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Zhi Y, Qiu W, Tian G, Song S, Zhao W, Du X, Sun X, Chen Y, Huang H, Li J, Yu Y, Li M, Lv G. Donor and recipient hematopoietic stem and progenitor cells mobilization in liver transplantation patients. Stem Cell Res Ther 2024; 15:231. [PMID: 39075608 PMCID: PMC11288126 DOI: 10.1186/s13287-024-03855-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 07/17/2024] [Indexed: 07/31/2024] Open
Abstract
BACKGROUND Hematopoietic stem and progenitor cells (HSPCs) mobilize from bone marrow to peripheral blood in response to stress. The impact of alloresponse-induced stress on HSPCs mobilization in human liver transplantation (LTx) recipients remains under-investigated. METHODS Peripheral blood mononuclear cell (PBMC) samples were longitudinally collected from pre- to post-LTx for one year from 36 recipients with acute rejection (AR), 74 recipients without rejection (NR), and 5 recipients with graft-versus-host disease (GVHD). 28 PBMC samples from age-matched healthy donors were collected as healthy control (HC). Multi-color flow cytometry (MCFC) was used to immunophenotype HSPCs and their subpopulations. Donor recipient-distinguishable major histocompatibility complex (MHC) antibodies determined cell origin. RESULTS Before LTx, patients who developed AR after transplant contained more HSPCs in PBMC samples than HC, while the NR group patients contained fewer HSPCs than HC. After LTx, the HSPC ratio in the AR group sharply decreased and became less than HC within six months, and dropped to a comparable NR level afterward. During the one-year follow-up period, myeloid progenitors (MPs) biased differentiation was observed in all LTx recipients who were under tacrolimus-based immunosuppressive treatment. During both AR and GVHD episodes, the recipient-derived and donor-derived HSPCs mobilized into the recipient's blood-circulation and migrated to the target tissue, respectively. The HSPCs percentage in blood reduced after the disease was cured. CONCLUSIONS A preoperative high HSPC ratio in blood characterizes recipients who developed AR after LTx. Recipients exhibited a decline in blood-circulating HSPCs after transplant, the cells mobilized into the blood and migrated to target tissue during alloresponse.
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Affiliation(s)
- Yao Zhi
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Wei Qiu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Guangyao Tian
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Shifei Song
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Wenchao Zhao
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Xiaodong Du
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Xiaodong Sun
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Yuguo Chen
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Heyu Huang
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Jing Li
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Ying Yu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Mingqian Li
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, China.
| | - Guoyue Lv
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, China.
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Abubakr S, Hazem NM, Sherif RN, Elhawary AA, Botros KG. Correlation between SDF-1α, CD34 positive hematopoietic stem cells and CXCR4 expression with liver fibrosis in CCl4 rat model. BMC Gastroenterol 2023; 23:323. [PMID: 37730560 PMCID: PMC10512633 DOI: 10.1186/s12876-023-02932-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Accepted: 08/25/2023] [Indexed: 09/22/2023] Open
Abstract
BACKGROUND One of the most frequent disorders is liver fibrosis. An improved understanding of the different events during the process of liver fibrosis & its reversibility could be helpful in its staging and in finding potential therapeutic agents. AIM The goal of this research was to evaluate the relationship among CD34 + HPSCs, SDF-1α, and CXCR4 receptor expression with the percentage of the area of hepatic fibrosis. MATERIALS AND METHODS Thirty-six male Sprague-Dawley rats were separated into the control group, liver injury group & spontaneous reversion group. The liver injury was induced by using 2 ml/kg CCl4 twice a week. Flow cytometric examination of CD34 + cells in the blood & liver was performed. Bone marrow & liver samples were taken for evaluation of the SDF-1α mRNA by PCR. Liver specimens were stained for histopathological and CXCR4 immuno-expression evaluation. RESULTS In the liver injury group, the hepatic enzymes, fibrosis area percentage, CXCR4 receptor expression in the liver, CD34 + cells in the blood and bone marrow & the level SDF-1α in the liver and its concentration gradient were statistically significantly elevated with the progression of the liver fibrosis. On the contrary, SDF-1α in the bone marrow was statistically significantly reduced with the development of liver fibrosis. During the spontaneous reversion group, all the studied parameters apart from SDF-1α in the bone marrow were statistically substantially decreased compared with the liver injury group. We found a statistically substantial positive correlation between fibrosis area and all of the following: liver enzymes, CXCR4 receptor expression in the liver, CD34 + cells in the blood and liver, and SDF- 1α in the liver and its concentration gradient. In conclusion, in CCl4 rat model, the fibrosis area is significantly correlated with many parameters in the blood, bone marrow, and liver, which can be used during the process of follow-up during the therapeutic interventions.
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Affiliation(s)
- Sara Abubakr
- Human Anatomy & Embryology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Noha M Hazem
- Medical Biochemistry and Molecular Biology Department, Medical Experimental Research Center (MERC), Faculty of Medicine, Mansoura University, Algomhoria Street, Mansoura, 35516, Egypt.
- Pathological Sciences Department, Fakeeh College for Medical Sciences, Jeddah, Saudi Arabia.
| | - R N Sherif
- Human Anatomy & Embryology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Adel Abdelmohdy Elhawary
- Human Anatomy & Embryology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Kamal G Botros
- Human Anatomy & Embryology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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3
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Medrano-Bosch M, Simón-Codina B, Jiménez W, Edelman ER, Melgar-Lesmes P. Monocyte-endothelial cell interactions in vascular and tissue remodeling. Front Immunol 2023; 14:1196033. [PMID: 37483594 PMCID: PMC10360188 DOI: 10.3389/fimmu.2023.1196033] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 06/21/2023] [Indexed: 07/25/2023] Open
Abstract
Monocytes are circulating leukocytes of innate immunity derived from the bone marrow that interact with endothelial cells under physiological or pathophysiological conditions to orchestrate inflammation, angiogenesis, or tissue remodeling. Monocytes are attracted by chemokines and specific receptors to precise areas in vessels or tissues and transdifferentiate into macrophages with tissue damage or infection. Adherent monocytes and infiltrated monocyte-derived macrophages locally release a myriad of cytokines, vasoactive agents, matrix metalloproteinases, and growth factors to induce vascular and tissue remodeling or for propagation of inflammatory responses. Infiltrated macrophages cooperate with tissue-resident macrophages during all the phases of tissue injury, repair, and regeneration. Substances released by infiltrated and resident macrophages serve not only to coordinate vessel and tissue growth but cellular interactions as well by attracting more circulating monocytes (e.g. MCP-1) and stimulating nearby endothelial cells (e.g. TNF-α) to expose monocyte adhesion molecules. Prolonged tissue accumulation and activation of infiltrated monocytes may result in alterations in extracellular matrix turnover, tissue functions, and vascular leakage. In this review, we highlight the link between interactions of infiltrating monocytes and endothelial cells to regulate vascular and tissue remodeling with a special focus on how these interactions contribute to pathophysiological conditions such as cardiovascular and chronic liver diseases.
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Affiliation(s)
- Mireia Medrano-Bosch
- Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain
| | - Blanca Simón-Codina
- Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain
| | - Wladimiro Jiménez
- Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain
- Biochemistry and Molecular Genetics Service, Hospital Clínic Universitari, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Elazer R. Edelman
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Pedro Melgar-Lesmes
- Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain
- Biochemistry and Molecular Genetics Service, Hospital Clínic Universitari, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, United States
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Nguyen NT, Umbaugh DS, Huang EL, Adelusi OB, Sanchez Guerrero G, Ramachandran A, Jaeschke H. Recovered Hepatocytes Promote Macrophage Apoptosis through CXCR4 after Acetaminophen-Induced Liver Injury in Mice. Toxicol Sci 2022; 188:248-260. [PMID: 35642939 DOI: 10.1093/toxsci/kfac057] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Acetaminophen (APAP) overdose is the main cause of acute liver failure in Western countries. The mechanism of APAP hepatotoxicity is associated with centrilobular necrosis which initiates infiltration of neutrophils, monocytes, and other leukocytes to the area of necrosis. While it has been recognized that this infiltration of immune cells plays a critical role in promoting liver repair, mechanism of immune cell clearance that is important for resolution of inflammation and the return to normal homeostasis are not well characterized. CXCR4 is a chemokine receptor expressed on hepatocytes as well as neutrophils, monocytes, and hematopoietic stem cells. CXCR4 function is dependent on its selective expression on different cell types and thus can vary depending on the pathophysiology. This study aimed to investigate the crosstalk between hepatocytes and macrophages through CXCR4 to promote macrophage apoptosis after APAP overdose. C57BL/6J mice were subjected to APAP overdose (300 mg/kg). Flow cytometry and immunohistochemistry were used to determine the mode of cell death of macrophages and expression pattern of CXCR4 during the resolution phase of APAP hepatotoxicity. The impact of CXCR4 in regulation of macrophage apoptosis and liver recovery was assessed after administration of a monoclonal antibody against CXCR4. RNAseq analysis was performed on flow cytometry sorted CXCR4+ macrophages at 72 h to confirm the apoptotic cell death of macrophages. Our data indicate that the inflammatory response is resolved by recovering hepatocytes through induction of CXCR4 on macrophages, which triggers their cell death by apoptosis at the end of the recovery phase.
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Affiliation(s)
- Nga T Nguyen
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - David S Umbaugh
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Eileen L Huang
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Olamide B Adelusi
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Giselle Sanchez Guerrero
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Anup Ramachandran
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
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Mehrabi M, Amini F, Mehrabi S. Kill and Clearance in HCC: An Approach Based on NK Cells and Macrophages. Front Oncol 2021; 11:693076. [PMID: 34557407 PMCID: PMC8453146 DOI: 10.3389/fonc.2021.693076] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 08/23/2021] [Indexed: 11/15/2022] Open
Affiliation(s)
| | | | - Shima Mehrabi
- Internal Medicine, Iran University of Medical Sciences, Tehran, Iran
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Chen H, Li G, Liu Y, Ji S, Li Y, Xiang J, Zhou L, Gao H, Zhang W, Sun X, Fu X, Li B. Pleiotropic Roles of CXCR4 in Wound Repair and Regeneration. Front Immunol 2021; 12:668758. [PMID: 34122427 PMCID: PMC8194072 DOI: 10.3389/fimmu.2021.668758] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 04/26/2021] [Indexed: 12/27/2022] Open
Abstract
Wound healing is a multi-step process that includes multiple cellular events such as cell proliferation, cell adhesion, and chemotactic response as well as cell apoptosis. Accumulating studies have documented the significance of stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor 4 (CXCR4) signaling in wound repair and regeneration. However, the molecular mechanism of regeneration is not clear. This review describes various types of tissue regeneration that CXCR4 participates in and how the efficiency of regeneration is increased by CXCR4 overexpression. It emphasizes the pleiotropic effects of CXCR4 in regeneration. By delving into the specific molecular mechanisms of CXCR4, we hope to provide a theoretical basis for tissue engineering and future regenerative medicine.
