazil
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Colli A, Prati D, Fraquelli M, Casazza G. Granulocyte colony‐stimulating factor with or without stem or progenitor cell infusion for people with compensated or decompensated advanced chronic liver disease. Cochrane Database Syst Rev 2020; 2020:CD013532. [PMCID: PMC7005932 DOI: 10.1002/14651858.cd013532] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2025]
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the benefits and harms of granulocyte colony‐stimulating factor with or without stem or progenitor cell infusion in people with compensated or decompensated advanced chronic liver disease.
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Affiliation(s)
- Agostino Colli
- A Manzoni Hospital ASST LeccoDepartment of Internal MedicineVia dell'Eremo, 9/11LeccoItaly23900
| | - Daniele Prati
- Ospedale Alessandro ManzoniDepartment of Transfusion Medicine and HaematologyLeccoItaly
| | - Mirella Fraquelli
- Fondazione IRCCS Ca´ Granda ‐ Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation, Università degli Studi di MilanoGastroenterology and Endoscopy UnitVia F. Sforza, 35MilanItaly20122
| | - Giovanni Casazza
- Università degli Studi di MilanoDipartimento di Scienze Biomediche e Cliniche "L. Sacco"via GB Grassi 74MilanItaly20157
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Wang WS, Zhu XL, Shen J, Li MM, Tang HH, Li WC, Miao JC, Wei WX, Ni CF. Feasibility and Short-Term Stability of Portal Vein Infusion Port Placement by Transjugular Access. J Vasc Interv Radiol 2020; 31:425-429. [PMID: 31982318 DOI: 10.1016/j.jvir.2019.08.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 08/02/2019] [Accepted: 08/13/2019] [Indexed: 11/25/2022] Open
Abstract
Six pigs underwent implantation of a portal vein infusion port by transjugular access. The technical success rate was 100% (n = 6), with no surgical complications or deaths. At 1 month after implantation, the catheter tip had moved from the splenic vein to the main portal vein, while the catheter protruded into the right ventricle through the right atrium in all cases. Hence, the infusion port system has not been used in clinical practice due to its obvious displacement after implantation. However, this study provides a new idea for future exploration of portal vein infusion pathways.
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Affiliation(s)
- Wan-Sheng Wang
- Department of Interventional Radiology, The First Affiliated Hospital, Soochow University, No. 188 Shizi Road, Suzhou 215006, China
| | - Xiao-Li Zhu
- Department of Interventional Radiology, The First Affiliated Hospital, Soochow University, No. 188 Shizi Road, Suzhou 215006, China
| | - Jian Shen
- Department of Interventional Radiology, The First Affiliated Hospital, Soochow University, No. 188 Shizi Road, Suzhou 215006, China; Department of Cell Biology and Institute of Bioengineering, School of Medicine, Soochow University, Suzhou, China
| | - Ming-Ming Li
- Department of Interventional Radiology, The First Affiliated Hospital, Soochow University, No. 188 Shizi Road, Suzhou 215006, China
| | - Hao-Huan Tang
- Department of Interventional Radiology, The First Affiliated Hospital, Soochow University, No. 188 Shizi Road, Suzhou 215006, China
| | - Wan-Ci Li
- Department of Interventional Radiology, The First Affiliated Hospital, Soochow University, No. 188 Shizi Road, Suzhou 215006, China
| | - Jing-Cheng Miao
- Department of Cell Biology and Institute of Bioengineering, School of Medicine, Soochow University, Suzhou, China
| | - Wen-Xiang Wei
- Department of Cell Biology and Institute of Bioengineering, School of Medicine, Soochow University, Suzhou, China
| | - Cai-Fang Ni
- Department of Interventional Radiology, The First Affiliated Hospital, Soochow University, No. 188 Shizi Road, Suzhou 215006, China.
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Philips CA, Augustine P, Ahamed R, Rajesh S, George T, Valiathan GC, John SK. Role of Granulocyte Colony-stimulating Factor Therapy in Cirrhosis, 'Inside Any Deep Asking Is the Answering'. J Clin Transl Hepatol 2019; 7:371-383. [PMID: 31915607 PMCID: PMC6943215 DOI: 10.14218/jcth.2019.00034] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 09/20/2019] [Accepted: 10/05/2019] [Indexed: 12/13/2022] Open
Abstract
Liver cirrhosis progresses through multiple clinical stages which culminate in either death or liver transplantation. Availability of organs, timely listing and prompt receipt of donor-livers pose difficulties in improving transplant-listed and transplant outcomes. In this regard, regenerative therapies, particularly with granulocyte colony-stimulating factor (GCSF), has become a lucrative option for improving transplant-free survival. However, the literature is confusing with regards to patient selection and real outcomes. In this exhaustive review, we describe the basics of liver fibrosis and cirrhosis through novel insights from a therapeutic point of view, discuss preclinical studies on GCSF in advanced liver disease to improve on clinical utility, shed light on the pertinent literature of GCSF in advanced cirrhosis, and provide astute inputs on growth factor therapy in decompensated cirrhosis.
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Affiliation(s)
- Cyriac Abby Philips
- The Liver Unit and Monarch Liver Lab, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, Kerala, India
| | - Philip Augustine
- Department of Gastroenterology, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, Kerala, India
| | - Rizwan Ahamed
- Department of Gastroenterology, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, Kerala, India
| | - Sasidharan Rajesh
- Interventional Radiology, Hepatobiliary Division, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, Kerala, India
| | - Tom George
- Interventional Radiology, Hepatobiliary Division, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, Kerala, India
| | - Gopakumar C. Valiathan
- Department of Hepatobiliary and Transplant Surgery, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, Kerala, India
| | - Solomon K. John
- Department of Hepatobiliary and Transplant Surgery, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, Kerala, India
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Noorwali A, Faidah M, Ahmed N, Bima A. Tracking iron oxide labelled mesenchymal stem cells(MSCs) using magnetic resonance imaging (MRI) in a rat model of hepatic cirrhosis. Bioinformation 2019; 15:1-10. [PMID: 31359992 PMCID: PMC6651036 DOI: 10.6026/97320630015001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 12/24/2018] [Indexed: 01/07/2023] Open
Abstract
Homing and tumor attenuation potential of BM-MSCs labelled with superparamagnetic iron-oxide nanoparticles (SPIONs) in a rat model of hepatic cirrhosis was evaluated. Rat BM-MSCs were derived, characterized and labelled with SPIONs (200 nm; 25 mg Fe/ml). Hepatic cirrhosis was induced in Wistar rats (n=30; 10/group) with carbon tetrachloride (CCl4; 0.3 mL/kg body weight) injected twice a week for 12 weeks. Group-I was administered vehicle (castor-oil) alone; Group-II received two doses of unlabelled BM-MSCs (3x106 cells) and Group-III received two doses of SPIONs labelled BM-MSCs (3x106 cells) via tail vein injection (0.5 ml) at weekly intervals. All animals were sacrificed after two weeks for histological, radiological and biochemical analysis. Derived BM-MSCs demonstrated MSCs related CD markers. Histology confirmed induction of hepatic cirrhosis with CCL4. Levels of alanine-aminotransferase, aspartate-aminotransferase,alkaline-phosphatase and gamma glutamyl-transferase returned to normal levels following treatment with BM-MSCs. Uptake and homing of SPIONs labelled BM-MSCs, and reduction in the size of cirrhotic nodules were confirmed using transmission electron microscopy and magnetic resonance imaging respectively. BM-MSCs reduced the pathological effects of CCL4 induced hepatic cirrhosis and labelling BMMSCs with SPIONs were non-toxic and enabled efficient tracking using non-invasive methods.
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Affiliation(s)
- Abdulwahab Noorwali
- Stem Cell Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Mamdooh Faidah
- Department of Medical Laboratory,College of Health Sciences,King Abdulaziz University,Jeddah 21589 Saudi Arabia
| | - Naushad Ahmed
- Department of Radiology,King Abdulaziz University Hospital,King Abdulaziz University,Jeddah 21589, Saudi Arabia
| | - Abdulhadi Bima
- Department of Clinical Biochemistry,King Abdulaziz University Hospital,King Abdulaziz University,Jeddah 21 89,Saudi Arabia
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10
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Verma N, Kaur A, Sharma R, Bhalla A, Sharma N, De A, Singh V. Outcomes after multiple courses of granulocyte colony-stimulating factor and growth hormone in decompensated cirrhosis: A randomized trial. Hepatology 2018; 68:1559-1573. [PMID: 29278428 DOI: 10.1002/hep.29763] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Revised: 11/27/2017] [Accepted: 12/15/2017] [Indexed: 12/20/2022]
Abstract
UNLABELLED Decompensated cirrhosis (DC) carries a high mortality. Liver transplantation (LT) is the treatment of choice; however, the limited availability of donor organs has resulted in high waitlist mortality. The present study investigated the impact of multiple courses of granulocyte-colony stimulating factor (G-CSF) with or without growth hormone (GH) in these patients. Sixty-five patients with DC were randomized to standard medical therapy (SMT) plus G-CSF 3 monthly plus GH daily (group A; n = 23) or SMT plus G-CSF (group B; n = 21) or SMT alone (group C; n = 21). The primary outcome was transplant-free survival (TFS) at 12 months. Secondary outcomes were mobilization of CD34+ cells at day 6 and improvement in clinical scores, liver stiffness, nutrition, episodes of infection, and quality of life (QOL) at 12 months. There was significantly better 12-month TFS in groups A and B than in group C (P = 0.001). At day 6 of therapy, CD34+ cells increased in groups A and B compared to baseline (P < 0.001). There was a significant decrease in clinical scores, improvement in nutrition, better control of ascites, reduction in liver stiffness, lesser infection episodes, and improvement in QOL scores in groups A and B at 12 months as compared to baseline (P < 0.05). The therapies were well tolerated. CONCLUSION Multiple courses of G-CSF improved 12-month TFS, mobilized hematopoietic stem cells, improved disease severity scores, nutrition, fibrosis, QOL scores, ascites control, reduced infections, and the need for LT in patients with DC. However, the use of GH was not found to have any additional benefit. (Hepatology 2017).