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Affiliation(s)
- Huating Chen
- Department of Wound Repair Surgery, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department and 4th Medical Center, PLA General Hospital and PLA Medical College; PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration; Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, Beijing, China
| | | | - Yiqiong Liu
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department and 4th Medical Center, PLA General Hospital and PLA Medical College; PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration; Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, Beijing, China
| | - Shuaifei Ji
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department and 4th Medical Center, PLA General Hospital and PLA Medical College; PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration; Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, Beijing, China
| | - Yan Li
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department and 4th Medical Center, PLA General Hospital and PLA Medical College; PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration; Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, Beijing, China.,Department of Southern Hospital of Southern Medical University, Southern Medical University, Guangzhou, China
| | - Jiangbing Xiang
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department and 4th Medical Center, PLA General Hospital and PLA Medical College; PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration; Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, Beijing, China.,Department of School of Biological Engineering, Chongqing University, Chongqing, China
| | - Laixian Zhou
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department and 4th Medical Center, PLA General Hospital and PLA Medical College; PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration; Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, Beijing, China
| | - Huanhuan Gao
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department and 4th Medical Center, PLA General Hospital and PLA Medical College; PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration; Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, Beijing, China
| | - Wenwen Zhang
- Department of Wound Repair Surgery, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoyan Sun
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department and 4th Medical Center, PLA General Hospital and PLA Medical College; PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration; Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaobing Fu
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department and 4th Medical Center, PLA General Hospital and PLA Medical College; PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration; Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, Beijing, China
| | - Binghui Li
- Department of Wound Repair Surgery, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Lipodystrophy as a Late Effect after Stem Cell Transplantation. J Clin Med 2021; 10:jcm10081559. [PMID: 33917653 PMCID: PMC8068033 DOI: 10.3390/jcm10081559] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/01/2021] [Accepted: 04/04/2021] [Indexed: 01/18/2023] Open
Abstract
Survivors of childhood cancer are at high risk of developing metabolic diseases in adulthood. Recently, several patients developing partial lipodystrophy following hematopoietic stem cell transplantation (HSCT) have been described. In this review, we summarize the cases described so far and discuss potential underlying mechanisms of the disease. The findings suggest that HSCT-associated lipodystrophies may be seen as a novel form of acquired lipodystrophy.
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In vitro differentiation effect of CCL 4-induced liver injured mice serum on bone marrow-derived mesenchymal stem cells toward hepatocytes like cells. Cell Tissue Bank 2020; 22:297-303. [PMID: 33169293 DOI: 10.1007/s10561-020-09878-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 10/23/2020] [Indexed: 10/23/2022]
Abstract
Liver dysfunction is a major health problem worldwide. Stem cells therapy has opened up new avenues for researches to treat liver diseases due to their multi lineage differentiation. As mesenchymal stem cells (MSCs) can be differentiated into hepatic lineages in the presence of different exogenous factors, the current study aimed to investigate the impact of carbon tetrachloride (CCl4) induced liver injured mice serum on MSCs differentiation toward hepatocytes in vitro. Male Balb/c mice were treated for liver injury with CCl4 as determined through biochemical tests spectrophotometrically and different growth factors (EGF, HGF) quantification through Sandwich ELISA in both normal and CCl4-induced liver injured mice serum. Mice bone marrow derived-MSCs at second passage were treated with normal and CCl4-induced liver injured mice serum. After 7 days, serum treated MSCs were investigated for hepatocytes like characteristics through RT-PCR. Serum biochemical tests (Bilirubin, ALT and ALP) and sandwich ELISA results of EGF and HGF showed marked increase in CCl4 treated mice serum as compared to normal mice serum. Periodic acid Schiff's staining and urea assay kit confirmed high level of glycogen storage and urea production in cells treated with CCl4-induced liver injured mice serum. RT-PCR results of CCl4-induced liver injured mice serum treated cells also showed expression of hepatic markers (Albumin, Cyto-8, Cyto-18, and Cyto-19). This study confirmed that CCl4-induced liver injured serum treatment can differentiate MSCs into hepatocyte-like cells in vitro.
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Platelets Boost Recruitment of CD133 + Bone Marrow Stem Cells to Endothelium and the Rodent Liver-The Role of P-Selectin/PSGL-1 Interactions. Int J Mol Sci 2020; 21:ijms21176431. [PMID: 32899390 PMCID: PMC7504029 DOI: 10.3390/ijms21176431] [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] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 08/28/2020] [Accepted: 08/31/2020] [Indexed: 02/06/2023] Open
Abstract
We previously demonstrated that clinical administration of mobilized CD133+ bone marrow stem cells (BMSC) accelerates hepatic regeneration. Here, we investigated the potential of platelets to modulate CD133+BMSC homing to hepatic endothelial cells and sequestration to warm ischemic livers. Modulatory effects of platelets on the adhesion of CD133+BMSC to human and mouse liver-sinusoidal- and micro- endothelial cells (EC) respectively were evaluated in in vitro co-culture systems. CD133+BMSC adhesion to all types of EC were increased in the presence of platelets under shear stress. This platelet effect was mostly diminished by antagonization of P-selectin and its ligand P-Selectin-Glyco-Ligand-1 (PSGL-1). Inhibition of PECAM-1 as well as SDF-1 receptor CXCR4 had no such effect. In a model of the isolated reperfused rat liver subsequent to warm ischemia, the co-infusion of platelets augmented CD133+BMSC homing to the injured liver with heightened transmigration towards the extra sinusoidal space when compared to perfusion conditions without platelets. Extravascular co-localization of CD133+BMSC with hepatocytes was confirmed by confocal microscopy. We demonstrated an enhancing effect of platelets on CD133+BMSC homing to and transmigrating along hepatic EC putatively depending on PSGL-1 and P-selectin. Our insights suggest a new mechanism of platelets to augment stem cell dependent hepatic repair.
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Tao YC, Chen EQ. Clinical application of stem cell in patients with end-stage liver disease: progress and challenges. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:564. [PMID: 32775365 PMCID: PMC7347777 DOI: 10.21037/atm.2020.03.153] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Accepted: 03/11/2020] [Indexed: 02/05/2023]
Abstract
End-stage liver disease (ESLD) is life-threatening disease worldwide, and patients with ESLD should be referred to liver transplantation (LT). However, the use of LT is limited by the lacking liver source, high cost and organ rejection. Thus, other alternative options have been explored. Stem cell therapy may be a potential alternative for ESLD treatment. With the potential of self-renewal and differentiation, both hepatic and extrahepatic stem cells have attracted a lot of attention. Among them, multipotent stem cells are most widely studies owing to their characteristics. Multipotent stem cells mainly consist of two subpopulations: hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). Accumulating evidences have proved that either bone marrow (BM)-derived HSCs mobilized by granulocyte colony-stimulating factor or MSCs transplantation can improve the biochemical indicators of patients with ESLD. However, there are some challenges to be resolved before stem cells widely used in clinic, including the best stem cell source, the optimal route for stem cells transplantation, and the dose and frequency of stem cell injected. The purpose of this review is to discuss the potential of stem cell in liver diseases, particularly, the clinical progress and challenges of multipotent stem cells in the field of ESLD.
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Affiliation(s)
- Ya-Chao Tao
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| | - En-Qiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
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11
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Philips CA, Augustine P, Rajesh S, Ahamed R, George T, Padsalgi G, Paramaguru R, Valiathan G, John SK. Granulocyte Colony-Stimulating Factor Use in Decompensated Cirrhosis: Lack of Survival Benefit. J Clin Exp Hepatol 2020; 10:124-134. [PMID: 32189927 PMCID: PMC7067994 DOI: 10.1016/j.jceh.2019.05.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 05/22/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Granulocyte colony-stimulating factor (GCSF) has been utilized in decompensated cirrhosis (DC) for improving transplant-free survival (TFS). Data from multiple centers are conflicting with regard to patient outcomes. In this retrospective study, we present our 'real-world experience' of GCSF use in a large group of DC. METHODS From September 2016 to September 2018, 1231 patients with cirrhosis were screened, of which 754 were found to have decompensation(s). Seventy-three patients with active ascites, jaundice, or both completed GCSF treatment (10 mcg/kg per day for 5 days, followed by 5 mcg/kg/day once every third day for total 12 doses). Per-protocol analysis (n = 56) was performed to study clinical events, liver disease severity, and outcomes at 3, 6, and 12 months after treatment. Modified intention-to-treat (mITT, n = 100) analysis was performed to study overall survival at 180 days. Outcomes were compared with a matched historical control (HC) group (n = 24). RESULTS Nine (16%, n = 56), 24 (43%, n = 56), and 36 (75%, n = 48) patients died at 3, 6, and 12-month follow-up after GCSF. The commonest cause of death was sepsis (53%) followed by progressive liver failure (33%). Nine percent of patients developed hepatocellular carcinoma on follow-up at the end of 1 year. Acute variceal bleeds, overt hepatic encephalopathy, intensive unit admissions, and liver disease severity scores were higher after treatment at the end of 1 year. The Child-Pugh score >11 and model for end-stage liver disease-sodium score >25 and > 20 predicted worse outcomes at all time points and at 6 and 12 months after GCSF, respectively. Compared to a matched HC group, patients receiving GCSF had higher mortality (75% vs 46%, P = 0.04) at one year. mITT analysis revealed poor overall survival at 6 months compared to HCs (48% vs 75%, P = 0.04). CONCLUSION Survival in DC was shorter than what was expected in the natural history of the disease after GCSF use.
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Key Words
- AKI, acute kidney injury
- AUC, area under the receiver operating curve
- AVB, acute variceal bleeding
- BMSCs, Bone marrow–derived stem cells
- CTP score, Child–Pugh score
- DC, decompensated cirrhosis
- DP, darbepoetin
- GCSF, granulocyte colony-stimulating factor
- HC, historical control
- HCC
- HCC, hepatocellular carcinoma
- HE, hepatic encephalopathy
- ICU, intensive care unit
- INR, international normalized ratio
- LT, liver transplantation
- MELD-Na, model for end-stage liver disease-sodium
- NASH, nonalcoholic steatohepatitis
- RCT, randomized controlled trial
- SBP, spontaneous bacterial peritonitis
- SMT, standard medical treatment
- TFS, transplant free survival
- encephalopathy
- erythropoietin
- growth factor
- hyponatremia
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Affiliation(s)
- Cyriac A. Philips
- The Liver Unit, Cochin Gastroenterology Group, Ernakulam Medical Center, Kochi, Kerala
| | - Philip Augustine
- Gastroenterology, Cochin Gastroenterology Group, Ernakulam Medical Center, Kochi, Kerala
| | - Sasidharan Rajesh
- Interventional Radiology, Cochin Gastroenterology Group, Ernakulam Medical Center, Kochi, Kerala
| | - Rizwan Ahamed
- Gastroenterology, Cochin Gastroenterology Group, Ernakulam Medical Center, Kochi, Kerala
| | - Tom George
- Interventional Radiology, Cochin Gastroenterology Group, Ernakulam Medical Center, Kochi, Kerala
| | - Guruprasad Padsalgi
- Gastroenterology, Cochin Gastroenterology Group, Ernakulam Medical Center, Kochi, Kerala
| | | | - Gopakumar Valiathan
- Gastrointestinal and Hepatobiliary Surgery, Cochin Gastroenterology Group, Ernakulam Medical Center, Kochi, Kerala
| | - Solomon K. John
- Hepatobiliary and Transplant Surgery, Cochin Gastroenterology Group, Ernakulam Medical Center, Kochi, Kerala
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12
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Recruitment of macrophages and bone marrow stem cells to regenerating liver promoted by sodium phthalhydrazide in mice. Biomed Pharmacother 2019; 110:594-601. [DOI: 10.1016/j.biopha.2018.07.086] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2018] [Revised: 07/17/2018] [Accepted: 07/17/2018] [Indexed: 12/15/2022] Open
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13
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Leitão L, Alves CJ, Alencastre IS, Sousa DM, Neto E, Conceição F, Leitão C, Aguiar P, Almeida-Porada G, Lamghari M. Bone marrow cell response after injury and during early stage of regeneration is independent of the tissue-of-injury in 2 injury models. FASEB J 2018; 33:857-872. [PMID: 30044924 DOI: 10.1096/fj.201800610rr] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Selectively recruiting bone marrow (BM)-derived stem and progenitor cells to injury sites is a promising therapeutic approach. The coordinated action of soluble factors is thought to trigger the mobilization of stem cells from the BM and recruit them to lesions to contribute to tissue regeneration. Nevertheless, the temporal response profile of the major cellular players and soluble factors involved in priming the BM and recruiting BM-derived cells to promote regeneration is unknown. We show that injury alters the BM cellular composition, introducing population-specific fluctuations during tissue regeneration. We demonstrate that injury causes an immediate, transient response of mesenchymal stromal cells and endothelial cells followed by a nonoverlapping increase in hematopoietic stem and progenitor cells. Moreover, BM reaction is identical whether the injury is inflicted on skin and muscle or also involves a bone defect, but these 2 injury paradigms trigger distinct systemic cytokine responses. Together, our results indicate that the BM response to injury in the early stages of regeneration is independent of the tissue-of-injury based on the 2 models used, but the injured tissue dictates the systemic cytokine response.-Leitão, L., Alves, C. J., Alencastre, I. S., Sousa, D. M., Neto, E., Conceição, F., Leitão, C., Aguiar, P., Almeida-Porada, G., Lamghari, M. Bone marrow cell response after injury and during early stage of regeneration is independent of the tissue-of-injury in 2 injury models.
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Affiliation(s)
- Luís Leitão
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
| | - Cecília J Alves
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal
| | - Inês S Alencastre
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal
| | - Daniela M Sousa
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal
| | - Estrela Neto
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.,Faculdade de Medicina da Universidade do Porto (FMUP), Porto, Portugal
| | - Francisco Conceição
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
| | - Catarina Leitão
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal; and
| | - Paulo Aguiar
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal
| | - Graça Almeida-Porada
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston Salem, North Carolina, USA
| | - Meriem Lamghari
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
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14
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Babaei A, Katoonizadeh A, Ranjbar A, Naderi M, Ahmadbeigi N. Directly injected native bone-marrow stem cells cannot incorporate into acetaminophen-induced liver injury. Biologicals 2018; 52:55-58. [PMID: 29317122 DOI: 10.1016/j.biologicals.2017.12.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2017] [Revised: 12/26/2017] [Accepted: 12/29/2017] [Indexed: 01/09/2023] Open
Abstract
The paucity of liver donation highlights the use of cell-based strategies for end-stage liver failure. We recently showed that bone marrow-derived aggregates (BMDAs) can completely restore the hematopoietic system in gamma-irradiated mice. These aggregates are stem and progenitor cells in the bone marrow (BM), composed of both hematopoietic and non-hematopoietic lineages. Furthermore, reports showed that resident BM cells migrate to the liver and integrate themselves into the tissue in small numbers. Hence, we hypothesized that direct delivery of BMDAs to the damaged liver might enhance the integration of BM cells in the liver because of its stemness property, intact BM architecture, the physical proximity of these niche-like structures to the damaged sites and the existence of liver paracrine factors. To this aim, we made an acute liver model by intraperitoneal injection of acetaminophen. Then, GFP-expressing BMDAs were intrahepatically injected. Despite the detection of GFP-expressing cells five days after intrahepatic injection, these cells were not detectable at days 15 and 60, indicating that the puzzle of BM cell integration in the liver still has more missing pieces other than stemness, physical proximity, and paracrine factors. Actually, it seems that even intact BM structures need further signals to be qualified for integration.
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Affiliation(s)
- Azadeh Babaei
- Cell-Based Therapies Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Azam Katoonizadeh
- Cell-Based Therapies Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Azam Ranjbar
- SABZ Biomedicals Science-based Company, Tehran, Iran
| | - Mahmood Naderi
- Cell-Based Therapies Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Naser Ahmadbeigi
- Cell-Based Therapies Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
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15
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Ko Y, Jeong YH, Lee JA. Transplantation of human umbilical cord blood CD34 + cells into the liver of newborn NOD/SCID/IL-2Rγ null (NSG) mice after busulfan conditioning. Blood Res 2017; 52:316-319. [PMID: 29333410 PMCID: PMC5762744 DOI: 10.5045/br.2017.52.4.316] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 04/05/2017] [Accepted: 06/15/2017] [Indexed: 11/17/2022] Open
Affiliation(s)
- Yunmi Ko
- Division of Clinical Translational Research, Korea Cancer Center Hospital, Seoul, Korea
| | - Yeon Ho Jeong
- Department of Medical Biotechnology, College of Biomedical Science, Kangwon National University, Chuncheon, Korea
| | - Jun Ah Lee
- Division of Clinical Translational Research, Korea Cancer Center Hospital, Seoul, Korea.,Department of Pediatrics, Korea Cancer Center Hospital, Seoul, Korea
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16
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Catani L, Sollazzo D, Bianchi E, Ciciarello M, Antoniani C, Foscoli L, Caraceni P, Giannone FA, Baldassarre M, Giordano R, Montemurro T, Montelatici E, D'Errico A, Andreone P, Giudice V, Curti A, Manfredini R, Lemoli RM. Molecular and functional characterization of CD133 + stem/progenitor cells infused in patients with end-stage liver disease reveals their interplay with stromal liver cells. Cytotherapy 2017; 19:1447-1461. [PMID: 28917627 DOI: 10.1016/j.jcyt.2017.08.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Revised: 08/01/2017] [Accepted: 08/03/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND AIMS Growing evidence supports the therapeutic potential of bone marrow (BM)-derived stem/progenitor cells for end-stage liver disease (ESLD). We recently demonstrated that CD133+ stem/progenitor cell (SPC) reinfusion in patients with ESLD is feasible and safe and improve, albeit transiently, liver function. However, the mechanism(s) through which BM-derived SPCs may improve liver function are not fully elucidated. METHODS Here, we characterized the circulating SPCs compartment of patients with ESLD undergoing CD133+ cell therapy. Next, we set up an in vitro model mimicking SPCs/liver microenvironment interaction by culturing granulocyte colony-stimulating factor (G-CSF)-mobilized CD133+and LX-2 hepatic stellate cells. RESULTS We found that patients with ESLD show normal basal levels of circulating hematopoietic and endothelial progenitors with impaired clonogenic ability. After G-CSF treatment, patients with ESLD were capable to mobilize significant numbers of functional multipotent SPCs, and interestingly, this was associated with increased levels of selected cytokines potentially facilitating SPC function. Co-culture experiments showed, at the molecular and functional levels, the bi-directional cross-talk between CD133+ SPCs and human hepatic stellate cells LX-2. Human hepatic stellate cells LX-2 showed reduced activation and fibrotic potential. In turn, hepatic stellate cells enhanced the proliferation and survival of CD133+ SPCs as well as their endothelial and hematopoietic function while promoting an anti-inflammatory profile. DISCUSSION We demonstrated that the interaction between CD133+ SPCs from patients with ESLD and hepatic stellate cells induces significant functional changes in both cellular types that may be instrumental for the improvement of liver function in cirrhotic patients undergoing cell therapy.
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Affiliation(s)
- Lucia Catani
- Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli," University of Bologna, Bologna, Italy.
| | - Daria Sollazzo
- Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli," University of Bologna, Bologna, Italy
| | - Elisa Bianchi
- Centre for Regenerative Medicine "Stefano Ferrari," Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Marilena Ciciarello
- Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli," University of Bologna, Bologna, Italy
| | - Chiara Antoniani
- Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli," University of Bologna, Bologna, Italy
| | - Licia Foscoli
- Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli," University of Bologna, Bologna, Italy
| | - Paolo Caraceni
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; Center for Applied Biomedical Research (C.R.B.A.), Azienda Ospedaliero/Universitaria di Bologna, Bologna, Italy
| | | | - Maurizio Baldassarre
- Center for Applied Biomedical Research (C.R.B.A.), Azienda Ospedaliero/Universitaria di Bologna, Bologna, Italy
| | - Rosaria Giordano
- Cell Factory, Unit of Cellular Therapy and Cryobiology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Tiziana Montemurro
- Cell Factory, Unit of Cellular Therapy and Cryobiology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Elisa Montelatici
- Cell Factory, Unit of Cellular Therapy and Cryobiology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Antonia D'Errico
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Pietro Andreone
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Valeria Giudice
- Immunohematology Service and Blood Bank-Azienda Ospedaliero/Universitaria di Bologna, Bologna, Italy
| | - Antonio Curti
- Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli," University of Bologna, Bologna, Italy
| | - Rossella Manfredini
- Centre for Regenerative Medicine "Stefano Ferrari," Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Roberto Massimo Lemoli
- Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy
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17
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Pedone E, Olteanu VA, Marucci L, Muñoz-Martin MI, Youssef SA, de Bruin A, Cosma MP. Modeling Dynamics and Function of Bone Marrow Cells in Mouse Liver Regeneration. Cell Rep 2017; 18:107-121. [PMID: 28052241 PMCID: PMC5236012 DOI: 10.1016/j.celrep.2016.12.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Revised: 07/15/2016] [Accepted: 12/01/2016] [Indexed: 12/13/2022] Open
Abstract
In rodents and humans, the liver can efficiently restore its mass after hepatectomy. This is largely attributed to the proliferation and cell cycle re-entry of hepatocytes. On the other hand, bone marrow cells (BMCs) migrate into the liver after resection. Here, we find that a block of BMC recruitment into the liver severely impairs its regeneration after the surgery. Mobilized hematopoietic stem and progenitor cells (HSPCs) in the resected liver can fuse with hepatocytes, and the hybrids proliferate earlier than the hepatocytes. Genetic ablation of the hybrids severely impairs hepatocyte proliferation and liver mass regeneration. Mathematical modeling reveals a key role of bone marrow (BM)-derived hybrids to drive proliferation in the regeneration process, and predicts regeneration efficiency in experimentally non-testable conditions. In conclusion, BM-derived hybrids are essential to trigger efficient liver regeneration after hepatectomy.
Bone marrow cell migration after liver hepatectomy is key for liver regeneration Migrated bone marrow cells fuse with hepatocytes Hybrids are essential for liver regeneration Mathematical modeling unveils the hybrid function for liver regeneration
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Affiliation(s)
- Elisa Pedone
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain
| | - Vlad-Aris Olteanu
- Department of Engineering Mathematics, University of Bristol, Bristol BS8 1UB, UK
| | - Lucia Marucci
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr Aiguader 88, 08003 Barcelona, Spain; Department of Engineering Mathematics, University of Bristol, Bristol BS8 1UB, UK.
| | - Maria Isabel Muñoz-Martin
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr Aiguader 88, 08003 Barcelona, Spain
| | - Sameh A Youssef
- Dutch Molecular Pathology Center, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, 3584 Utrecht, the Netherlands; Department of Pathology, Alexandria Veterinary College, University of Alexandria-Egypt, 21612 Alexandria, Egypt
| | - Alain de Bruin
- Dutch Molecular Pathology Center, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, 3584 Utrecht, the Netherlands; University Medical Center Groningen, Department of Pediatrics, University of Groningen, 9713 Groningen, the Netherlands
| | - Maria Pia Cosma
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain; ICREA, Pg. Lluís Companys 23, 08010 Barcelona, Spain.