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Affiliation(s)
- Nipun Verma
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Amritjyot Kaur
- Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Ratiram Sharma
- Department of Transfusion Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Ashish Bhalla
- Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Navneet Sharma
- Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Arka De
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Virendra Singh
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
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11
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Verma N, Singh A, Singh V. Reply. Hepatology 2018; 68:388. [PMID: 29500901 DOI: 10.1002/hep.29864] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 02/22/2018] [Accepted: 02/27/2018] [Indexed: 12/07/2022]
Affiliation(s)
- Nipun Verma
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Akash Singh
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Virendra Singh
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
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12
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13
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Lanthier N, Lin-Marq N, Rubbia-Brandt L, Clément S, Goossens N, Spahr L. Autologous bone marrow-derived cell transplantation in decompensated alcoholic liver disease: what is the impact on liver histology and gene expression patterns? Stem Cell Res Ther 2017; 8:88. [PMID: 28420441 PMCID: PMC5395856 DOI: 10.1186/s13287-017-0541-2] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 03/20/2017] [Accepted: 03/22/2017] [Indexed: 01/01/2023] Open
Abstract
Background Liver stem cell therapy (SCT) has been suggested as a promising means to improve liver regeneration in advanced liver disease. However, data from trials are heterogeneous, with no systematic histological evaluation. The aim of this study is to specifically analyze the effect of autologous SCT on liver regeneration and on gene expression changes. Methods Individuals in the randomized controlled trial of SCT in alcoholic hepatitis with paired liver biopsies were included (n = 58). Immunohistochemistry (Ki67, K7, and CD68), in situ hybridization (SPINK1), and global gene expression analysis were performed on liver biopsies (30 control patients and 28 patients with transarterial administration of bone marrow-derived stem cells) both at baseline and after 4 weeks of follow-up. Results No difference between the two groups could be observed regarding the proliferative hepatocyte number, proliferative K7-positive cells, or total K7-positive cells at the 4-week follow-up liver biopsy. However, patients who received SCT showed a more important liver macrophagic expansion as compared to standard treatment. Transcriptome data revealed changes in genes linked with inflammation (CD68 and SAA), regeneration (SPINK1 and HGF), fibrosis (COL1A1), and stem cells (CD45). No changes in gene pathways involved in liver growth and cell cycle proteins were evident. SPINK1 mRNA was present by in situ hybridization at week 4 in SCT patients in the liver parenchyma areas adjacent to macrophage recruitment and liver cell proliferation. Conclusions The analysis of liver tissue after SCT demonstrated an expansion of macrophages concurrent with an upregulated expression of genes involved in inflammatory and regenerative pathways. With the negative results from the clinical trial, the impact of the SCT has to be interpreted as weak, and it is not able to modify the clinical course of this severe liver disease. Electronic supplementary material The online version of this article (doi:10.1186/s13287-017-0541-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Nicolas Lanthier
- Gastroenterology and Hepatology, University Hospitals and Faculty of Medicine, 4, Rue Gabrielle Perret-Gentil CH-1211, Geneva 14, Switzerland.,Laboratory of Gastroenterology and Hepatology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
| | - Nathalie Lin-Marq
- Clinical Pathology, University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Laura Rubbia-Brandt
- Clinical Pathology, University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Sophie Clément
- Clinical Pathology, University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Nicolas Goossens
- Gastroenterology and Hepatology, University Hospitals and Faculty of Medicine, 4, Rue Gabrielle Perret-Gentil CH-1211, Geneva 14, Switzerland
| | - Laurent Spahr
- Gastroenterology and Hepatology, University Hospitals and Faculty of Medicine, 4, Rue Gabrielle Perret-Gentil CH-1211, Geneva 14, Switzerland.
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14
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Kholodenko IV, Kholodenko RV, Manukyan GV, Yarygin KN. [The hepatic differentiation of adult and fetal liver stromal cells in vitro]. BIOMEDIT︠S︡INSKAI︠A︡ KHIMII︠A︡ 2017; 62:674-682. [PMID: 28026812 DOI: 10.18097/pbmc20166206674] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The liver has a marked capacity for regeneration. In most cases the liver regeneration is determined by hepatocytes. The regenerative capacity of hepatocytes is significantly reduced in acute or chronic damage. In particular, repair mechanisms are not activated in patients with alcoholic cirrhosis. Organ transplantation or advanced methods of regenerative medicine can help such patients. The promising results were obtained in clinical trials involving patients with various forms of liver disease who received transplantation of autologous bone marrow stem cells. However, to improve the effectiveness of such treatment it is necessary to search for more optimal sources of progenitor cells, as well as to evaluate the possibility of using descendants of these cells differentiated in vitro. In this study we isolated stromal cells from the liver biopsies of three patients with alcoholic cirrhosis, conducted their morphological and phenotypic analysis, and evaluated the hepatic potential of these cells in vitro. The stromal cells isolated from fetal liver were used for comparison. The results of this can serve as a basis for the development of a new method for the treatment of end-stage liver disease. The stromal cells isolated from the liver biopsies for a long time proliferate in a culture and this which makes it possible to expand them to large amounts for subsequent differentiation into hepatocyte-like cells and autologous transplantation.
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Affiliation(s)
| | - R V Kholodenko
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
| | - G V Manukyan
- Russian National Research Center of Surgery, Moscow, Russia
| | - K N Yarygin
- Institute of Biomedical Chemistry, Moscow, Russia
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15
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Zakikhan K, Pournasr B, Vosough M, Nassiri-Asl M. In Vitro Generated Hepatocyte-Like Cells: A Novel Tool in Regenerative Medicine and Drug Discovery. CELL JOURNAL 2017; 19:204-217. [PMID: 28670513 PMCID: PMC5412779 DOI: 10.22074/cellj.2016.4362] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Accepted: 09/05/2016] [Indexed: 12/19/2022]
Abstract
Hepatocyte-like cells (HLCs) are generated from either various human pluripotent stem
cells (hPSCs) including induced pluripotent stem cells (iPSCs) and embryonic stem cells
(ESCs), or direct cell conversion, mesenchymal stem cells as well as other stem cells like
gestational tissues. They provide potential cell sources for biomedical applications. Liver
transplantation is the gold standard treatment for the patients with end stage liver disease,
but there are many obstacles limiting this process, like insufficient number of donated
healthy livers. Meanwhile, the number of patients receiving a liver organ transplant for
a better life is increasing. In this regard, HLCs may provide an adequate cell source to
overcome these shortages. New molecular engineering approaches such as CRISPR/
Cas system applying in iPSCs technology provide the basic principles of gene correction
for monogenic inherited metabolic liver diseases, as another application of HLCs. It has
been shown that HLCs could replace primary human hepatocytes in drug discovery and
hepatotoxicity tests. However, generation of fully functional HLCs is still a big challenge;
several research groups have been trying to improve current differentiation protocols to
achieve better HLCs according to morphology and function of cells. Large-scale generation
of functional HLCs in bioreactors could make a new opportunity in producing enough
hepatocytes for treating end-stage liver patients as well as other biomedical applications
such as drug studies. In this review, regarding the biomedical value of HLCs, we focus
on the current and efficient approaches for generating hepatocyte-like cells in vitro and
discuss about their applications in regenerative medicine and drug discovery.
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Affiliation(s)
- Kobra Zakikhan
- Cellular and Molecular Research Center, Department of Molecular Medicine, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Behshad Pournasr
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Biomedicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Marjan Nassiri-Asl
- Cellular and Molecular Research Center, Department of Molecular Medicine, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran.,Cellular and Molecular Research Center, Department of Pharmacology, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
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16
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Wang H, Wang D, Yang L, Wang Y, Jia J, Na D, Chen H, Luo Y, Liu C. Compact bone-derived mesenchymal stem cells attenuate nonalcoholic steatohepatitis in a mouse model by modulation of CD4 cells differentiation. Int Immunopharmacol 2016; 42:67-73. [PMID: 27889556 DOI: 10.1016/j.intimp.2016.11.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 11/03/2016] [Accepted: 11/14/2016] [Indexed: 12/29/2022]
Abstract
Increasing evidence has accrued which indicates that mesenchymal stem cells (MSCs) have a potential clinical value in the treatment of certain diseases. Globally, nonalcoholic steatohepatitis (NASH) is a widespread disorder. In the present study, MSCs were isolated successfully from compact bone and a mouse model of NASH was established as achieved with use of a methionine-choline deficient (MCD) diet. Compact bone-derived MSCs transplantation reduced MCD diet-induced weight loss, hepatic lipid peroxidation, steatosis, ballooning, lobular inflammation and fibrogenesis. It was shown that MSCs treatment hampered MCD diet-induced proliferation of CD4+ IFN-γ+ and CD4+IL-6+ T spleen cells. In addition, CD4+IL-17+ lymphocytes that associated with anti-inflammation show little change in MCD as well as in MCD+MSCs splenocytes. We conclude that MSCs may have a potential clinical value upon NASH, through their capacity to suppress activation of CD4+ IFN-γ+ and CD4+IL-6+ lymphocytes.
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Affiliation(s)
- Huafeng Wang
- Modern College of Arts and Science, or School of Life Science, Shanxi Normal University, Linfen, China.
| | - Dong Wang
- Central Blood Station of Tianjin, Tianjin, China
| | - Luhong Yang
- Modern College of Arts and Science, or School of Life Science, Shanxi Normal University, Linfen, China
| | - Yanxia Wang
- Modern College of Arts and Science, or School of Life Science, Shanxi Normal University, Linfen, China
| | - Junli Jia
- Modern College of Arts and Science, or School of Life Science, Shanxi Normal University, Linfen, China
| | - Dongchen Na
- Modern College of Arts and Science, or School of Life Science, Shanxi Normal University, Linfen, China
| | - Huize Chen
- Modern College of Arts and Science, or School of Life Science, Shanxi Normal University, Linfen, China
| | - Yongping Luo
- Modern College of Arts and Science, or School of Life Science, Shanxi Normal University, Linfen, China
| | - Chengfang Liu
- Department of Human anatomy, Shanxi Medical University, Taiyuan, China; Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
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17
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Fagoonee S, Famulari ES, Silengo L, Camussi G, Altruda F. Prospects for Adult Stem Cells in the Treatment of Liver Diseases. Stem Cells Dev 2016; 25:1471-1482. [PMID: 27503633 DOI: 10.1089/scd.2016.0144] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Hepatocytes constitute the main bulk of the liver and perform several essential functions. After injury, the hepatocytes have a remarkable capacity to regenerate and restore functionality. However, in some cases, the endogenous hepatocytes cannot replicate or restore the function, and liver transplantation, which is not exempt of complications, is required. Stem cells offer in theory the possibility of generating unlimited supply of hepatocytes in vitro due to their capacity to self-renew and differentiate when given the right cues. Stem cells isolated from an array of tissues have been investigated for their capacity to differentiate into hepatocyte-like cells in vitro and are employed in rescue experiments in vivo. Adult stem cells have gained in attractiveness over embryonic stem cells for liver cell therapy due to their origin, multipotentiality, and the possibility of autologous transplantation. This review deals with the promise and limitations of adult stem cells in clinically restoring liver functionality.