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18
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Goichberg P. Current Understanding of the Pathways Involved in Adult Stem and Progenitor Cell Migration for Tissue Homeostasis and Repair. Stem Cell Rev Rep 2017; 12:421-37. [PMID: 27209167 DOI: 10.1007/s12015-016-9663-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
With the advancements in the field of adult stem and progenitor cells grows the recognition that the motility of primitive cells is a pivotal aspect of their functionality. There is accumulating evidence that the recruitment of tissue-resident and circulating cells is critical for organ homeostasis and effective injury responses, whereas the pathobiology of degenerative diseases, neoplasm and aging, might be rooted in the altered ability of immature cells to migrate. Furthermore, understanding the biological machinery determining the translocation patterns of tissue progenitors is of great relevance for the emerging methodologies for cell-based therapies and regenerative medicine. The present article provides an overview of studies addressing the physiological significance and diverse modes of stem and progenitor cell trafficking in adult mammalian organs, discusses the major microenvironmental cues regulating cell migration, and describes the implementation of live imaging approaches for the exploration of stem cell movement in tissues and the factors dictating the motility of endogenous and transplanted cells with regenerative potential.
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Affiliation(s)
- Polina Goichberg
- Department Anesthesiology, Perioperative and Pain Medicine, Harvard Medical School, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA.
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19
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Baig MT, Ali G, Awan SJ, Shehzad U, Mehmood A, Mohsin S, Khan SN, Riazuddin S. Serum from CCl 4-induced acute rat injury model induces differentiation of ADSCs towards hepatic cells and reduces liver fibrosis. Growth Factors 2017; 35:144-160. [PMID: 29110545 DOI: 10.1080/08977194.2017.1392945] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Cellular therapies hold promise to alleviate liver diseases. This study explored the potential of allogenic serum isolated from rat with acute CCl4 injury to differentiate adipose derived stem cells (ADSCs) towards hepatic lineage. Acute liver injury was induced by CCl4 which caused significant increase in serum levels of VEGF, SDF1α and EGF. ADSCs were preconditioned with 3% serum isolated from normal and acute liver injury models. ADSCs showed enhanced expression of hepatic markers (AFP, albumin, CK8 and CK19). These differentiated ADSCs were transplanted intra-hepatically in CCl4-induced liver fibrosis model. After one month of transplantation, fibrosis and liver functions (alkaline phosphatase, ALAT and bilirubin) showed marked improvement in acute injury group. Elevated expression of hepatic (AFP, albumin, CK 18 and HNF4a) and pro survival markers (PCNA and VEGF) and improvement in liver architecture as deduced from results of alpha smooth muscle actin, Sirius red and Masson's trichome staining was observed.
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Affiliation(s)
- Maria Tayyab Baig
- a Centre of Excellence in Molecular Biology , University of Punjab , Lahore , Pakistan
| | - Gibran Ali
- a Centre of Excellence in Molecular Biology , University of Punjab , Lahore , Pakistan
| | - Sana Javaid Awan
- a Centre of Excellence in Molecular Biology , University of Punjab , Lahore , Pakistan
| | - Umara Shehzad
- a Centre of Excellence in Molecular Biology , University of Punjab , Lahore , Pakistan
| | - Azra Mehmood
- a Centre of Excellence in Molecular Biology , University of Punjab , Lahore , Pakistan
| | - Sadia Mohsin
- b Cardiovascular Research Centre, Lewis Katz School of Medicine at Temple University , Philadelphia , PA , USA
| | - Shaheen N Khan
- a Centre of Excellence in Molecular Biology , University of Punjab , Lahore , Pakistan
| | - Sheikh Riazuddin
- a Centre of Excellence in Molecular Biology , University of Punjab , Lahore , Pakistan
- c Allama Iqbal Medical College , Lahore , Pakistan
- d Shaheed Zulfiqar Ali Bhutto Medical University (SZABMU) , Islamabad , Pakistan
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20
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Ribas JLC, Sherry JP, Zampronio AR, Silva de Assis HC, Simmons DBD. Inhibition of immune responses and related proteins in Rhamdia quelen exposed to diclofenac. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY 2017; 36:2092-2107. [PMID: 28106285 DOI: 10.1002/etc.3742] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 11/22/2016] [Accepted: 01/16/2017] [Indexed: 06/06/2023]
Abstract
Nonsteroidal anti-inflammatory drugs are among the most widely detected pharmaceuticals in surface water worldwide. The nonsteroidal anti-inflammatory drug diclofenac is used to treat many types of pain and inflammation. Diclofenac's potential to cause adverse effects in exposed wildlife is a growing concern. To evaluate the effects of waterborne diclofenac on the immune response in Rhamdia quelen (South American catfish), fish were exposed to 3 concentrations of diclofenac (0.2, 2.0, and 20.0 μg/L) for 14 d. Some of the exposed fish were also given an intraperitoneal injection on day 14 of 1 mg/kg of carrageenan to evaluate cell migration to the peritoneum. Total blood leukocyte count and carrageenan-induced leukocyte migration to the peritoneal cavity, particularly of polymorphonuclear cells, were significantly affected for all diclofenac exposure groups. Nitric oxide production was significantly reduced in the diclofenac-treated fish. Plasma and kidney proteins were analyzed by means of liquid chromatography-tandem mass spectrometry in a shotgun proteomic approach. In both plasma and kidney of diclofenac-exposed R. quelen, the expression of 20 proteins related to the inflammatory process, nitric oxide production, leukocyte migration, and the complement cascade was significantly altered. In addition, class I major histocompatibility complex was significantly decreased in plasma of diclofenac-treated fish. Thus, waterborne exposure to diclofenac could lead to suppression of the innate immune system in R. quelen. Environ Toxicol Chem 2017;36:2092-2107. © 2017 SETAC.
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Affiliation(s)
- João L C Ribas
- Department of Pharmacology, Federal University of Parana, Curitiba-Paraná, Brazil
- Department of Biomedicine, Positivo University, Curitiba-Paraná, Brazil
| | - James P Sherry
- Water Science and Technology, Aquatic Contaminants Research Division, Environment and Climate Change Canada, Burlington, Ontario, Canada
| | | | | | - Denina B D Simmons
- Water Science and Technology, Aquatic Contaminants Research Division, Environment and Climate Change Canada, Burlington, Ontario, Canada
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21
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Melgar-Lesmes P, Balcells M, Edelman ER. Implantation of healthy matrix-embedded endothelial cells rescues dysfunctional endothelium and ischaemic tissue in liver engraftment. Gut 2017; 66:1297-1305. [PMID: 26851165 PMCID: PMC5288307 DOI: 10.1136/gutjnl-2015-310409] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Revised: 01/12/2016] [Accepted: 01/14/2016] [Indexed: 12/23/2022]
Abstract
OBJECTIVE Liver transplantation is limited by ischaemic injury which promotes endothelial cell and hepatocyte dysfunction and eventually organ failure. We sought to understand how endothelial state determines liver recovery after hepatectomy and engraftment. DESIGN Matrix-embedded endothelial cells (MEECs) with retained healthy phenotype or control acellular matrices were implanted in direct contact with the remaining median lobe of donor mice undergoing partial hepatectomy (70%), or in the interface between the remaining median lobe and an autograft or isograft from the left lobe in hepatectomised recipient mice. Hepatic vascular architecture, DNA fragmentation and apoptosis in the median lobe and grafts, serum markers of liver damage and phenotype of macrophage and lymphocyte subsets in the liver after engraftment were analysed 7 days post-op. RESULTS Healthy MEECs create a functional vascular splice in donor and recipient liver after 70% hepatectomy in mouse protecting these livers from ischaemic injury, hepatic congestion and inflammation. Macrophages recruited adjacent to the vascular nodes into the implants switched to an anti-inflammatory and regenerative profile M2. MEECs improved liver function and the rate of liver regeneration and prevented apoptosis in donor liver lobes, autologous grafts and syngeneic engraftment. CONCLUSIONS Implants with healthy endothelial cells rescue liver donor and recipient endothelium and parenchyma from ischaemic injury after major hepatectomy and engraftment. This study highlights endothelial-hepatocyte crosstalk in hepatic repair and provides a promising new approach to improve regenerative medicine outcomes and liver transplantation.
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Affiliation(s)
- Pedro Melgar-Lesmes
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, US,Corresponding author: Pedro Melgar-Lesmes, PhD, Massachusetts Institute of Technology, Cambridge, Massachusetts; 77 Massachusetts Avenue, Building E25-438. Cambridge, MA 02139. USA. Phone: +1 617-715-2026, FAX: +1 617-253-2514,
| | - Mercedes Balcells
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, US,Bioengineering Department, Institut Químic de Sarrià, Ramon Llull Univ, Barcelona, Spain
| | - Elazer R. Edelman
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, US,Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, US
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22
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Shiota G, Itaba N. Progress in stem cell-based therapy for liver disease. Hepatol Res 2017; 47:127-141. [PMID: 27188253 DOI: 10.1111/hepr.12747] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Revised: 05/03/2016] [Accepted: 05/12/2016] [Indexed: 12/16/2022]
Abstract
Liver transplantation has been accepted as a useful therapeutic approach for patients with end-stage liver disease. However, the mismatch between the great demand for liver transplants and the number of available donor organs underscores the urgent need for alternative therapeutic strategies for patients with acute and chronic liver failure. The rapidly growing knowledge on stem cell biology has opened new avenues toward stem cell-based therapy for liver disease. As stem cells have capacity for high proliferation and multipotent differentiation, the characteristics of stem cells fit the cell therapy. Several types of cells have been investigated as possible sources of liver regeneration: mesenchymal stem cells, hematopoietic stem cells, liver progenitor cells, induced pluripotent stem cells, and bone marrow mononuclear cells. In vitro and in vivo experiments revealed that these cells have great potential as candidates of stem cell therapy. We reviewed the reports on clinical trials of cell therapy for liver disease that have been recently undertaken using mesenchymal stem cells, hematopoietic stem cells, bone marrow mononuclear cells, and liver progenitor cells. These reports have heterogeneity of description of trial design, types of infused cells, patient population, and efficacy of therapies. We addressed these reports from these viewpoints and clarified their significance. We hope that this review article will provide a perspective on the available approaches based on stem cell-based therapy for liver disease.
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Affiliation(s)
- Goshi Shiota
- Division of Molecular and Genetic Medicine, Graduate School of Medicine, Tottori University, Yonago, Japan
| | - Noriko Itaba
- Departments of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University, Yonago, Japan
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23
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Elberry DA, Amin SN, Esmail RSEN, Rashed LA, Gamal MM. Effect of undifferentiated versus hepatogenic partially differentiated mesenchymal stem cells on hepatic and cognitive functions in liver cirrhosis. EXCLI JOURNAL 2016; 15:652-670. [PMID: 28337098 PMCID: PMC5318675 DOI: 10.17179/excli2016-645] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 10/31/2016] [Indexed: 12/21/2022]
Abstract
Liver cirrhosis is the outcome of chronic liver injury. The current study aimed to investigate the therapeutic effect of undifferentiated mesenchymal stem cells versus in vitro partially differentiated mesenchymal stem cells on liver cirrhosis and hepatic encephalopathy. 50 adult male albino rats constituted the animal model and were divided into the following groups: control, thioacetamide, undifferentiated mesenchymal stem cells and hepatocyte growth factor-differentiated mesenchymal stem cells groups. Cognitive assessment was achieved by open field test and Y-maze task. We measured serum alanine aminotransferase, albumin and transforming growth factor-beta1, gene expression of α-smooth muscle actin, matrix metalloprotein-2, its tissue inhibitor and apoptotic markers: Bax and Bcl2, brain glial fibrillary acidic protein, synaptophysin, and dopaminergic receptors.