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Affiliation(s)
- Sharmila Fagoonee
- 1 Institute of Biostructure and Bioimaging , CNR, Turin, Italy .,2 Molecular Biotechnology Center, University of Turin , Turin, Italy .,3 Department of Molecular Biotechnology and Health Sciences, University of Turin , Turin, Italy
| | - Elvira Smeralda Famulari
- 2 Molecular Biotechnology Center, University of Turin , Turin, Italy .,3 Department of Molecular Biotechnology and Health Sciences, University of Turin , Turin, Italy
| | - Lorenzo Silengo
- 2 Molecular Biotechnology Center, University of Turin , Turin, Italy .,3 Department of Molecular Biotechnology and Health Sciences, University of Turin , Turin, Italy
| | - Giovanni Camussi
- 2 Molecular Biotechnology Center, University of Turin , Turin, Italy .,4 Department of Medical Sciences, University of Torino , Torino, Italy
| | - Fiorella Altruda
- 2 Molecular Biotechnology Center, University of Turin , Turin, Italy .,3 Department of Molecular Biotechnology and Health Sciences, University of Turin , Turin, Italy
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18
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Than NN, Tomlinson CL, Haldar D, King AL, Moore D, Newsome PN. Clinical effectiveness of cell therapies in patients with chronic liver disease and acute-on-chronic liver failure: a systematic review protocol. Syst Rev 2016; 5:100. [PMID: 27301957 PMCID: PMC4908794 DOI: 10.1186/s13643-016-0277-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 05/31/2016] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Chronic liver disease (CLD) is a major health burden worldwide. Liver cirrhosis, a form of CLD is the fifth most common cause of death in the UK. Acute-on-chronic liver failure (ACLF) is the result of an acute insult superimposed on patients with liver cirrhosis as a result of precipitating events such as infection or bleeding. ACLF has a high associated mortality as a result of multi-organ failure. The only effective treatment for CLD is liver transplantation, but the treatment is limited by shortage of donor organs. As a result, alternative treatments such as cell therapies have been studied in patients with liver diseases. This study will systematically review the evidence on clinical effectiveness of cell therapies in patients. METHODS All types of study design that investigate the effectiveness of cell therapies (haematopoietic, mesenchymal and unsorted cell types) of autologous or allogeneic origin and/or the use of granulocyte colony-stimulating factor in patients with CLD including ACLF will be included (except case reports). Both autologous and allogenic cell types will be included. The primary outcomes of interest are survival, model for end-stage liver disease score, quality of life and adverse events. Secondary outcomes include liver function tests, Child-Pugh score and events of liver decompensation. A literature search will be conducted in the following databases: MEDLINE, MEDLINE in Process, EMBASE and Cochrane Library (CENTRAL, CDSR, DARE, HTA databases). Trial registers will be searched for ongoing trials, as will conference proceedings. Reference lists of relevant articles and systematic reviews will be screened. Randomised controlled trial (RCT) evidence is likely to be scant; therefore, controlled trials and concurrently controlled observational studies will be primarily analysed and uncontrolled observational studies will be analysed where primary outcomes are not reported in the control studies or where uncontrolled studies have longer follow-up. Initial screening of studies will be carried by one reviewer with a proportion checked by another reviewer. Full-text selection will be performed by two reviewers independently against the pre-defined selection criteria. The data collection and the risk of bias assessment will be completed by one reviewer and counter checked by another reviewer for all selected studies. Where appropriate, data will be meta-analysed for each study design, therapy and outcome. Data specifically on ACLF will be treated as a subgroup. DISCUSSION This systematic review will identify the available evidence on the effectiveness of cell therapies in patients with CLD and in ACLF subgroup. The findings will aid decision-making by clinicians and health service leaders. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42016016104.
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Affiliation(s)
- Nwe Ni Than
- National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
| | - Claire L Tomlinson
- Birmingham Clinical Trials Unit, Institute of Applied Health Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
| | - Debashis Haldar
- National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
| | - Andrew L King
- National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
| | - David Moore
- Institute of Applied Health Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
| | - Philip N Newsome
- National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
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19
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Sarin SK, Choudhury A. Acute-on-chronic liver failure: terminology, mechanisms and management. Nat Rev Gastroenterol Hepatol 2016; 13:131-49. [PMID: 26837712 DOI: 10.1038/nrgastro.2015.219] [Citation(s) in RCA: 250] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Acute-on-chronic liver failure (ACLF) is a distinct clinical entity and differs from acute liver failure and decompensated cirrhosis in timing, presence of acute precipitant, course of disease and potential for unaided recovery. The definition involves outlining the acute and chronic insults to include a homogenous patient group with liver failure and an expected outcome in a specific timeframe. The pathophysiology of ACLF relates to persistent inflammation, immune dysregulation with initial wide-spread immune activation, a state of systematic inflammatory response syndrome and subsequent sepsis due to immune paresis. The disease severity and outcome can be predicted by both hepatic and extrahepatic organ failure(s). Clinical recovery is expected with the use of nucleoside analogues for hepatitis B, and steroids for severe alcoholic hepatitis and, possibly, severe autoimmune hepatitis. Artificial liver support systems help remove toxins and metabolites and serve as a bridge therapy before liver transplantation. Hepatic regeneration during ongoing liver failure, although challenging, is possible through the use of growth factors. Liver transplantation remains the definitive treatment with a good outcome. Pre-emptive antiviral agents for hepatitis B before chemotherapy to prevent viral reactivation and caution in using potentially hepatotoxic drugs can prevent the development of ACLF.
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Affiliation(s)
- Shiv K Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, D-1, Vasant Kunj, New Delhi 110070, India
| | - Ashok Choudhury
- Department of Hepatology, Institute of Liver and Biliary Sciences, D-1, Vasant Kunj, New Delhi 110070, India
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20
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Shevela EY, Starostina NM, Pal'tsev AI, Shipunov MV, Zheltova OI, Meledina IV, Khvan LA, Leplina OY, Ostanin AA, Chernykh ER, Kozlov VA. Efficiency of Cell Therapy in Liver Cirrhosis. Bull Exp Biol Med 2016; 160:542-7. [PMID: 26902361 DOI: 10.1007/s10517-016-3215-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Indexed: 12/14/2022]
Abstract
We studied safety and clinical efficacy of transplantation of autologous bone marrow cell in complex therapy of 158 patients with chronic hepatitis and cirrhosis of the liver. The efficiency of cell therapy was assessed in 12 months after single injection of the cells. The positive response (alleviation of liver cirrhosis or stabilization of the pathological process) was observed in 70% cases. The efficacy of therapy correlated with the severity and etiology of the disease and was maximum in patients with Child-Pugh class A (in 82.5% cases) and class B liver cirrhosis (in 79% cases); in patients with class C liver cirrhosis, the positive response was achieved in 42.5% cases. In 39 patients, ultrasonic examination performed in 3 years after transplantation revealed no focal lesions or ectopic ossification foci.
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Affiliation(s)
- E Ya Shevela
- Research Institute of Clinical Immunology, Novosibirsk, Russia.
| | - N M Starostina
- Research Institute of Clinical Immunology, Novosibirsk, Russia
| | - A I Pal'tsev
- Research Institute of Clinical Immunology, Novosibirsk, Russia
| | - M V Shipunov
- Research Institute of Clinical Immunology, Novosibirsk, Russia
| | - O I Zheltova
- Research Institute of Clinical Immunology, Novosibirsk, Russia
| | - I V Meledina
- Research Institute of Clinical Immunology, Novosibirsk, Russia
| | - L A Khvan
- Research Institute of Clinical Immunology, Novosibirsk, Russia
| | - O Yu Leplina
- Research Institute of Clinical Immunology, Novosibirsk, Russia
| | - A A Ostanin
- Research Institute of Clinical Immunology, Novosibirsk, Russia
| | - E R Chernykh
- Research Institute of Clinical Immunology, Novosibirsk, Russia
| | - V A Kozlov
- Research Institute of Clinical Immunology, Novosibirsk, Russia
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21
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Huang B, Cheng X, Wang H, Huang W, la Ga Hu Z, Wang D, Zhang K, Zhang H, Xue Z, Da Y, Zhang N, Hu Y, Yao Z, Qiao L, Gao F, Zhang R. Mesenchymal stem cells and their secreted molecules predominantly ameliorate fulminant hepatic failure and chronic liver fibrosis in mice respectively. J Transl Med 2016; 14:45. [PMID: 26861623 PMCID: PMC4746907 DOI: 10.1186/s12967-016-0792-1] [Citation(s) in RCA: 131] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Accepted: 01/20/2016] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Orthotopic liver transplantation is the only effective treatment for liver failure but limited with shortage of available donor organs. Recent studies show promising results of mesenchymal stem cells (MSCs)-based therapies. METHODS We systematically investigate the therapeutic effects of MSCs or MSC-conditioned medium (MSC-CM) in ameliorating fulminant hepatic failure (FHF) and chronic liver fibrosis in mice. In addition, extensive flow cytometry analysis of spleens from vehicle and MSC- and MSC-CM-treated mice was applied to reveal the alteration of inflammatory state. RESULTS In FHF model, MSCs treatment reduced remarkably the death incidents; the analysis of gross histopathology showed that control livers were soft and shrunken with extensive extravasated blood, which was gradually reduced at later time points, while MSC-treated livers showed gross pathological changes, even 24 h after MSC infusion, and hematoxylin and eosin staining revealed dramatical hepatocellular death with cytoplasmic vacuolization suppressed by MSCs treatment; flow cytometry analysis of total lymphocytes showed that macrophages (F4/80) infiltrated into control livers more than MSC-treated livers; by contrast, MSC-CM partially ameliorates FHF. In chronic liver injury model, MSC and MSC-CM both suppressed fibrogenesis and necroinflammatory, and the later was better; activation of hepatic stellate cells (α-SMA) was inhibited; glycogen synthesis and storage (indicated by periodic acid-Schiff -staining) was improved; liver regeneration (Ki67) was promoted while liver apoptosis (TUNEL) was reduced. In the in vitro, MSCs promote macrophage line RAW264.7 apoptosis and MSC-CM promotes apoptosis and inhibits proliferation of HSC line LX-2. We also found that MSCs and MSC-CM could improve spleen; MSC-CM increased levels of Th2 and Treg cells, and reduced levels of Th17 cells, whereas levels of Th1 cells were unchanged; comparatively, MSC treatment did not affect Th17 and Treg cells and only slightly alters inflammatory state; MSC and MSC-CM treatment both substantially down-regulated macrophages in the spleens. CONCLUSION Both MSCs and MSC-CM exert therapeutic effects by acting on various key cells during the pathogenesis of FHF and chronic fibrosis, stimulating hepatocyte proliferation and suppressing apoptosis, down-regulating infiltrating macrophages, converting CD4(+) T lymphocyte system into an anti-inflammatory state, and facilitating hepatic stellate cell death.
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Affiliation(s)
- Biao Huang
- Department of Immunology and Research Center of Basic Medical Science; Tianjin Key Laboratory of Cellular and Molecular Immunology; Key Laboratory of Immune Microenvironment and Diseases, Ministry of Education of China, Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Qi Xiang Tai Road No.22, Tianjin, 300070, China.
| | - Xixi Cheng
- Department of Immunology and Research Center of Basic Medical Science; Tianjin Key Laboratory of Cellular and Molecular Immunology; Key Laboratory of Immune Microenvironment and Diseases, Ministry of Education of China, Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Qi Xiang Tai Road No.22, Tianjin, 300070, China.
| | - Huafeng Wang
- Department of Immunology and Research Center of Basic Medical Science; Tianjin Key Laboratory of Cellular and Molecular Immunology; Key Laboratory of Immune Microenvironment and Diseases, Ministry of Education of China, Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Qi Xiang Tai Road No.22, Tianjin, 300070, China. .,School of Life Science, Shanxi Normal University, Linfen, Shanxi Province, China.
| | - Wenjing Huang
- Department of Immunology and Research Center of Basic Medical Science; Tianjin Key Laboratory of Cellular and Molecular Immunology; Key Laboratory of Immune Microenvironment and Diseases, Ministry of Education of China, Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Qi Xiang Tai Road No.22, Tianjin, 300070, China.
| | - Zha la Ga Hu
- Department of Cell Biology, Logistic College of CAPF, Tianjin, China.
| | - Dan Wang
- Department of Immunology and Research Center of Basic Medical Science; Tianjin Key Laboratory of Cellular and Molecular Immunology; Key Laboratory of Immune Microenvironment and Diseases, Ministry of Education of China, Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Qi Xiang Tai Road No.22, Tianjin, 300070, China.
| | - Kai Zhang
- Department of Immunology and Research Center of Basic Medical Science; Tianjin Key Laboratory of Cellular and Molecular Immunology; Key Laboratory of Immune Microenvironment and Diseases, Ministry of Education of China, Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Qi Xiang Tai Road No.22, Tianjin, 300070, China.
| | - Huan Zhang
- Department of Immunology and Research Center of Basic Medical Science; Tianjin Key Laboratory of Cellular and Molecular Immunology; Key Laboratory of Immune Microenvironment and Diseases, Ministry of Education of China, Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Qi Xiang Tai Road No.22, Tianjin, 300070, China.