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Affiliation(s)
- Dalia Azmy Elberry
- Department of Medical Physiology, Kasr Al Ainy Faculty of Medicine, Cairo University, Egypt
| | - Shaimaa Nasr Amin
- Department of Medical Physiology, Kasr Al Ainy Faculty of Medicine, Cairo University, Egypt
| | | | - Laila Ahmed Rashed
- Department of Biochemistry, Kasr Al Ainy Faculty of Medicine, Cairo University, Egypt
| | - Maha Mohamed Gamal
- Department of Medical Physiology, Kasr Al Ainy Faculty of Medicine, Cairo University, Egypt
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Wang X, Gao M, Schouteden S, Roebroek A, Eggermont K, van Veldhoven PP, Liu G, Peters T, Scharffetter-Kochanek K, Verfaillie CM, Feng Y. Hematopoietic stem/progenitor cells directly contribute to arteriosclerotic progression via integrin β2. Stem Cells 2016; 33:1230-40. [PMID: 25546260 PMCID: PMC4409030 DOI: 10.1002/stem.1939] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Revised: 11/10/2014] [Accepted: 12/08/2014] [Indexed: 12/21/2022]
Abstract
Recent studies described the association between hematopoietic stem/progenitor cell (HSPC) expansion in the bone marrow (BM), leukocytosis in the peripheral blood, and accelerated atherosclerosis. We hypothesized that circulating HSPC may home to inflamed vessels, where they might contribute to inflammation and neointima formation. We demonstrated that Lin− Sca-1+ cKit+ (LSK cells) in BM and peripheral blood of LDLr−/− mice on high fat diet expressed significantly more integrin β2, which was responsible for LSK cell adhesion and migration toward ICAM-1 in vitro, and homing to injured arteries in vivo, all of which were blocked with an anti-CD18 blocking antibody. When homed LSK cells were isolated from ligated artery and injected to irradiated recipients, they resulted in BM reconstitution. Injection of CD18+/+ LSK cells to immunodeficient Balb/C Rag2− γC−/− recipients resulted in more severe inflammation and reinforced neointima formation in the ligated carotid artery, compared to mice injected with PBS and CD18−/− LSK cells. Hypercholesterolemia stimulated ERK phosphorylation (pERK) in LSK cells of LDLr−/− mice in vivo. Blockade of pERK reduced ARF1 expression, leading to decreased integrin β2 function on HSPC. In addition, integrin β2 function could be regulated via ERK-independent LRP1 pathway. Integrin β2 expression on HSPC is regulated by hypercholesterolemia, specifically LDL, in pERK-dependent and -independent manners, leading to increased homing and localization of HSPC to injured arteries, which is highly correlated with arteriosclerosis. Stem Cells2015;33:1230–1240
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Affiliation(s)
- Xuhong Wang
- Beijing Key Laboratory of Diabetes Prevention and Research, Department of Endocrinology, Lu He Hospital, Capital Medical University, Beijing, People's Republic of China
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25
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Xiao Ling K, Peng L, Jian Feng Z, Wei C, Wei Yan Y, Nan S, Cheng Qi G, Zhi Wei W. Stromal Derived Factor-1/CXCR4 Axis Involved in Bone Marrow Mesenchymal Stem Cells Recruitment to Injured Liver. Stem Cells Int 2016; 2016:8906945. [PMID: 26880995 PMCID: PMC4737461 DOI: 10.1155/2016/8906945] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 10/10/2015] [Accepted: 10/15/2015] [Indexed: 01/18/2023] Open
Abstract
The molecular mechanism of bone marrow mesenchymal stromal stem cells (BMSCs) mobilization and migration to the liver was poorly understood. Stromal cell-derived factor-1 (SDF-1) participates in BMSCs homing and migration into injury organs. We try to investigate the role of SDF-1 signaling in BMSCs migration towards injured liver. The expression of CXCR4 in BMSCs at mRNA level and protein level was confirmed by RT-PCR, flow cytometry, and immunocytochemistry. The SDF-1 or liver lysates induced BMSCs migration was detected by transwell inserts. CXCR4 antagonist, AMD3100, and anti-CXCR4 antibody were used to inhibit the migration. The Sprague-Dawley rat liver injury model was established by intraperitoneal injection of thioacetamide. The concentration of SDF-1 increased as modeling time extended, which was determined by ELISA method. The Dir-labeled BMSCs were injected into the liver of the rats through portal vein. The cell migration in the liver was tracked by in vivo imaging system and the fluorescent intensity was measured. In vivo, BMSCs migrated into injured liver which was partially blocked by AMD3100 or anti-CXCR4 antibody. Taken together, the results demonstrated that the migration of BMSCs was regulated by SDF-1/CXCR4 signaling which involved in BMSCs recruitment to injured liver.
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Affiliation(s)
- Kuai Xiao Ling
- Department of Gastroenterology, Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, China
| | - Li Peng
- Department of General Surgery, Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, China
| | - Zhang Jian Feng
- Department of Gastroenterology, Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, China
| | - Cao Wei
- Department of Gastroenterology, Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, China
| | - Yuan Wei Yan
- Department of Gastroenterology, Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, China
| | - Shao Nan
- Department of Gastroenterology, Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, China
| | - Guan Cheng Qi
- Department of Gastroenterology, Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, China
| | - Wang Zhi Wei
- Department of General Surgery, Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, China
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Kašėta V, Vaitkuvienė A, Liubavičiūtė A, Maciulevičienė R, Stirkė A, Biziulevičienė G. Quantitative evaluation of the transplanted lin(-) hematopoietic cell migration kinetics. Transpl Immunol 2015; 34:54-9. [PMID: 26598388 DOI: 10.1016/j.trim.2015.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Revised: 11/10/2015] [Accepted: 11/17/2015] [Indexed: 11/27/2022]
Abstract
Stem cells take part in organogenesis, cell maturation and injury repair. The migration is necessary for each of these functions to occur. The aim of this study was to investigate the kinetics of transplanted hematopoietic lin(-) cell population (which consists mainly of the stem and progenitor cells) in BALB/c mouse contact hypersensitivity model and quantify the migration to the site of inflammation in the affected foot and other healthy organs. Quantitative analysis was carried out with the real-time polymerase chain reaction method. Spleen, kidney, bone marrow, lung, liver, damaged and healthy foot tissue samples at different time points were collected for analysis. The quantitative data normalization was performed according to the comparative quantification method. The analysis of foot samples shows the significant migration of transplanted cells to the recipient mice affected foot. The quantity was more than 1000 times higher, as compared with that of the untreated foot. Due to the inflammation, the number of donor origin cells migrating to the lungs, liver, spleen and bone marrow was found to be decreased. Our data shows that transplanted cells selectively migrated into the inflammation areas of the foot edema. Also, the inflammation caused a secondary migration in ectopic spleen of hematopoietic stem cell niches and re-homing from the spleen to the bone marrow took place.
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Affiliation(s)
- Vytautas Kašėta
- State Research Institute Center for Innovative Medicine, Žygimantų str. 9, LT-01102 Vilnius, Lithuania; Center for Physical Sciences and Technology, A. Goštauto Str. 11, LT-01108 Vilnius, Lithuania.
| | - Aida Vaitkuvienė
- State Research Institute Center for Innovative Medicine, Žygimantų str. 9, LT-01102 Vilnius, Lithuania
| | - Aušra Liubavičiūtė
- State Research Institute Center for Innovative Medicine, Žygimantų str. 9, LT-01102 Vilnius, Lithuania
| | - Rūta Maciulevičienė
- Center for Physical Sciences and Technology, A. Goštauto Str. 11, LT-01108 Vilnius, Lithuania
| | - Arūnas Stirkė
- Center for Physical Sciences and Technology, A. Goštauto Str. 11, LT-01108 Vilnius, Lithuania
| | - Genė Biziulevičienė
- State Research Institute Center for Innovative Medicine, Žygimantų str. 9, LT-01102 Vilnius, Lithuania
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Jian ZH, Wang LC, Lin CC, Wang JD. The correlation between plasma cytokine levels in jaundice-free children with biliary atresia. World J Pediatr 2015; 11:352-7. [PMID: 25846069 DOI: 10.1007/s12519-015-0023-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Accepted: 05/30/2014] [Indexed: 01/05/2023]
Abstract
BACKGROUND T helper (Th) cell cytokines modulate inflammation and play a role in biliary atresia (BA). The aim of the study is a cross-sectional assessment of the levels of Th cytokines in the jaundice-free post Kasai procedure patients. METHODS There were 40 jaundice-free patients with BA and 28 normal controls enrolled. Patients were divided into 3 groups, including normal liver function, impaired liver function, and portal hypertension. Plasma concentration of Th1 [interferon-γ (INF-γ), interleukin (IL)-2], Th2 (IL-4, IL-10), Th3 [transforming growth factor-β1 (TGF-β1)], Th17 (IL-17) cytokines, and stromal cell-derived factor-1α (SDF-1α) were investigated. RESULTS The IFN-γ level was significantly higher in the BA patients with impaired liver function and portal hypertension than controls (P<0.0001 and P<0.0001, respectively). There was a significantly increase of TGF-ß1 in all BA groups compared with controls (P=0.003). The reduction of SDF-1α expression was found in BA groups (P<0.0001). IL-10 levels significantly correlated with aspartate aminotransferase to platelet ratio index (r=0.496, P=0.001). For the cytokine correlations, there were no correlations of Th1, Th2 and Th17 cytokine with the other measured cytokines, but TGF-ß1 was negatively correlated with SDF-1α levels (r=-0.327, P=0.039). CONCLUSIONS IFN-γ and IL-10 are likely to be involved in the disease progression in BA. Besides, TGF-β1 is found to be a suppression marker associated with SDF-1α levels and reduced production of TGF-β1 may be associated with the disease progression.
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Affiliation(s)
- Zhi-Hong Jian
- , Taiwan, China
- Division of Pediatric Gastroenterology, Department of Pediatrics, Taichung Veterans General Hospital, Taichung City, 40705, Taiwan, China
- Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung City, 40201, Taiwan, China
| | - Li-Ching Wang
- , Taiwan, China
- Division of Pediatric Gastroenterology, Department of Pediatrics, Taichung Veterans General Hospital, Taichung City, 40705, Taiwan, China
| | - Chieh-Chung Lin
- , Taiwan, China
- Division of Pediatric Gastroenterology, Department of Pediatrics, Taichung Veterans General Hospital, Taichung City, 40705, Taiwan, China
| | - Jiaan-Der Wang
- , Taiwan, China.
- Division of Pediatric Gastroenterology, Department of Pediatrics, Taichung Veterans General Hospital, Taichung City, 40705, Taiwan, China.
- School of Medicine, China Medical University, Taichung, Taiwan, China.
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28
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El-Akabawy G, El-Mehi A. Mobilization of endogenous bone marrow-derived stem cells in a thioacetamide-induced mouse model of liver fibrosis. Tissue Cell 2015; 47:257-65. [PMID: 25857836 DOI: 10.1016/j.tice.2015.03.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2015] [Revised: 03/01/2015] [Accepted: 03/03/2015] [Indexed: 02/07/2023]
Abstract
The clinical significance of enhancing endogenous circulating haematopoietic stem cells is becoming increasingly recognized, and the augmentation of circulating stem cells using granulocyte-colony stimulating factor (G-CSF) has led to promising preclinical and clinical results for several liver fibrotic conditions. However, this approach is largely limited by cost and the infeasibility of maintaining long-term administration. Preclinical studies have reported that StemEnhance, a mild haematopoietic stem cell mobilizer, promotes cardiac muscle regeneration and remedies the manifestation of diabetes. However, the effectiveness of StemEnhance in ameliorating liver cirrhosis has not been studied. This study is the first to evaluate the beneficial effect of StemEnhance administration in a thioacetamide-induced mouse model of liver fibrosis. StemEnhance augmented the number of peripheral CD34-positive cells, reduced hepatic fibrosis, improved histopathological changes, and induced endogenous liver proliferation. In addition, VEGF expression was up-regulated, while TNF-α expression was down-regulated in thioacetamide-induced fibrotic livers after StemEnhance intake. These data suggest that StemEnhance may be useful as a potential therapeutic candidate for liver fibrosis by inducing reparative effects via mobilization of haematopoietic stem cells.
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Affiliation(s)
- Gehan El-Akabawy
- Menoufia University, Department of Anatomy and Embryology, Faculty of Medicine, Egypt.
| | - Abeer El-Mehi
- Menoufia University, Department of Anatomy and Embryology, Faculty of Medicine, Egypt
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29
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Roccaro AM, Sacco A, Purschke WG, Moschetta M, Buchner K, Maasch C, Zboralski D, Zöllner S, Vonhoff S, Mishima Y, Maiso P, Reagan MR, Lonardi S, Ungari M, Facchetti F, Eulberg D, Kruschinski A, Vater A, Rossi G, Klussmann S, Ghobrial IM. SDF-1 inhibition targets the bone marrow niche for cancer therapy. Cell Rep 2014; 9:118-128. [PMID: 25263552 PMCID: PMC4194173 DOI: 10.1016/j.celrep.2014.08.042] [Citation(s) in RCA: 104] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Revised: 07/23/2014] [Accepted: 08/19/2014] [Indexed: 11/30/2022] Open
Abstract
Bone marrow (BM) metastasis remains one of the main causes of death associated with solid tumors as well as multiple myeloma (MM). Targeting the BM niche to prevent or modulate metastasis has not been successful to date. Here, we show that stromal cell-derived factor-1 (SDF-1/CXCL12) is highly expressed in active MM, as well as in BM sites of tumor metastasis and report on the discovery of the high-affinity anti-SDF-1 PEGylated mirror-image l-oligonucleotide (olaptesed-pegol). In vivo confocal imaging showed that SDF-1 levels are increased within MM cell-colonized BM areas. Using in vivo murine and xenograft mouse models, we document that in vivo SDF-1 neutralization within BM niches leads to a microenvironment that is less receptive for MM cells and reduces MM cell homing and growth, thereby inhibiting MM disease progression. Targeting of SDF-1 represents a valid strategy for preventing or disrupting colonization of the BM by MM cells.
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Affiliation(s)
- Aldo M Roccaro
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Antonio Sacco
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | | | - Michele Moschetta
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | | | | | | | | | | | - Yuji Mishima
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Patricia Maiso
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Michaela R Reagan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Silvia Lonardi
- Department of Pathology, University of Brescia Medical School, Spedali Civili di Brescia, 25123 Brescia, Italy
| | - Marco Ungari
- Department of Pathology, University of Brescia Medical School, Spedali Civili di Brescia, 25123 Brescia, Italy
| | - Fabio Facchetti
- Department of Pathology, University of Brescia Medical School, Spedali Civili di Brescia, 25123 Brescia, Italy
| | | | | | | | - Giuseppe Rossi
- Spedali Civili di Brescia, Department of Hematology, Centro per la Ricerca Onco-ematologica AIL, (CREA), 25123 Brescia, Italy
| | | | - Irene M Ghobrial
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
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Facciorusso A, Antonino M, Del Prete V, Neve V, Scavo MP, Barone M. Are hematopoietic stem cells involved in hepatocarcinogenesis? Hepatobiliary Surg Nutr 2014; 3:199-206. [PMID: 25202697 DOI: 10.3978/j.issn.2304-3881.2014.06.02] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Accepted: 06/10/2014] [Indexed: 12/13/2022]
Abstract
THE LIVER HAS THREE CELL LINEAGES ABLE TO PROLIFERATE AFTER A HEPATIC INJURY: the mature hepatocyte, the ductular "bipolar" progenitor cell termed "oval cell" and the putative periductular stem cell. Hepatocytes can only produce other hepatocytes whereas ductular progenitor cells are considerate bipolar since they can give rise to biliary cells or hepatocytes. Periductular stem cells are rare in the liver, have a very long proliferation potential and may be multipotent, being this aspect still under investigation. They originate in the bone marrow since their progeny express genetic markers of donor hematopoietic cells after bone marrow transplantation. Since the liver is the hematopoietic organ of the fetus, it is possible that hematopoietic stem cells may reside in the liver of the adult. This assumption is proved by the finding that oval cells express hematopoietic markers like CD34, CD45, CD 109, Thy-1, c-kit, and others, which are also expressed by bone marrow-derived hematopoietic stem cells (BMSCs). Few and discordant studies have evaluated the role of BMSC in hepatocarcinogenesis so far and further studies in vitro and in vivo are warranted in order to definitively clarify such an issue.
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Affiliation(s)
- Antonio Facciorusso
- 1 Gastroenterology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy ; 2 Methodist Research Institute, Houston, USA
| | - Matteo Antonino
- 1 Gastroenterology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy ; 2 Methodist Research Institute, Houston, USA
| | - Valentina Del Prete
- 1 Gastroenterology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy ; 2 Methodist Research Institute, Houston, USA
| | - Viviana Neve
- 1 Gastroenterology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy ; 2 Methodist Research Institute, Houston, USA
| | - Maria Principia Scavo
- 1 Gastroenterology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy ; 2 Methodist Research Institute, Houston, USA
| | - Michele Barone
- 1 Gastroenterology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy ; 2 Methodist Research Institute, Houston, USA
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Vainshtein JM, Kabarriti R, Mehta KJ, Roy-Chowdhury J, Guha C. Bone marrow-derived stromal cell therapy in cirrhosis: clinical evidence, cellular mechanisms, and implications for the treatment of hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2014; 89:786-803. [PMID: 24969793 DOI: 10.1016/j.ijrobp.2014.02.017] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Revised: 02/09/2014] [Accepted: 02/12/2014] [Indexed: 01/18/2023]
Abstract
Current treatment options for hepatocellular carcinoma (HCC) are often limited by the presence of underlying liver disease. In patients with liver cirrhosis, surgery, chemotherapy, and radiation therapy all carry a high risk of hepatic complications, ranging from ascites to fulminant liver failure. For patients receiving radiation therapy, cirrhosis dramatically reduces the already limited radiation tolerance of the liver and represents the most important clinical risk factor for the development of radiation-induced liver disease. Although improvements in conformal radiation delivery techniques have improved our ability to safely irradiate confined areas of the liver to increasingly higher doses with excellent local disease control, patients with moderate-to-severe liver cirrhosis continue to face a shortage of treatment options for HCC. In recent years, evidence has emerged supporting the use of bone marrow-derived stromal cells (BMSCs) as a promising treatment for liver cirrhosis, with several clinical studies demonstrating sustained improvement in clinical parameters of liver function after autologous BMSC infusion. Three predominant populations of BMSCs, namely hematopoietic stem cells, mesenchymal stem cells, and endothelial progenitor cells, seem to have therapeutic potential in liver injury and cirrhosis. Preclinical studies of BMSC transplantation have identified a range of mechanisms through which these cells mediate their therapeutic effects, including hepatocyte transdifferentiation and fusion, paracrine stimulation of hepatocyte proliferation, inhibition of activated hepatic stellate cells, enhancement of fibrolytic matrix metalloproteinase activity, and neovascularization of regenerating liver. By bolstering liver function in patients with underlying Child's B or C cirrhosis, autologous BMSC infusion holds great promise as a therapy to improve the safety, efficacy, and utility of surgery, chemotherapy, and hepatic radiation therapy in the treatment of HCC.
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Affiliation(s)
| | - Rafi Kabarriti
- Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
| | - Keyur J Mehta
- Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
| | - Jayanta Roy-Chowdhury
- Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; Department of Genetics, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
| | - Chandan Guha
- Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York.
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32
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Modulation of Macrophages and Response of CD117+ Cells of Different Localization after Liver Damage in Mice. Bull Exp Biol Med 2014; 157:357-9. [DOI: 10.1007/s10517-014-2565-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Indexed: 10/25/2022]
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Levine P, McDaniel K, Francis H, Kennedy L, Alpini G, Meng F. Molecular mechanisms of stem cell therapy in alcoholic liver disease. Dig Liver Dis 2014; 46:391-7. [PMID: 24440312 DOI: 10.1016/j.dld.2013.11.015] [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] [Received: 07/30/2013] [Revised: 10/19/2013] [Accepted: 11/17/2013] [Indexed: 12/11/2022]
Abstract
Alcoholic liver disease affects a great number of people worldwide. With limited therapeutic options, stem cell therapy offers significant potential for these patients. To date, a limited number of clinical trials have produced transient clinical responses to cell therapy in patients with alcoholic liver disease. Stem cell therapy to reorganize the postnatal liver is an important theme and mission for patients with chronic liver disorders including alcoholic liver injury. We therefore should redevelop the evidence of cell-based liver regeneration therapy, focusing on targets (disease, patient's status and hepatic function), materials (cells, cytokines and genes), and methodology (stem cell types and their derived microparticles, transplantation route, implantation technology and tissue engineering). In this review, we summarize the recent findings regarding the experimental and clinical use of mesenchymal and liver stem cells, focusing mainly on the treatment of alcoholic liver disorders and their relevance in the field of regenerative medicine, and advances on the role of microvesicles and exosomes in this process. We discuss new advances in stem cell therapy from liver regeneration to liver re-organization, which is involved in the recent progress of on-going clinical trials, basic research in stem cell therapy and liver regeneration, and updated exosomes/microvesicles recovery/repairing technology.
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Affiliation(s)
- Phillip Levine
- Research, Central Texas Veterans Health Care System, Temple, TX, USA; Department of Medicine, Scott & White Digestive Disease Research Center, Texas A&M University Health Science Center and Scott & White Healthcare, Temple, TX, USA; Academic Operations, Scott & White Hospital, Temple, TX, USA
| | - Kelly McDaniel
- Department of Medicine, Scott & White Digestive Disease Research Center, Texas A&M University Health Science Center and Scott & White Healthcare, Temple, TX, USA; Academic Operations, Scott & White Hospital, Temple, TX, USA
| | - Heather Francis
- Research, Central Texas Veterans Health Care System, Temple, TX, USA; Department of Medicine, Scott & White Digestive Disease Research Center, Texas A&M University Health Science Center and Scott & White Healthcare, Temple, TX, USA; Academic Operations, Scott & White Hospital, Temple, TX, USA
| | - Lindsey Kennedy
- Department of Medicine, Scott & White Digestive Disease Research Center, Texas A&M University Health Science Center and Scott & White Healthcare, Temple, TX, USA; Academic Operations, Scott & White Hospital, Temple, TX, USA
| | - Gianfranco Alpini
- Research, Central Texas Veterans Health Care System, Temple, TX, USA; Department of Medicine, Scott & White Digestive Disease Research Center, Texas A&M University Health Science Center and Scott & White Healthcare, Temple, TX, USA.
| | - Fanyin Meng
- Research, Central Texas Veterans Health Care System, Temple, TX, USA; Department of Medicine, Scott & White Digestive Disease Research Center, Texas A&M University Health Science Center and Scott & White Healthcare, Temple, TX, USA; Academic Operations, Scott & White Hospital, Temple, TX, USA.