| | - Zhenyi Xue
- Department of Immunology and Research Center of Basic Medical Science; Tianjin Key Laboratory of Cellular and Molecular Immunology; Key Laboratory of Immune Microenvironment and Diseases, Ministry of Education of China, Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Qi Xiang Tai Road No.22, Tianjin, 300070, China.
| | - Yurong Da
- Department of Immunology and Research Center of Basic Medical Science; Tianjin Key Laboratory of Cellular and Molecular Immunology; Key Laboratory of Immune Microenvironment and Diseases, Ministry of Education of China, Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Qi Xiang Tai Road No.22, Tianjin, 300070, China.
| | - Ning Zhang
- Department of Immunology and Research Center of Basic Medical Science; Tianjin Key Laboratory of Cellular and Molecular Immunology; Key Laboratory of Immune Microenvironment and Diseases, Ministry of Education of China, Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Qi Xiang Tai Road No.22, Tianjin, 300070, China.
| | - Yongcheng Hu
- Department of Orthopaedic Oncology, Tianjin Hospital, Tianjin, China.
| | - Zhi Yao
- Department of Immunology and Research Center of Basic Medical Science; Tianjin Key Laboratory of Cellular and Molecular Immunology; Key Laboratory of Immune Microenvironment and Diseases, Ministry of Education of China, Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Qi Xiang Tai Road No.22, Tianjin, 300070, China.
| | - Liang Qiao
- Storr Liver Unit, Westmead Millennium Institute, The Western Clinical School of the University of Sydney, Westmead, NSW, Australia.
| | - Fei Gao
- State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Rongxin Zhang
- Department of Immunology and Research Center of Basic Medical Science; Tianjin Key Laboratory of Cellular and Molecular Immunology; Key Laboratory of Immune Microenvironment and Diseases, Ministry of Education of China, Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Qi Xiang Tai Road No.22, Tianjin, 300070, China.
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Mohamed HE, Elswefy SE, Rashed LA, Younis NN, Shaheen MA, Ghanim AMH. Bone marrow-derived mesenchymal stem cells effectively regenerate fibrotic liver in bile duct ligation rat model. Exp Biol Med (Maywood) 2016; 241:581-91. [PMID: 26811102 DOI: 10.1177/1535370215627219] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Accepted: 12/21/2015] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have attracted lots of attention for the treatment of acute liver failure and end-stage liver diseases. This study aimed at investigating the fundamental mechanism by which bone marrow-derived MSCs (BM-MSCs) induce liver regeneration of fibrotic liver in rats. Rats underwent bile duct ligation (BDL) surgery and four weeks later they were treated with either BM-MSCs (3 × 10(6) cells /rat, once, tail vein injection) or silymarin (100 mg/kg, daily, orally) for four weeks. Liver function tests and hepatic oxidative stress were determined. Hepatic injury and fibrosis were assessed by H and E, Sirus red staining and immunohistochemical expression of α-smooth muscle actin (α-SMA). Hepatocyte growth factor (HGF) and the gene expression of cytokeratin-19 (CK-19) and matrix metalloproteinase-2 (MMP-2) in liver tissue were determined. BDL induced cholestatic liver injury characterized by elevated ALT and AST activities, bilirubin and decreased albumin. The architecture damage was staged as Metavir score: F3, A3. Fibrosis increased around proliferating bile duct as indicated by sirus red staining and α-SMA immunostaining. Fibrogenesis was favored over fibrolysis and confirmed by decreased HGF with increased expression of CK-19, but decreased MMP-2 expression. BM-MSCs treatment restored deteriorated liver functions and restored the histological changes, resolved fibrosis by improving liver regenerative capabilities (P < 0.001), increases in HGF and MMP-2 mRNA and downregulating CK-19 mRNA. Sliymarin, however, induced similar but less prominent effects compared to BM-MSCs. In conclusion, liver regenerative capabilities can be stimulated by BM-MSCs via augmentation of HGF that subsequently up-regulate MMP-2 mRNA while downregulating CK-19 mRNA.
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Affiliation(s)
- Hoda E Mohamed
- Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
| | - Sahar E Elswefy
- Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
| | - Laila A Rashed
- Department of Medical Biochemistry, Unit of Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo 11562, Egypt
| | - Nahla N Younis
- Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
| | - Mohamed A Shaheen
- Histology and Cell Biology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Amal M H Ghanim
- Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
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Alsaggar M, Liu D. Liver-Targeted Gene and Cell Therapies: An Overview. GENE THERAPY AND CELL THERAPY THROUGH THE LIVER 2016:1-11. [DOI: 10.1007/978-4-431-55666-4_1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Xin J, Ding W, Hao S, Jiang L, Zhou Q, Wu T, Shi D, Cao H, Li L, Li J. Human bone marrow mesenchymal stem cell-derived hepatocytes express tissue inhibitor of metalloproteinases 4 and follistatin. Liver Int 2015; 35:2301-10. [PMID: 25645195 DOI: 10.1111/liv.12797] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Accepted: 01/29/2015] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Human bone marrow mesenchymal stem cell (hBMSC) transplantation is expected to become an alternative regenerative technique for liver diseases. However, the mechanism by which hBMSCs differentiate into hepatocytes is still unclear. The aim of this study was to establish the specific characteristics of hBMSC-derived hepatocytes (hBMSC-Heps) for future clinical applications. METHODS Potential hBMSC-Hep biomarkers were screened using cytokine arrays. Significant biomarkers were then validated by enzyme-linked immunosorbent assay (ELISA) in vitro and in an in vivo xenotransplantation model in fulminant hepatic failure (FHF) pigs. RESULTS After 20 days of differentiation, the expression levels of tissue inhibitor of metalloproteinases 4 (TIMP-4) and follistatin (FST) in functional hBMSC-Heps were significantly increased, whereas those of activin A, osteoprotegerin and platelet-derived growth factor α polypeptide (PDGF-A) were significantly decreased. The high levels of TIMP-4 and FST were validated by ELISA in hBMSC-Heps grown in differentiation medium. The in vivo xenotransplantation model in FHF pigs showed that the serum levels of TIMP-4 and FST were significantly increased 6 h after hBMSC transplantation and reached their highest levels at 24 and 48 h, respectively, after hBMSC transplantation. Immunohistochemistry confirmed that TIMP-4 and FST were expressed in cultured hBMSC-Heps and in implanted hBMSC-Heps in pig livers. CONCLUSIONS The transdifferentiation of hBMSCs into hepatocytes is associated with the expression of TIMP-4 and FST. TIMP-4 and FST represent potential novel biomarkers for the characterisation of hBMSC-Heps and may be useful for future clinical applications.
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Affiliation(s)
- Jiaojiao Xin
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wenchao Ding
- Systems Biology Division, Zhejiang-California International Nanosystems Institute, Zhejiang University, Hangzhou, China
| | - Shaorui Hao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Longyan Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qian Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tianzhou Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dongyan Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hongcui Cao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Pankaj P, Zhang Q, Bai XL, Liang TB. Autologous bone marrow transplantation in decompensated liver: Systematic review and meta-analysis. World J Gastroenterol 2015; 21:8697-8710. [PMID: 26229412 PMCID: PMC4515851 DOI: 10.3748/wjg.v21.i28.8697] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2014] [Revised: 03/27/2015] [Accepted: 04/28/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the efficacy of autologous bone marrow mononuclear cell transplantation in decompensated liver disease.
METHODS: Medline, EMBASE, PubMed, Science Direct, and the Cochrane Library were searched for relevant studies. Retrospective case-control studies were included along with randomized clinical trials. Meta-analysis was performed in line with recommendations from the Cochrane Collaboration software review manager. Heterogeneity was assessed using a random-effects model.
RESULTS: Four randomized controlled trials and four retrospective studies were included. Cell transplantation increased serum albumin level by 1.96 g/L (95%CI: 0.74-3.17; P = 0.002], 2.55 g/L (95%CI: 0.32-4.79; P = 0.03), and 3.65 g/L (95%CI: 0.76-6.54; P = 0.01) after 1, 3, and 6 mo, respectively. Patients who had undergone cell transplantation also had a lower level of total bilirubin [mean difference (MD): -1.37 mg/dL; 95%CI: -2.68-(-0.06); P = 0.04] after 6 mo. This decreased after 1 year when compared to standard treatment (MD: -1.26; 95%CI: -2.48-(-0.03); P = 0.04]. A temporary decrease in alanine transaminase and aspartate transaminase were significant in the cell transplantation group. However, after 6 mo treatment, patients who had undergone cell transplantation had a slightly longer prothrombin time (MD: 5.66 s, 95%CI: 0.04-11.28; P = 0.05). Changes in the model for end-stage liver disease score and Child-Pugh score were not statistically significant.
CONCLUSION: Autologous bone marrow transplantation showed some benefits in patients with decompensated liver disease. However, further studies are still needed to verify its role in clinical treatment for end-stage liver disease.
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26
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Huang M, Feng Z, Ji D, Cao Y, Shi X, Chen P, Wang P, Tang M, Liu K. Use of a transjugular intrahepatic portosystemic shunt combined with autologous bone marrow cell infusion in patients with decompensated liver cirrhosis: an exploratory study. Cytotherapy 2015; 16:1575-1583. [PMID: 25287603 DOI: 10.1016/j.jcyt.2014.04.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 03/27/2014] [Accepted: 04/04/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND AIMS Currently, there is no treatment for decompensated liver cirrhosis except for liver transplantation. The safety and effect on liver function of a transjugular intrahepatic portosystemic shunt (TIPS) with and without autologous bone marrow cell (BMC) infusion in patients with decompensated liver cirrhosis were determined. METHODS Ten patients who were diagnosed with decompensated liver cirrhosis during the period from September 2011 to July 2012 were enrolled in this study. The patients underwent TIPS (TIPS group) or combined treatment with TIPS and BMC infusion through the hepatic artery (TIPS+BMC group). All patients were monitored for adverse events, liver function and complications caused by portal hypertension during a period of 52 weeks. RESULTS The number of infused BMCs was 2.65 ± 1.20 ×10(9). Significant improvements in the serum levels of albumin and total bilirubin and decreased Child-Pugh scores were observed in patients treated with both TIPS and BMCs (P < 0.05), whereas no such changes were observed in the TIPS group. Endoscopic findings showed that varices in the esophagus and the gastric fundus were alleviated after either treatment. All 10 patients showed a complete or partial resolution of ascites at 4 weeks. No major adverse effects were noted during the follow-up period for patients in either group. CONCLUSIONS TIPS combined with BMC infusion is clinically safe; the treatment improved liver function and alleviated complications caused by portal hypertension; therefore, this combination has potential for treatment of patients with decompensated liver cirrhosis.
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Affiliation(s)
- Maotao Huang
- Department of Gastroenterology and Endocrinology, The 452(nd) Hospital of PLA, Chengdu, China.
| | - Zaoming Feng
- Department of Gastroenterology and Endocrinology, The 452(nd) Hospital of PLA, Chengdu, China
| | - Daijin Ji
- Department of Gastroenterology and Endocrinology, The 452(nd) Hospital of PLA, Chengdu, China
| | - Yaling Cao
- Department of Gastroenterology and Endocrinology, The 452(nd) Hospital of PLA, Chengdu, China
| | - Xiaoying Shi
- Department of Gastroenterology and Endocrinology, The 452(nd) Hospital of PLA, Chengdu, China
| | - Ping Chen
- Department of Nursing, The 452(nd) Hospital of PLA, Chengdu, China
| | - Ping Wang
- Department of Gastroenterology and Endocrinology, The 452(nd) Hospital of PLA, Chengdu, China
| | - Min Tang
- Department of Gastroenterology and Endocrinology, The 452(nd) Hospital of PLA, Chengdu, China
| | - Kai Liu
- Department of Gastroenterology and Endocrinology, The 452(nd) Hospital of PLA, Chengdu, China
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Cai T, Deng Q, Zhang S, Hu A, Gong Q, Zhang X. Peripheral blood stem cell transplantation improves liver functional reserve. Med Sci Monit 2015; 21:1381-6. [PMID: 25970080 PMCID: PMC4444145 DOI: 10.12659/msm.892990] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Currently available treatment options for decompensated hepatitis B-induced liver cirrhosis are limited and largely ineffective. Recently, stem cell transplantation has emerged as a promising treatment for cirrhosis. The aim of this study was to determine whether autologous peripheral blood stem cell transplantation can improve liver functional reserve in patients with hepatitis B-induced cirrhosis. Material/Methods In this study, 51 patients with hepatitis B-induced liver cirrhosis were assigned to the treatment group (n=23) or the control group (n=28). The treatment group underwent autologous peripheral blood stem cell transplantation in addition to comprehensive medical treatment, and the control group received comprehensive medical treatment alone. Liver functional reserve was monitored for 48 weeks after autologous peripheral blood stem cell transplantation. Results After transplantation, most patients showed improvements in symptoms such as fatigue, anorexia, and abdominal distension. The retention rate of indocyanine green at 15 minutes, a common indicator of liver functional reserve, declined from 41.99±4.68 at baseline to 37.79±3.75 by 48 weeks after transplantation, showing significant improvement. Conclusions Autologous peripheral blood stem cell transplantation can improve several markers of liver health and liver functional reserve and is a promising prospect for clinical application.
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Affiliation(s)
- Ting Cai
- Department of Infectious Diseases, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China (mainland)
| | - Qinzhi Deng
- Department of Infectious Diseases, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China (mainland)
| | - Shun Zhang
- Stem Cell Laboratory, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China (mainland)
| | - Airong Hu
- Department of Research and Teaching, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China (mainland)
| | - Qinghai Gong
- Department of Epidemiological Survey, Ningbo Center for Disease Control and Prevention, Ningbo, Zhejiang, China (mainland)
| | - Xingfen Zhang
- Department of infectious diseases, Ningbo No. 2 Hospital, Ningbo, China (mainland)
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Kalogeridi MA, Zygogianni A, Kyrgias G, Kouvaris J, Chatziioannou S, Kelekis N, Kouloulias V. Role of radiotherapy in the management of hepatocellular carcinoma: A systematic review. World J Hepatol 2015; 7:101-112. [PMID: 25625001 PMCID: PMC4295187 DOI: 10.4254/wjh.v7.i1.101] [Citation(s) in RCA: 112] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2014] [Revised: 10/26/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Many patients with hepatocellular carcinoma (HCC) present with advanced disease, not amenable to curative therapies such as surgery, transplantation or radiofrequency ablation. Treatment options for this group of patients include transarterial chemoembolization (TACE) and radiation therapy. Especially TACE, delivering a highly concentrated dose of chemotherapy to tumor cells while minimizing systemic toxicity of chemotherapy, has given favorable results on local control and survival. Radiotherapy, as a therapeutic modality of internal radiation therapy with radioisotopes, has also achieved efficacious tumor control in advanced disease. On the contrary, the role of external beam radiotherapy for HCC has been limited in the past, due to the low tolerance of surrounding normal liver parenchyma. However, technological innovations in the field of radiotherapy treatment planning and delivery, have provided the means of delivering radical doses to the tumor, while sparing normal tissues. Advanced and highly conformal radiotherapy approaches such as stereotactic body radiotherapy and proton therapy, evaluated for efficacy and safety for HCC, report encouraging results. In this review, we present the role of radiotherapy in hepatocellular carcinoma patients not suitable for radical treatment.
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Berardis S, Sattwika PD, Najimi M, Sokal EM. Use of mesenchymal stem cells to treat liver fibrosis: Current situation and future prospects. World J Gastroenterol 2015; 21:742-758. [PMID: 25624709 PMCID: PMC4299328 DOI: 10.3748/wjg.v21.i3.742] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 09/05/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Progressive liver fibrosis is a major health issue for which no effective treatment is available, leading to cirrhosis and orthotopic liver transplantation. However, organ shortage is a reality. Hence, there is an urgent need to find alternative therapeutic strategies. Cell-based therapy using mesenchymal stem cells (MSCs) may represent an attractive therapeutic option, based on their immunomodulatory properties, their potential to differentiate into hepatocytes, allowing the replacement of damaged hepatocytes, their potential to promote residual hepatocytes regeneration and their capacity to inhibit hepatic stellate cell activation or induce their apoptosis, particularly via paracrine mechanisms. The current review will highlight recent findings regarding the input of MSC-based therapy for the treatment of liver fibrosis, from in vitro studies to pre-clinical and clinical trials. Several studies have shown the ability of MSCs to reduce liver fibrosis and improve liver function. However, despite these promising results, some limitations need to be considered. Future prospects will also be discussed in this review.
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Affiliation(s)
- Young Woo Eom
- Cell Therapy and Tissue Engineering Center, Yonsei University, Wonju College of Medicine, Wonju, Korea
| | - Soon Koo Baik
- Cell Therapy and Tissue Engineering Center, Yonsei University, Wonju College of Medicine, Wonju, Korea
- Department of Internal Medicine, Yonsei University, Wonju College of Medicine, Wonju, Korea
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Nakamura T, Torimura T, Iwamoto H, Kurogi J, Inoue H, Hori Y, Sumie S, Fukushima N, Sakata M, Koga H, Abe M, Ikezono Y, Hashimoto O, Ueno T, Oho K, Okamura T, Okuda S, Kawamoto A, Ii M, Asahara T, Sata M. CD34(+) cell therapy is safe and effective in slowing the decline of hepatic reserve function in patients with decompensated liver cirrhosis. J Gastroenterol Hepatol 2014; 29:1830-8. [PMID: 24731186 DOI: 10.1111/jgh.12622] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/28/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIM Preclinical studies in rodent models of chronic liver fibrosis have shown that transplantation of peripheral blood (PB) CD34(+) cells leads to hepatic regeneration and a reduction of liver fibrosis by suppressing hepatic stellate cell activity and increasing matrix metalloproteinase activity. The aim of this study was to examine the safety and clinical efficacy of intrahepatic transplantation of autologous granulocyte colony-stimulating factor (G-CSF)-mobilized PB-CD34(+) cells in patients with decompensated liver cirrhosis. METHODS PB-CD34(+) cells were isolated from G-CSF-mobilized apheresis products. Ten patients were treated with G-CSF-mobilized PB-CD34(+) cells (treatment group) and seven patients were treated with standard medical therapy. For mobilization, patients in the treatment group received subcutaneous injections of 10 μg G-CSF/kg/day for 5 days. The cells were then injected at three different doses (5 × 10(5) , 1 × 10(6) and 2 × 10(6) cells/kg) through the hepatic artery. Thereafter, all patients were followed up for 24 months. RESULTS G-CSF treatment and leukapheresis were well tolerated, and no serious adverse events were observed. Patients in the treatment group had a significant but transient splenomegaly. After 24 weeks, serum albumin was significantly increased in patients who had received middle or high doses of CD34(+) cells compared with baseline. Doppler ultrasound showed a significant increase in hepatic blood flow velocity and blood flow volume after CD34(+) cell therapy. The hepatic vein pressure gradient decreased in two patients who received high-dose CD34(+) cells at week 16. CONCLUSIONS CD34(+) cell therapy is feasible, safe and effective in slowing the decline of hepatic reserve function.
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Affiliation(s)
- Toru Nakamura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan
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Behbahan IS, Keating A, Gale RP. Concise review: bone marrow autotransplants for liver disease? Stem Cells 2014; 31:2313-29. [PMID: 23939914 DOI: 10.1002/stem.1510] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2013] [Revised: 07/08/2013] [Accepted: 07/15/2013] [Indexed: 12/11/2022]
Abstract
There are increasing reports of using bone marrow-derived stem cells to treat advanced liver disease. We consider several critical issues that underlie this approach. For example, are there multipotent stem cell populations in human adult bone marrow? Can they develop into liver cells or supporting cell types? What are stromal stem/progenitor cells, and can they promote tissue repair without replacing hepatocytes? Does reversal of end-stage liver disease require new hepatocytes, a new liver microenvironment, both, neither or something else? Although many of these questions are unanswered, we consider the conceptual and experimental bases underlying these issues and critically analyze results of clinical trials of stem cell therapy of end-stage liver disease.
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Affiliation(s)
- Iman Saramipoor Behbahan
- Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
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Xu L, Gong Y, Wang B, Shi K, Hou Y, Wang L, Lin Z, Han Y, Lu L, Chen D, Lin X, Zeng Q, Feng W, Chen Y. Randomized trial of autologous bone marrow mesenchymal stem cells transplantation for hepatitis B virus cirrhosis: regulation of Treg/Th17 cells. J Gastroenterol Hepatol 2014; 29:1620-8. [PMID: 24942592 DOI: 10.1111/jgh.12653] [Citation(s) in RCA: 82] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/17/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Liver cirrhosis is one of the major consequences of hepatitis B virus (HBV) infection, and transplantation of autologous bone marrow mesenchymal stem cells (ABMSCs) is one of promising therapies for patients with HBV-related liver cirrhosis (HBV-LC). However, the mechanism is unclear. The aim of the current study was to explore the role of Treg/Th17 cells in ABMSCs transplantation in patients with HBV-LC. METHODS In this prospective study, 56 patients were enrolled and randomly assigned to transplantation group and control group. After 24-week follow-up, 39 patients completed the study (20 cases in transplantation group and 19 cases in control group). The Model for End-Stage Liver Disease scores, liver function, changes of Treg/Th17 cells, as well as related transcription factors and serum cytokines, were determined. RESULTS Although patients in both groups showed significant improvement after Entecavir treatment, ABMSC transplantation further improved patients' liver function. Moreover, there was a significant increase in Treg cells and a marked decrease in Th17 cells in the transplantation group compared with control, leading to an increased Treg/Th17 ratio. Furthermore, mRNA levels of Treg-related transcription factor (Foxp3) and Th17-related transcription factor (RORγt) were increased and decreased, respectively. In addition, serum transforming growth factor-β levels were significantly higher at early weeks of transplantation, while serum levels of interleukin-17, tumor necrosis factor-α, and interleukin-6 were significantly lower in patients in the transplantation group compared with control. CONCLUSION ABMSCs transplantation was effective in improving liver function in patients with HBV-LC, which was mediated, at least in part, through the regulation of Treg/Th17 cell balance.