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Barone M, Scavo MP, Maiorano E, Di Leo A, Francavilla A. Bone marrow-derived stem cells and hepatocarcinogenesis in hepatitis B virus transgenic mice. Dig Liver Dis 2014; 46:243-250. [PMID: 24286758 DOI: 10.1016/j.dld.2013.10.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2013] [Revised: 09/10/2013] [Accepted: 10/09/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND Several studies have demonstrated that cancer can develop with the contribution of bone marrow-derived cancer stem cells. We evaluated the possible involvement of bone marrow-derived stem cells in hepatocarcinogenesis in a hepatitis B virus (HBV) transgenic mouse model. METHODS Bone marrow cells from wild type male mice were transplanted into sublethally irradiated, female, HBV transgenic mice with hepatocarcinoma nodules. Four months later, liver tissue was examined to localize neoplastic nodules/foci and characterize cells by evaluating the Y-chromosome and the hepatocyte lineage marker hepatocyte nuclear factor-1 (HNF1), as well as the HBsAg encoding gene (HBs-Eg) and HBsAg protein (HBs-Pr) (present only in cells of female origin). RESULTS Hepatocytes were HBs-Eg/HBs-Pr-positive in "normal" tissue, while resulted only HBs-Eg-positive in regenerative areas. Neoplastic foci/nodules were both HBs-Eg/HBs-Pr-negative. In the liver, 19 ± 5% of cells were Y-chromosome-positive and about one fifth were HNF1-positive. Y-chromosome and HBs-Eg colocalized in HNF1-positive cells. Y-chromosome-positive cells never localized in neoplastic foci/nodules (HBs-Pr/HBs-Eg-negative). CONCLUSIONS Bone marrow-derived stem cells participate in the hepatic regenerative process but not in neoplastic growth. Simultaneous detection of both Y-chromosome and HBs-Eg in the nucleus of an HNF1-positive cell (hepatocyte) demonstrates a phenomenon of cell fusion.
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Affiliation(s)
- Michele Barone
- Section of Gastroenterology, Department of Emergency and Organ Transplantation (DETO), University of Bari, Bari, Italy
| | - Maria Principia Scavo
- Section of Gastroenterology, Department of Emergency and Organ Transplantation (DETO), University of Bari, Bari, Italy
| | - Eugenio Maiorano
- Section of Pathological Anatomy, Department of Pathological Anatomy and Genetics, University of Bari, Bari, Italy
| | - Alfredo Di Leo
- Section of Gastroenterology, Department of Emergency and Organ Transplantation (DETO), University of Bari, Bari, Italy
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Mocco J, Afzal A, Ansari S, Wolfe A, Caldwell K, Connolly ES, Scott EW. SDF1-a facilitates Lin-/Sca1+ cell homing following murine experimental cerebral ischemia. PLoS One 2014; 9:e85615. [PMID: 24465621 PMCID: PMC3896412 DOI: 10.1371/journal.pone.0085615] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Accepted: 12/05/2013] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Hematopoietic stem cells mobilize to the peripheral circulation in response to stroke. However, the mechanism by which the brain initiates this mobilization is uncharacterized. METHODS Animals underwent a murine intraluminal filament model of focal cerebral ischemia and the SDF1-A pathway was evaluated in a blinded manner via serum and brain SDF1-A level assessment, Lin-/Sca1+ cell mobilization quantification, and exogenous cell migration confirmation; all with or without SDF1-A blockade. RESULTS Bone marrow demonstrated a significant increase in Lin-/Sca1+ cell counts at 24 hrs (272 ± 60%; P<0.05 vs sham). Mobilization of Lin-/Sca1+ cells to blood was significantly elevated at 24 hrs (607 ± 159%; P<0.05). Serum SDF1-A levels were significant at 24 hrs (Sham (103 ± 14), 4 hrs (94 ± 20%, p = NS) and 24 hrs (130 ± 17; p<0.05)). Brain SDF1-A levels were significantly elevated at both 4 hrs and 24 hrs (113 ± 7 pg/ml and 112 ± 10 pg/ml, respectively; p<0.05 versus sham 76 ± 11 pg/ml). Following administration of an SDF1-A antibody, Lin-/Sca1+ cells failed to mobilize to peripheral blood following stroke, despite continued up regulation in bone marrow (stroke bone marrow cell count: 536 ± 65, blood cell count: 127 ± 24; p<0.05 versus placebo). Exogenously administered Lin-/Sca1+ cells resulted in a significant reduction in infarct volume: 42 ± 5% (stroke alone), versus 21 ± 15% (Stroke+Lin-/Sca1+ cells), and administration of an SDF1-A antibody concomitant to exogenous administration of the Lin-/Sca1+ cells prevented this reduction. Following stroke, exogenously administered Lin-/Sca1+ FISH positive cells were significantly reduced when administered concomitant to an SDF1-A antibody as compared to without SDF1-A antibody (10 ± 4 vs 0.7 ± 1, p<0.05). CONCLUSIONS SDF1-A appears to play a critical role in modulating Lin-/Sca1+ cell migration to ischemic brain.
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Affiliation(s)
- J. Mocco
- Department of Neurological Surgery, Vanderbilt University, Nashville, Tennessee, United States of America
- * E-mail:
| | - Aqeela Afzal
- Department of Neurological Surgery, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Saeed Ansari
- Department of Neurosurgery, University of Florida, Gainesville, Florida, United States of America
| | - Annemarie Wolfe
- Department of Neurosurgery, University of Florida, Gainesville, Florida, United States of America
| | - Kenneth Caldwell
- Department of Neurosurgery, University of Florida, Gainesville, Florida, United States of America
| | - E S. Connolly
- Department of Neurological Surgery, Columbia University, New York, New York, United States of America
| | - Edward W. Scott
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States of America
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Lehwald N, Duhme C, Wildner M, Kuhn S, Fürst G, Forbes SJ, Jonas S, Robson SC, Knoefel WT, Schmelzle M, Schulte Am Esch J. HGF and SDF-1-mediated mobilization of CD133+ BMSC for hepatic regeneration following extensive liver resection. Liver Int 2014; 34:89-101. [PMID: 23701640 DOI: 10.1111/liv.12195] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2012] [Accepted: 04/04/2013] [Indexed: 02/13/2023]
Abstract
BACKGROUND The molecular mechanisms of haematopoietic stem cells (HSC) mobilization and homing to the liver after partial hepatectomy (PH) remain largely unexplored. METHODS Functional liver volume loss and regain was determined by computerized tomography (CT) volumetry in 30 patients following PH. Peripheral HSC mobilization was investigated by fluorescence-activated cell sorting (FACS) analyses and cytokine enzyme-linked immunosorbent assay assays. Migration of purified HSC towards hepatic growth factor (HGF) and stroma-derived factor-1 (SDF-1) gradients was tested in vitro. Mice after 70% PH were examined for HSC mobilization by FACS and cytokine mRNA expression in the liver. FACS-sorted HSC were administered after PH and hepatocyte proliferation was evaluated by immunohistochemical staining for Ki67. RESULTS Impaired liver function was noted after extended hepatic resection when compared to smaller resections. Patients with large liver resections were characterized by significantly higher levels of peripheral HSC which were positively correlated with the extent of resected liver volume and its regain after 3 weeks. Increased plasma levels of HGF, SDF-1 and insulin like growth factor (IGF-1) were evident within the first 6 hours post resection. Migration assays of human HSC in vitro showed a specific target-demonstrated migration towards recombinant HGF and SDF-1 gradients in a concentration and specific receptor (c-Met and CXCR4) dependent manner. The evaluation of peripheral human alpha foetoprotein expression demonstrated pronounced stemness following increased CD133(+) HSC in the course of liver regeneration following PH. Our human data were further validated in a murine model of PH and furthermore demonstrated increased hepatocyte proliferation subsequent to CD133(+) HSC treatment. CONCLUSION HGF and SDF-1 are required for effective HSC mobilization and homing to the liver after hepatic resection. These findings have significant implications for potential therapeutic strategies targeting chemotactant modulation and stem cell mobilization for liver protection and regeneration.
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Affiliation(s)
- Nadja Lehwald
- Department of Surgery, University Hospital Düsseldorf, Düsseldorf, Germany
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Lee J, Marrero L, Yu L, Dawson LA, Muneoka K, Han M. SDF-1α/CXCR4 signaling mediates digit tip regeneration promoted by BMP-2. Dev Biol 2013; 382:98-109. [PMID: 23916851 DOI: 10.1016/j.ydbio.2013.07.020] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Revised: 06/29/2013] [Accepted: 07/23/2013] [Indexed: 12/16/2022]
Abstract
Previously we demonstrated that BMP signaling is required for endogenous digit tip regeneration, and that treatment with BMP-2 or -7 induces a regenerative response following amputation at regeneration-incompetent levels (Yu et al., 2010, 2012). Both endogenous regeneration and BMP-induced regeneration are associated with the transient formation of a blastema, however the formation of a regeneration blastema in mammals is poorly understood. In this study, we focus on how blastema cells respond to BMP signaling during neonatal digit regeneration in mice. First, we show that blastema cells retain regenerative properties after expansion in vitro, and when re-introduced into the amputated digit, these cells display directed migration in response to BMP-2. However, in vitro studies demonstrate that BMP-2 alone does not influence blastema cell migration, suggesting a requirement of another pivotal downstream factor for cell recruitment. We show that blastema cell migration is stimulated by the cytokine, SDF-1α, and that SDF-1α is expressed by the wound epidermis as well as endothelial cells of the blastema. Blastema cells express both SDF-1α receptors, CXCR4 and CXCR7, although the migration response is inhibited by the CXCR4-specific antagonist, AMD3100. Mice treated with AMD3100 display a partial inhibition of skeletal regrowth associated with the regeneration response. We provide evidence that BMP-2 regulates Sdf-1α expression in endothelial cells but not cells of the wound epidermis. Finally, we show that SDF-1α-expressing COS1 cells engrafted into a regeneration-incompetent digit amputation wound resulted in a locally enhanced population of CXCR4 positive cells, and induced a partial regenerative response. Taken together, this study provides evidence that one downstream mechanism of BMP signaling during mammalian digit regeneration involves activation of SDF-1α/CXCR4 signaling by endothelial cells to recruit blastema cells.