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Affiliation(s)
- Lanman Xu
- Department of Infection and Liver Diseases of the First Affiliated Hospital and Liver Research Center, Wenzhou Medical University, Wenzhou, Zhejiang, China
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López ML, Kieling CO, Uribe Cruz C, Osvaldt A, Ochs de Muñoz G, Meurer L, Silla L, Matte U. Platelet increases survival in a model of 90% hepatectomy in rats. Liver Int 2014; 34:1049-56. [PMID: 24119092 DOI: 10.1111/liv.12326] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Accepted: 08/29/2013] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Ninety per cent hepatectomy in rodents is a model for acute liver failure. It has been reported that platelets have a strong effect enhancing liver regeneration, because of the production of several growth factors such as serotonin. The aim of this study was to investigate the role of microencapsulated platelets on 90% hepatectomy in rats. METHODS Platelets (PLT) were microencapsulated in sodium alginate and implanted in the peritoneum of rats after 90% partial hepatectomy (PH). Control group received empty capsules (EC). Animals were euthanized at 6, 12, 24, 48 and 72 h post PH (n=9-12/group/time) to evaluate liver regeneration rate, mitotic index, liver content, serum and tissue levels of Interleukin 6 (IL-6) and serotonin and its receptor 5-hydroxytryptamine type 2B (5Ht2b). Survival rate in 10 days was evaluated in a different set of animals (n=20/group). RESULTS Platelets group showed the highest survival rate despite the lowest liver regeneration rate at any time point. Mitotic and BrdU index showed no difference between groups. However, the number of hepatocytes was higher and the internuclear distance was shorter for PLT group. Liver dry weight was similar in both groups indicating that water was the main responsible factor for the weight difference. Gene expression of IL-6 in the liver was significantly higher in EC group 6 h after PH, whereas 5Ht2b was up-regulated at 72 h in PLT group. CONCLUSIONS Platelets enhance survival of animals with 90% PH, probably by an early protective effect on hepatocytes and the increase in growth factor receptors.
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Affiliation(s)
- Mónica L López
- Gene Therapy Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, do Rio Grande do Sul, Brazil; Post-Graduation Program on Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, do Rio Grande do Sul, Brazil
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Bishi DK, Mathapati S, Cherian KM, Guhathakurta S, Verma RS. In vitro hepatic trans-differentiation of human mesenchymal stem cells using sera from congestive/ischemic liver during cardiac failure. PLoS One 2014; 9:e92397. [PMID: 24642599 PMCID: PMC3958528 DOI: 10.1371/journal.pone.0092397] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2013] [Accepted: 02/22/2014] [Indexed: 12/17/2022] Open
Abstract
Cellular therapy for end-stage liver failures using human mesenchymal stem cells (hMSCs)-derived hepatocytes is a potential alternative to liver transplantation. Hepatic trans-differentiation of hMSCs is routinely accomplished by induction with commercially available recombinant growth factors, which is of limited clinical applications. In the present study, we have evaluated the potential of sera from cardiac-failure-associated congestive/ischemic liver patients for hepatic trans-differentiation of hMSCs. Results from such experiments were confirmed through morphological changes and expression of hepatocyte-specific markers at molecular and cellular level. Furthermore, the process of mesenchymal-to-epithelial transition during hepatic trans-differentiation of hMSCs was confirmed by elevated expression of E-Cadherin and down-regulation of Snail. The functionality of hMSCs-derived hepatocytes was validated by various liver function tests such as albumin synthesis, urea release, glycogen accumulation and presence of a drug inducible cytochrome P450 system. Based on these findings, we conclude that sera from congestive/ischemic liver during cardiac failure support a liver specific microenvironment for effective hepatic trans-differentiation of hMSCs in vitro.
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Affiliation(s)
- Dillip Kumar Bishi
- Stem Cells and Molecular Biology Laboratory, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, India
- Stem Cells and Tissue Engineering Laboratory, International Centre for Cardiothoracic and Vascular Diseases, Frontier Lifeline, Chennai, India
| | - Santosh Mathapati
- Stem Cells and Molecular Biology Laboratory, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, India
- Stem Cells and Tissue Engineering Laboratory, International Centre for Cardiothoracic and Vascular Diseases, Frontier Lifeline, Chennai, India
| | - Kotturathu Mammen Cherian
- Stem Cells and Tissue Engineering Laboratory, International Centre for Cardiothoracic and Vascular Diseases, Frontier Lifeline, Chennai, India
| | - Soma Guhathakurta
- Department of Engineering Design, Indian Institute of Technology Madras, Chennai, India
- * E-mail: (SG); (RSV)
| | - Rama Shanker Verma
- Stem Cells and Molecular Biology Laboratory, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, India
- * E-mail: (SG); (RSV)
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Li J, Xin J, Zhang L, Wu J, Jiang L, Zhou Q, Li J, Guo J, Cao H, Li L. Human hepatic progenitor cells express hematopoietic cell markers CD45 and CD109. Int J Med Sci 2014; 11:65-79. [PMID: 24396288 PMCID: PMC3880993 DOI: 10.7150/ijms.7426] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2013] [Accepted: 12/11/2013] [Indexed: 01/11/2023] Open
Abstract
OBJECTIVE To clarify the precise characteristics of human hepatic progenitor cells (HPCs) for future cytotherapy in liver diseases. METHODS Hepatic progenitor-like cells were isolated and cultured from the livers of patients who had undergone partial hepatectomy for various pathologies but displayed no sign of hepatic dysfunction. These cells were characterized by transcriptomic profiling, quantitative real-time PCR and immunocyto/histochemistry. RESULTS Cultured HPCs contained polygonal, high nucleus/cytoplasm ratio and exhibited a global gene expression profile similar (67.8%) to that of primary hepatocytes. Among the genes with more than 20-fold higher expression in HPCs were a progenitor marker (CD90), a pentraxin-related gene (PTX3), collagen proteins (COL5A2, COL1A1 and COL4A2), cytokines (EGF and PDGFD), metabolic enzymes (CYBRD1, BCAT1, TIMP2 and PAM), a secreted protein (SPARC) and an endothelial protein C receptor (PROCR). Moreover, eight markers (ALB, AFP, CK8, CK18, CK19, CD90, CD117 and Oval-6) previously described as HPC markers were validated by qRT-PCR and/or immunocyto/histochemistry. Interestingly, human HPCs were also positive for the hematopoietic cell markers CD45 and CD109. Finally, we characterized the localization of HPCs in the canals of Hering and periportal areas with six previously described markers (Oval-6, CK8, CK18, CK19, CD90 and CD117) and two potential markers (CD45 and CD109). CONCLUSION The human HPCs are highly similar to primary hepatocytes in their transcriptional profiles. The CD45 and CD109 markers could potentially be utilized to identify and isolate HPCs for further cytotherapy of liver diseases.
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Affiliation(s)
- Jun Li
- 1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University. 79 Qingchun Rd., Hangzhou, 310003. China
| | - Jiaojiao Xin
- 1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University. 79 Qingchun Rd., Hangzhou, 310003. China
| | - Liyuan Zhang
- 1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University. 79 Qingchun Rd., Hangzhou, 310003. China
| | - Jian Wu
- 2. Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University. 79 Qingchun Rd., Hangzhou, 310003. China
| | - Longyan Jiang
- 1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University. 79 Qingchun Rd., Hangzhou, 310003. China
| | - Qian Zhou
- 1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University. 79 Qingchun Rd., Hangzhou, 310003. China
| | - Jun Li
- 3. Department of Pathology, The First Affiliated Hospital, School of Medicine, Zhejiang University. 79 Qingchun Rd., Hangzhou, China. 310003
| | - Jing Guo
- 1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University. 79 Qingchun Rd., Hangzhou, 310003. China
| | - Hongcui Cao
- 1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University. 79 Qingchun Rd., Hangzhou, 310003. China
| | - Lanjuan Li
- 1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University. 79 Qingchun Rd., Hangzhou, 310003. China
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Nunes de Carvalho S, Helal-Neto E, de Andrade DC, Costa Cortez EA, Thole AA, Barja-Fidalgo C, de Carvalho L. Bone marrow mononuclear cell transplantation increases metalloproteinase-9 and 13 and decreases tissue inhibitors of metalloproteinase-1 and 2 expression in the liver of cholestatic rats. Cells Tissues Organs 2013; 198:139-48. [PMID: 23886643 DOI: 10.1159/000353215] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/21/2013] [Indexed: 11/19/2022] Open
Abstract
Liver fibrosis results from chronic injury followed by activation of macrophages and fibrogenic cells like myofibroblasts and activated hepatic stellate cells. These fibrogenic cells express α-smooth muscle actin (α-SMA) and produce excessive extracellular matrix (ECM), with disorganization and loss of function of hepatic parenchyma. It is known that increased levels of metalloproteinases (MMPs) in liver fibrosis are associated with reduction of the pathologic ECM and fibrosis resolution. Recently, it has been shown that bone marrow mononuclear cells (BMMNCs) may reduce collagen and α-SMA expression, and ameliorate liver function in cholestatic rats. Therefore, this study aimed to analyze MMP-2, MMP-9 and MMP-13, and tissue inhibitors of MMPs (TIMPs)-1 and TIMP-2 in the liver of cholestatic rats transplanted with BMMNC. Animals were divided into normal rats, cholestatic rats obtained after 14 and 21 days of bile duct ligation (BDL), and rats obtained after 14 days of BDL that received BMMNCs and were killed after 7 days. MMP and TIMP expression was assessed by Western blotting, along with α-SMA, CD68 and CD11b expression by confocal microscopy. Western blotting analysis showed that 14-day BDL animals had significantly reduced amounts of MMP-2 and MMP-13, but increased amounts of MMP-9 compared to normal rats. After 21 days of BDL, overall MMP amounts were decreased and TIMPs were increased. BMMNC transplantation significantly increased MMP-9 and MMP-13, and decreased TIMP expression. Increased MMP activity was confirmed by zymography. MMP-9 and MMP-13 were expressed by macrophages near fibrotic septa, suggesting BMMNC may stimulate MMP production in fibrotic livers, contributing to ECM degradation and hepatic regeneration.
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Affiliation(s)
- Simone Nunes de Carvalho
- Laboratório Cultura de Células, Departamento de Histologia e Embriologia, Instituto de Biologia, Universidade do Estado do Rio de Janeiro, UERJ, Rio de Janeiro, Brazil
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Bae SH. Recent achievements in stem cell therapy for pediatric gastrointestinal tract disease. Pediatr Gastroenterol Hepatol Nutr 2013; 16:10-6. [PMID: 24010100 PMCID: PMC3746046 DOI: 10.5223/pghn.2013.16.1.10] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Revised: 03/12/2013] [Accepted: 03/14/2013] [Indexed: 12/24/2022] Open
Abstract
The field of stem cell research has been rapidly expanding. Although the clinical usefulness of research remains to be ascertained through human trials, the use of stem cells as a therapeutic option for currently disabling diseases holds fascinating potential. Many pediatric gastrointestinal tract diseases have defect in enterocytes, enteric nervous system cells, smooth muscles, and interstitial cells of Cajal. Various kinds of therapeutic trials using stem cells could be applied to these diseases. This review article focuses on the recent achievements in stem cell applications for pediatric gastrointestinal tract diseases.
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Affiliation(s)
- Sun Hwan Bae
- Department of Pediatrics, School of Medicine, Konkuk University, Seoul, Korea
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Spahr L, Chalandon Y, Terraz S, Kindler V, Rubbia-Brandt L, Frossard JL, Breguet R, Lanthier N, Farina A, Passweg J, Becker CD, Hadengue A. Autologous bone marrow mononuclear cell transplantation in patients with decompensated alcoholic liver disease: a randomized controlled trial. PLoS One 2013; 8:e53719. [PMID: 23341981 PMCID: PMC3544843 DOI: 10.1371/journal.pone.0053719] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Accepted: 12/05/2012] [Indexed: 12/20/2022] Open
Abstract
Objective Impaired liver regeneration is associated with a poor outcome in patients with decompensated alcoholic liver disease (ALD). We assessed whether autologous bone marrow mononuclear cell transplantation (BMMCT) improved liver function in decompensated ALD. Design 58 patients (mean age 54 yrs; mean MELD score 19, all with cirrhosis, 81% with alcoholic steatohepatitis at baseline liver biopsy) were randomized early after hospital admission to standard medical therapy (SMT) alone (n = 30), including steroids in patients with a Maddrey’s score ≥32, or combined with G-CSF injections and autologous BMMCT into the hepatic artery (n = 28). Bone marrow cells were harvested, isolated and reinfused the same day. The primary endpoint was a ≥3 points decrease in the MELD score at 3 months, corresponding to a clinically relevant improvement in liver function. Liver biopsy was repeated at week 4 to assess changes in Ki67+/CK7+ hepatic progenitor cells (HPC) compartment. Results Both study groups were comparable at baseline. After 3 months, 2 and 4 patients died in the BMMCT and SMT groups, respectively. Adverse events were equally distributed between groups. Moderate alcohol relapse occurred in 31% of patients. The MELD score improved in parallel in both groups during follow-up with 18 patients (64%) from the BMMCT group and 18 patients (53%) from the SMT group reaching the primary endpoint (p = 0.43 (OR 1.6, CI 0.49–5.4) in an intention to treat analysis. Comparing liver biopsy at 4 weeks to baseline, steatosis improved (p<0.001), and proliferating HPC tended to decrease in both groups (−35 and −33%, respectively). Conclusion Autologous BMMCT, compared to SMT is a safe procedure but did not result in an expanded HPC compartment or improved liver function. These data suggest either insufficient regenerative stimulation after BMMCT or resistance to liver regenerative drive in patients with decompensated alcoholic cirrhosis. Trial Registration Controlled-Trials.com ISRCTN83972743.
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Affiliation(s)
- Laurent Spahr
- Division of Gastroenterology and Hepatology, University Hospitals and Faculty of Medicine, Geneva, Switzerland.
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Salamon A, Toldy E, Nagy L, Lőcsei Z. [The role of adult bone marrow derived mesenchymal stem cells in the repair of tissue injuries]. Orv Hetil 2012; 153:1807-15. [PMID: 23146781 DOI: 10.1556/oh.2012.29490] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Mesenchymal stem cells, which reside in adult bone marrow are multipotent, have an excellent regeneration potential for tissue repair. These cells are able to differentiate in cell culture not only into mesodermal lineages but also into other lineages of ectodermal and endodermal cells. This regenerative process is assisted by application of bioactive molecules, specific growth factors and biomaterials (scaffolds). The cell therapy is successfully used in the treatment of bone defects, nonunions, osteoblasts formed from the mesenchymal stem cells. At present, there are encouraging data in the clinical practice. The mesenchymal stem cell seems to be successful in the regeneration of articular cartilage. There are further promising data for the application of mesenchymal stem cells in the treatment of myocardial infarction, neurologic diseases, liver and kidney diseases and injuries and diabetes mellitus. The aim of this review is to survey the molecular characteristics of mesenchymal stem cells and specific growth factors using the data of preclinical investigations and to call attention to their possible clinical application.
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Affiliation(s)
- Antal Salamon
- Egyetemi Oktatókórház Nonprofit Zrt. Baleseti Sebészeti Osztály, Szombathely.
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Comparison of endometrial regenerative cells and bone marrow stromal cells. J Transl Med 2012; 10:207. [PMID: 23038994 PMCID: PMC3504519 DOI: 10.1186/1479-5876-10-207] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2012] [Accepted: 09/19/2012] [Indexed: 12/17/2022] Open
Abstract
Background Endometrial regenerative cells (ERC) and bone marrow stromal cells (BMSC) are being used in clinical trials. While they have been reported to have similar characteristics, they have not been directly compared. Methods We compared micro RNA (miRNA) and gene expression profiles, soluble cytokine and growth factor levels and ability to inhibit ongoing mixed leukocyte reaction (MLR) of ERC and BMSC each derived from 6 healthy subjects. Results ERC and BMSC miRNA and gene expression profiles were similar, but not identical; more differences were noted in the expression of genes than in miRNAs. Genes overexpressed in ERCs were more likely to be in immune and inflammation pathways and those overexpressed in BMSCs were more likely to be in stem cell and cancer signaling pathways. In addition, the levels of IL-8 and ICAM-1 were greater in ERC supernatants while the levels of HGF, VEGF, IL-6, CXCL12, TGFB1 and TGFB2 were greater in BMSC supernatants. Additionally, ERC demonstrated greater inhibition of the proliferation of mixed leukocyte cultures. Conclusions These results suggest that the in vivo effects of ERC and BMSC may differ. Multiple properties of stromal cells are responsible for their in vivo effectiveness and ERC may be more effective for some of the clinical applications and BMSC for others. Studies in animal models or clinical trials will be required to more fully characterize the differences between ERC and BMSC.
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Hepatogenic differentiation of mesenchymal stem cells in a rat model of thioacetamide-induced liver cirrhosis. Cell Biol Int 2012; 36:279-88. [PMID: 21966929 DOI: 10.1042/cbi20110325] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Implantation of bone-marrow-derived MSCs (mesenchymal stem cells) has emerged as a potential treatment modality for liver failure, but in vivo differentiation of MSCs into functioning hepatocytes and its therapeutic effects have not yet been determined. We investigated MSC differentiation process in a rat model of TAA (thioacetamide)-induced liver cirrhosis. Male Sprague-Dawley rats were administered 0.04% TAA-containing water for 8 weeks, MSCs were injected into the spleen for transsplenic migration into the liver, and liver tissues were examined over 3 weeks. Ingestion of TAA for 8 weeks induced micronodular liver cirrhosis in 93% of rats. Injected MSCs were diffusely engrafted in the liver parenchyma, differentiated into CK19 (cytokeratin 19)- and thy1-positive oval cells and later into albumin-producing hepatocyte-like cells. MSC engraftment rate per slice was measured as 1.0-1.6%. MSC injection resulted in apoptosis of hepatic stellate cells and resultant resolution of fibrosis, but did not cause apoptosis of hepatocytes. Injection of MSCs treated with HGF (hepatocyte growth factor) in vitro for 2 weeks, which became CD90-negative and CK18-positive, resulted in chronological advancement of hepatogenic cellular differentiation by 2 weeks and decrease in anti-fibrotic activity. Early differentiation of MSCs to progenitor oval cells and hepatocytes results in various therapeutic effects, including repair of damaged hepatocytes, intracellular glycogen restoration and resolution of fibrosis. Thus, these results support that the in vivo hepatogenic differentiation of MSCs is related to the beneficial effects of MSCs rather than the differentiated hepatocytes themselves.
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Li J, Zhang L, Xin J, Jiang L, Li J, Zhang T, Jin L, Li J, Zhou P, Hao S, Cao H, Li L. Immediate intraportal transplantation of human bone marrow mesenchymal stem cells prevents death from fulminant hepatic failure in pigs. Hepatology 2012; 56:1044-52. [PMID: 22422600 DOI: 10.1002/hep.25722] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2012] [Accepted: 02/29/2012] [Indexed: 12/15/2022]
Abstract
UNLABELLED The effectiveness of human bone marrow mesenchymal stem cell (hBMSC) transplantation to treat acute and chronic liver injury has been demonstrated in animal models and in a few nonrandomized clinical trials. However, no studies have investigated hBMSC transplantation in the treatment of fulminant hepatic failure (FHF), especially in large animal (pig) models. The aim of this study was to demonstrate the safety, effectiveness, and underlying mechanism of hBMSC transplantation for treating FHF in pigs through the intraportal route. Human BMSCs (3 × 10(7) ) were transplanted into pigs with FHF via the intraportal route or peripheral vein immediately after D-galactosamine injection, and a sham group underwent intraportal transplantation (IPT) without cells (IPT, peripheral vein transplantation [PVT], and control groups, respectively, n = 15 per group). All of the animals in the PVT and control groups died of FHF within 96 hours. In contrast, 13 of 15 animals in the IPT group achieved long-term survival (>6 months). Immunohistochemistry demonstrated that transplanted hBMSC-derived hepatocytes in surviving animals were widely distributed in the hepatic lobules and the liver parenchyma from weeks 2 to 10. Thirty percent of the hepatocytes were hBMSC-derived. However, the number of transplanted cells decreased significantly at week 15. Only a few single cells were scattered in the regenerated liver lobules at week 20, and the liver tissues exhibited a nearly normal structure. CONCLUSION Immediate IPT of hBMSCs is a safe and effective treatment for FHF. The transplanted hBMSCs may quickly participate in liver regeneration via proliferation and transdifferentiation into hepatocytes during the initial stage of FHF. This method can possibly be used in future clinical therapy.
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Affiliation(s)
- Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Zhang ZQ, Yao P, Yang DW, Zhang CP. Evaluation of curative effect of autologous bone marrow stem cell transplantation on decompensated cirrhosis by Fibroscan. Shijie Huaren Xiaohua Zazhi 2012; 20:1630-1637. [DOI: 10.11569/wcjd.v20.i18.1630] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the efficacy of autologous bone marrow stem cell transplantation in the treatment of decompensated cirrhosis by Fibroscan combined with multiple parameters.
METHODS: A total of 58 patients with decompensated cirrhosis were divided into transplantation group (n = 27) and control group (n = 31). Baseline examinations, including liver biopsy and Fibroscan, were performed before therapy. Both groups underwent routine medical treatment, and the transplantation group additionally underwent autologous bone marrow stem cell transplantation. At 2, 4, 8, 12, 24 and 48 wk after therapy, liver function and coagulation function were measured. Fibroscan and FIB-4 tests were performed at 12, 24 and 48 wk. At 48 wk after therapy, some patients underwent a liver biopsy. Then the efficacy of autologous bone marrow stem cell transplantation in the treatment of cirrhosis and the role of Fibroscan in evaluation of the curative effect were analyzed comprehensively.
RESULTS: Successful transplantation was achieved in all the 27 patients. Seven patients from each group underwent a liver biopsy, and they were clearly diagnosed with cirrhosis by histopathology. At 8 wk after therapy, the improvement in symptoms and physical signs in the transplantation group was better than that in the control group. The liver function and coagulation function improved in both groups, and the improvement was more significant in the transplantation group than in the control group. The liver stiffness values in the transplantation group did not differ significantly between before treatment and 12 and 24 wk after transplantation (31.66 kPa ± 6.97 kPa vs 31.98 kPa ± 7.36 kPa, 31.35 kPa ± 6.73 kPa, both P > 0.05), but were significantly higher at 48 wk than at other time points (31.78 kPa ± 7.35 kPa, P < 0.05). The liver stiffness values in the control group increased gradually from 32.05 kPa ± 9.09 kPa at pretreatment to 36.39 kPa ± 9.39 kPa at 48 wk after therapy (P < 0.05), and there was a statistical difference in the liver stiffness values between the two groups at 48 wk. The level of HA in the transplantation group decreased more significantly than that in the control group (P < 0.05 at 24 wk).
CONCLUSION: Autologous bone marrow stem cell transplantation can significantly improve symptoms and liver function in patients with decompensated cirrhosis. Fibroscan is an important means of evaluating the curative effect of autologous bone marrow stem cell transplantation on decompensated cirrhosis.
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Manuelpillai U, Lourensz D, Vaghjiani V, Tchongue J, Lacey D, Tee JY, Murthi P, Chan J, Hodge A, Sievert W. Human amniotic epithelial cell transplantation induces markers of alternative macrophage activation and reduces established hepatic fibrosis. PLoS One 2012; 7:e38631. [PMID: 22719909 PMCID: PMC3375296 DOI: 10.1371/journal.pone.0038631] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Accepted: 05/08/2012] [Indexed: 01/07/2023] Open
Abstract
Chronic hepatic inflammation from multiple etiologies leads to a fibrogenic response that can progress to cirrhosis and liver failure. Transplantation of human amniotic epithelial cells (hAEC) from term delivered placenta has been shown to decrease mild to moderate hepatic fibrosis in a murine model. To model advanced human liver disease and assess the efficacy of hAEC therapy, we transplanted hAEC in mice with advanced hepatic fibrosis. Immunocompetent C57BL/6 mice were administered carbon tetrachloride (CCl4) twice weekly resulting in bridging fibrosis by 12 weeks. hAEC (2×106) were infused via the tail vein at week 8 or weeks 8 and 10 (single and double dose, respectively). Human cells were detected in mouse liver four weeks after transplantation showing hAEC engraftment. CCl4 treated mice receiving single or double hAEC doses showed a significant but similar decrease in liver fibrosis area associated with decreased activation of collagen-producing hepatic stellate cells and decreased hepatic protein levels of the pro-fibrogenic cytokine, transforming growth factor-beta1. CCl4 administration caused hepatic T cell infiltration that decreased significantly following hAEC transplantation. Hepatic macrophages play a crucial role in both fibrogenesis and fibrosis resolution. Mice exposed to CCl4 demonstrated increased numbers of hepatic macrophages compared to normal mice; the number of macrophages decreased significantly in CCl4 treated mice given hAEC. These mice had significantly lower hepatic protein levels of the chemokine monocyte chemoattractant protein-1 than mice given CCl4 alone. Alternatively activated M2 macrophages are associated with fibrosis resolution. CCl4 treated mice given hAEC showed increased expression of genes associated with M2 macrophages including YM-1, IL-10 and CD206. We provide novel data showing that hAEC transplantation induces a wound healing M2 macrophage phenotype associated with reduction of established hepatic fibrosis that justifies further investigation of this potential cell-based therapy for advanced hepatic fibrosis.
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Affiliation(s)
- Ursula Manuelpillai
- Center for Reproduction and Development, Monash Institute of Medical Research, Monash University, Melbourne, Australia
| | - Dinushka Lourensz
- Center for Inflammatory Diseases, Monash University, Melbourne, Australia
- Gastroenterology and Hepatology Unit, Southern Health, Melbourne, Australia
| | - Vijesh Vaghjiani
- Center for Reproduction and Development, Monash Institute of Medical Research, Monash University, Melbourne, Australia
| | - Jorge Tchongue
- Center for Inflammatory Diseases, Monash University, Melbourne, Australia
- Gastroenterology and Hepatology Unit, Southern Health, Melbourne, Australia
| | - Derek Lacey
- University of Melbourne, Arthritis and Inflammation Research Centre, Royal Melbourne Hospital, Melbourne, Australia
| | - Jing-Yang Tee
- Center for Reproduction and Development, Monash Institute of Medical Research, Monash University, Melbourne, Australia
| | - Padma Murthi
- Department of Obstetrics and Gynecology, University of Melbourne, Melbourne, Australia
- Pregnancy Research Center, Department of Perinatal Medicine, Royal Women’s Hospital, Melbourne, Australia
| | - James Chan
- Center for Inflammatory Diseases, Monash University, Melbourne, Australia
| | - Alexander Hodge
- Center for Inflammatory Diseases, Monash University, Melbourne, Australia
- Gastroenterology and Hepatology Unit, Southern Health, Melbourne, Australia
| | - William Sievert
- Center for Inflammatory Diseases, Monash University, Melbourne, Australia
- Gastroenterology and Hepatology Unit, Southern Health, Melbourne, Australia
- * E-mail:
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Li J, Xin J, Hao S, Zhang L, Jiang L, Chen D, Xie Q, Xu W, Cao H, Li L. Return of the metabolic trajectory to the original area after human bone marrow mesenchymal stem cell transplantation for the treatment of fulminant hepatic failure. J Proteome Res 2012; 11:3414-22. [PMID: 22582960 DOI: 10.1021/pr3002639] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Our recent study first demonstrated that human bone marrow mesenchymal stem cell (hBMSC) transplantation could prevent death from fulminant hepatic failure (FHF) in pigs. To further clarify the metabolic mechanism of hBMSC transplantation in FHF, the plasma collected from FHF pigs that received transplantation of hBMSCs was examined using metabolic analysis to identify the key molecular markers that regulate recovery. The results showed that obvious metabolic disturbance occurred during FHF, whereas the hBMSC transplantation group showed less severe liver injury. The metabolic trajectory returns to its original state at week 3 following the hBMSC transplantation. In total, the concentration of 26 metabolites, including conjugated bile acids, phosphatidylcholines, lysophosphatidylcholines, fatty acids, amino acid and sphingomyelin, are significantly different between the FHF group and the hBMSC transplantation group. Moreover, the time course of changes in the metabolites corresponded with that of the biochemical and histological analyses. Real-time PCR further confirmed that the gene expression of phospholipase A1, lecithin-cholesterol acyltransferase and lysophosphatidylcholine acyltransferase 1 decreased significantly, whereas that of phospholipase A2 remained stable, which explains the decrease of the phosphatidylcholines and lysophosphatidylcholines. These novel results have revealed a metabolic mechanism for the hBMSC transplantation in FHF, which could lead to the future development of treatment strategies for stem cell therapies.
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Affiliation(s)
- Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University , 79 Qingchun Rd., Hangzhou 310003, China
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Cienfuegos JA, Baixauli J. [Stem cells and liver regeneration: looking toward the future]. GASTROENTEROLOGIA Y HEPATOLOGIA 2012; 35:675. [PMID: 22534115 DOI: 10.1016/j.gastrohep.2012.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2012] [Accepted: 02/15/2012] [Indexed: 11/27/2022]
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Gao LL, Guan FX, Zheng PY, Yang B, Chi LK, Liang S, Zou RQ, Liu ZQ. Therapeutic effect of transplantation of human amniotic membrane- and umbilical cord-derived mesenchymal stem cells on hepatic cirrhosis in rats. Shijie Huaren Xiaohua Zazhi 2012; 20:916-922. [DOI: 10.11569/wcjd.v20.i11.916] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the therapeutic effect of transplantation of human amniotic membrane-derived mesenchymal stem cells (hAM-MSCs) and human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) on carbon tetrachloride (CCl4)-induced hepatic cirrhosis in rats.
METHODS: hAM-MSCs and hUC-MSCs were isolated and analyzed by flow cytometry for detection of expression of CD44, CD29 and CD34. Hepatic cirrhosis was induced in rats with CCl4. At week 8, five rats were killed to conduct pathological examination to confirm successful induction of hepatic cirrhosis, and 30 rats with hepatic cirrhosis were randomly and equally divided into three groups: hAM-MSCs group, hUC-MSCs group and control group. The hAM-MSCs and hUC-MSCs groups were infused wit 2×106 MSCs in 2 mL of saline via the tail vein, while the control group was given equal volume of saline. Liver function was examined before cell transplantation and 4 wk after cell transplantation. HE staining and Masson dyeing were performed to observe pathological changes in the liver. The expression of alpha-smooth muscle actin (α-SMA) in the liver was determined by immunohistochemistry.
RESULTS: Both isolated hAM-MSCs and hUC-MSCs expressed CD29 and CD44, but did not express CD34. After cell transplantation, liver function parameters were markedly improved (all P < 0.05) and the expression of α-SMA was reduced in the hAM-MSCs and hUC-MSCs groups compared to the control group (130.6 ± 3.0, 127.0 ± 2.6 vs 152.2 ± 5.4, both P < 0.05). There were no statistically significant differences in liver function parameters and α-SMA expression between the hAM-MSCs and hUC-MSCs groups.
CONCLUSION: Transplantation of hAM-MSCs and hUC-MSCs could efficiently improve liver functions and inhibit liver fibrosis in rats.
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Nakamura T, Tsutsumi V, Torimura T, Naitou M, Iwamoto H, Masuda H, Hashimoto O, Koga H, Abe M, Ii M, Kawamoto A, Asahara T, Ueno T, Sata M. Human peripheral blood CD34-positive cells enhance therapeutic regeneration of chronically injured liver in nude rats. J Cell Physiol 2012; 227:1538-52. [PMID: 21678408 DOI: 10.1002/jcp.22873] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
We investigated whether transplantation of purified human peripheral blood CD34(+) cells could reduce established liver fibrosis and up-regulate therapeutic regeneration. Human peripheral blood CD34(+) cells were isolated from total mononuclear cells of healthy volunteers by magnetic cell sorting. Recipient nude rats were injected intraperitoneally with carbon tetrachloride (CCl(4)) twice weekly for 3 weeks before single administration of CD34(+) cells. CCl(4) was then re-administered twice weekly for 3 more weeks, and the nude rats were sacrificed. Saline (control group), 1 × 10(5) (low-dose group), 5 × 10(5) (middle-dose group), or 2 × 10(6) (high-dose group) CD34(+) cells/kg body weight were intrasplenically transplanted after CCl(4) treatment for 3 weeks. Reverse transcriptase-polymerase chain reaction analysis of the freshly isolated CD34(+) cells revealed the expression of CD31, keratin19, α-smooth muscle actin (α-SMA), and epithelial growth factor, but not other liver related markers. The transplanted cells differentiated into vascular and sinusoidal endothelial cells, and vascular smooth muscle cells. CD34(+) cell transplantation reduced liver fibrosis in a dose-dependent fashion, with decreased collagen type-I and α-SMA-positive cells after 6 weeks of CCl(4) treatment by Mallory's Azan and immunohistochemical staining. Gelatin zymography showed that the expression levels of active matrix metalloproteinase-2 and -9 in CD34(+) cell transplanted livers were significantly stronger than those in saline-infused livers. In recipients of high-doses of CD34(+) cells, the number of PCNA-positive hepatocyte increased 6 weeks after CCl(4) treatment compared with saline-infused livers. We conclude that human peripheral blood CD34(+) cell transplantation halts established liver fibrosis and promotes hepatic regeneration in CCl(4)-induced chronic liver injury.
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Affiliation(s)
- Toru Nakamura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
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Abstract
The refinement of radiation therapy and radioembolization techniques has led to a resurgent interest in radiation-induced liver disease (RILD). The awareness of technical and clinical parameters that influence the chance of RILD is important to guide patient selection and toxicity minimization strategies. "Classic" RILD is characterized by anicteric ascites and hepatomegaly and is unlikely to occur after a mean liver dose of approximately 30 Gy in conventional fractionation. By maintaining a low mean liver dose and sparing a "critical volume" of liver from radiation, stereotactic delivery techniques allow for the safe administration of higher tumor doses. Caution must be exercised for patients with hepatocellular carcinoma or pre-existing liver disease (eg, Child-Pugh score of B or C) because they are more susceptible to RILD that can manifest in a nonclassic pattern. Although no pharmacologic interventions have yet been proven to mitigate RILD, preclinical research shows the potential for therapies targeting transforming growth factor-β and for the transplantation of stem cells, hepatocytes, and liver progenitor cells as strategies that may restore liver function. Also, in the clinical setting of veno-occlusive liver disease after high-dose chemotherapy, agents with fibrinolytic and antithrombotic properties can reverse liver failure, suggesting a possible role in the setting of RILD.
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Affiliation(s)
- Chandan Guha
- Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10467, USA.
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