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Affiliation(s)
- Jangwoo Lee
- Division of Developmental Biology, Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA
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Liu H, Patel NR, Walter L, Ingersoll S, Sitaraman SV, Garg P. Constitutive expression of MMP9 in intestinal epithelium worsens murine acute colitis and is associated with increased levels of proinflammatory cytokine Kc. Am J Physiol Gastrointest Liver Physiol 2013; 304:G793-803. [PMID: 23471340 DOI: 10.1152/ajpgi.00249.2012] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is a chronic inflammatory disease associated with an increased risk for colon cancer. Matrix metalloproteinases (MMPs) are the predominant proteinases expressed in the gut mucosa during active IBD. Our laboratory has previously demonstrated that epithelial-derived MMP9 is absent in normal colonic tissue but is upregulated during IBD. In this study MMP9 transgenic mice (Tg-villin-MMP9) are generated specifically to overexpress MMP9 in intestinal epithelium to examine the role and underlying mechanism by which it modulates the pathogenesis of acute colitis. Dextran sodium sulfate (3% DSS)- and Salmonella typhimurium (S.T.)-induced colitis models were used to study gut inflammation in Tg-villin-MMP9 and wild-type littermates (WT). Colonic tissue was analyzed via Western blot, histology, myeloperoxidase (MPO) assay, and quantitative PCR. Tg-villin-MMP9 mice expressed significantly increased MMP9 mRNA and protein expression at basal level. There was a significant decrease in the goblet cells, but a significant increase in proliferation and apoptosis were observed among Tg-villin-MMP9 mice compared with WT mice. There was also a significant increase in the proinflammatory chemokine Kc among Tg-villin-MMP9 compared with WT mice. Tg-villin-MMP9 exhibited a severe inflammatory response than WT mice in both DSS- and S.T.-induced colitis models as evident by greater weight loss and higher clinical score, histological score, and MPO activity, which correlated with relative levels of Kc mRNA. MMP9 expressed by intestinal epithelial cells mediates inflammation in colitis with simultaneous increase in proinflammatory cytokine Kc.
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Affiliation(s)
- Hongchun Liu
- Center for Diagnostics and Therapeutics, Department of Biology, Georgia State University, Atlanta, GA 30303, USA
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Sun J, Yuan Y, Qin H, Ying C, Liu W, Zhang J, He Y, Liu Z. Serum from hepatectomized rats induces the differentiation of adipose tissue mesenchymal stem cells into hepatocyte-like cells and upregulates the expression of hepatocyte growth factor and interleukin-6 in vitro. Int J Mol Med 2013; 31:667-75. [PMID: 23353936 DOI: 10.3892/ijmm.2013.1257] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2012] [Accepted: 12/19/2012] [Indexed: 11/06/2022] Open
Abstract
Adipose tissue-derived mesenchymal stem cells (AT-MSCs) are an attractive alternative for clinical application due to their minimally invasive accessibility and availability in the body. However, the hepatic differentiation efficiency of AT-MSCs is insufficient for therapeutic application and the role of extrahepatic stem cells in liver regeneration remains poorly understood. This study was designed to investigate the effects of serum from rats subjected to 70% partial hepatectomy (PH) on the differentiation ability of rat AT-MSCs in vitro, and to explore the potential role of AT-MSCs in vivo following PH injury. Results showed that AT-MSCs treated with serum collected from rats 24 h after 70% PH differen-tiated into hepatocyte-like cells, resembled hepatocyte-like cells with round or polygonal shape, expressed α-fetoprotein, secreted albumin, synthesized urea and acquired cytochrome P450 type 3A4 enzyme activity, and upregulated the expression of interleukin (IL)-6 and hepatocyte growth factor (HGF) transiently in vitro, although the hepatic differentiation efficiency was extremely low. AT-MSC transplantation after 70% PH ameliorated liver injury and promoted liver regeneration, but did not increase the serum levels of IL-6 and HGF in vivo. This result suggests that the therapeutic effect of AT-MSCs in vivo after 24 h of 70% PH does not increase IL-6 and HGF expression.
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Affiliation(s)
- Jiangyang Sun
- Department of General Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, PR China
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Lim KH, Han JH, Roh YS, Kim B, Kwon JK, You MJ, Han HJ, Ejaz S, Kang CW, Kim JH. Generation of CD2(+)CD8(+) NK Cells from c-kit(+) Bone Marrow Cells in Porcine. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2012; 16:167-74. [PMID: 22802697 PMCID: PMC3394918 DOI: 10.4196/kjpp.2012.16.3.167] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/06/2012] [Revised: 04/17/2012] [Accepted: 04/17/2012] [Indexed: 11/15/2022]
Abstract
Natural killer (NK) cells provide one of the initial barriers of cellular host defense against pathogens, in particular intracellular pathogens. Because bone marrow-derived hematopoietic stem cells (HSCs), lymphoid protenitors, can give rise to NK cells, NK ontogeny has been considered to be exclusively lymphoid. Here, we show that porcine c-kit+ bone marrow cells (c-kit+ BM cells) develop into NK cells in vitro in the presence of various cytokines [interleukin (IL)-2, IL-7, IL-15, IL-21, stem cell factor (SCF), and fms-like tyrosine kinase-3 ligand (FLT3L)]. Adding hydrocortisone (HDC) and stromal cells greatly increases the frequency of c-kit+ BM cells that give rise to CD2+CD8+ NK cells. Also, intracellular levels of perforin, granzyme B, and NKG2D were determined by RT-PCR and western blotting analysis. It was found that of perforin, granzyme B, and NKG2D levels significantly were increased in cytokine-stimulated c-kit+ BM cells than those of controls. And, we compared the ability of the cytotoxicity of CD2+CD8+ NK cells differentiated by cytokines from c-kit+ BM cells against K562 target cells for 28 days. Cytokines-induced NK cells as effector cells were incubated with K562 cells as target in a ratio of 100:1 for 4 h once a week. In results, CD2+CD8+ NK cells induced by cytokines and stromal cells showed a significantly increased cytotoxicity 21 days later. Whereas, our results indicated that c-kit+ BM cells not pretreated with cytokines have lower levels of cytotoxicity. Taken together, this study suggests that cytokines-induced NK cells from porcine c-kit+ BM cells may be used as adoptive transfer therapy if the known obstacles to xenografting (e.g. immune and non-immune problems) were overcome in the future.
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Affiliation(s)
- Kyu Hee Lim
- Department of Physiology and Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Jeonju 561-756, Korea
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Integrated analysis of gene expression and tumor nuclear image profiles associated with chemotherapy response in serous ovarian carcinoma. PLoS One 2012; 7:e36383. [PMID: 22590536 PMCID: PMC3348145 DOI: 10.1371/journal.pone.0036383] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2011] [Accepted: 03/30/2012] [Indexed: 01/05/2023] Open
Abstract
Background Small sample sizes used in previous studies result in a lack of overlap between the reported gene signatures for prediction of chemotherapy response. Although morphologic features, especially tumor nuclear morphology, are important for cancer grading, little research has been reported on quantitatively correlating cellular morphology with chemotherapy response, especially in a large data set. In this study, we have used a large population of patients to identify molecular and morphologic signatures associated with chemotherapy response in serous ovarian carcinoma. Methodology/Principal Findings A gene expression model that predicts response to chemotherapy is developed and validated using a large-scale data set consisting of 493 samples from The Cancer Genome Atlas (TCGA) and 244 samples from an Australian report. An identified 227-gene signature achieves an overall predictive accuracy of greater than 85% with a sensitivity of approximately 95% and specificity of approximately 70%. The gene signature significantly distinguishes between patients with unfavorable versus favorable prognosis, when applied to either an independent data set (P = 0.04) or an external validation set (P<0.0001). In parallel, we present the production of a tumor nuclear image profile generated from 253 sample slides by characterizing patients with nuclear features (such as size, elongation, and roundness) in incremental bins, and we identify a morphologic signature that demonstrates a strong association with chemotherapy response in serous ovarian carcinoma. Conclusions A gene signature discovered on a large data set provides robustness in accurately predicting chemotherapy response in serous ovarian carcinoma. The combination of the molecular and morphologic signatures yields a new understanding of potential mechanisms involved in drug resistance.
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Abe Y, Uchinami H, Kudoh K, Nakagawa Y, Ise N, Watanabe G, Sato T, Seki E, Yamamoto Y. Liver epithelial cells proliferate under hypoxia and protect the liver from ischemic injury via expression of HIF-1 alpha target genes. Surgery 2012; 152:869-78. [PMID: 22575885 DOI: 10.1016/j.surg.2012.03.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2011] [Accepted: 03/01/2012] [Indexed: 01/15/2023]
Abstract
BACKGROUND The remnant liver after extended liver resection is susceptible to ischemic injury, resulting in the failure of liver regeneration and liver dysfunction. The present study is aimed to investigate the protective role of the liver epithelial cells (LEC), a liver progenitor cell, on hepatocytes with ischemia in vitro and in vivo. METHODS LECs were isolated from rats and cultured under hypoxic conditions (2% O(2)). The cell viability and intracellular ATP levels were measured. The activation of hypoxia-inducible factor-1α (HIF-1α) was assessed by immunofluorescence. The expression of pyruvate dehydrogenase kinase-1 (PDK-1), stromal cell-derived factor-1 (SDF-1), and chemokine receptor 4 (CXCR4) were measured. Hepatocytes were treated with SDF-1 or LEC-conditioned medium under hypoxia, and cell viability was assessed. Finally, hemorrhagic shock was induced in rats with in vivo induction of endogenous LECs, and liver damage was assessed. RESULTS In LECs, but not in hepatocytes, cellular viability and intracellular ATP levels were maintained, and nuclear translocation of HIF-1α and expression of pyruvate dehydrogenase kinase-1 mRNA were increased under hypoxic culture conditions. LECs express SDF-1, and CXCR4 expression was increased in hepatocytes under hypoxia. The survival of hepatocytes under hypoxic condition was significantly increased after treatment with SDF-1 or LEC-conditioned medium. The protective effect of conditioned medium was impaired by CXCR4 antagonists. In vivo induction of endogenous LECs suppressed elevation of serum AST and ALT levels after hemorrhage shock and ischemia-reperfusion. CONCLUSION LECs are resistant to hypoxia and have a protective role for hepatocytes against hypoxia. Our results suggest that induction of endogenous LECs protected the liver from lethal insults by paracrine signaling of SDF-1 and differentiation into parenchymal cells.
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Affiliation(s)
- Yuki Abe
- Department of Gastroenterological Surgery, Akita University Graduate School of Medicine, Akita, Japan
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Iwamoto T, Terai S, Mizunaga Y, Yamamoto N, Omori K, Uchida K, Yamasaki T, Fujii Y, Nishina H, Sakaida I. Splenectomy enhances the anti-fibrotic effect of bone marrow cell infusion and improves liver function in cirrhotic mice and patients. J Gastroenterol 2012; 47:300-12. [PMID: 22065159 DOI: 10.1007/s00535-011-0486-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2011] [Accepted: 09/11/2011] [Indexed: 02/04/2023]
Abstract
BACKGROUND In 2003, we initiated a clinical trial to examine autologous bone marrow cell infusion (ABMi) therapy for cirrhotic patients and reported the clinical effect of the therapy. To analyze how splenectomy may potentiate the effects of bone marrow cell infusion on cirrhosis, we performed a mouse study and a clinical trial on patients with cirrhosis. METHODS In mice, we analyzed the effect of splenectomy on bone marrow cell infusion in four experimental groups (group A, splenectomy + bone marrow cell infusion + CCl(4); group B, sham operation + bone marrow cell infusion + CCl(4); group C, splenectomy + CCl(4); group D, sham operation + CCl(4)). In clinical, we compared the effect of splenectomy on ABMi therapy. RESULTS We observed significantly increased average serum albumin levels and higher expression of green fluorescent protein (GFP), matrix metalloproteinase 9 (MMP9), and proliferating cell nuclear antigen in the livers of group A. We observed MMP9/GFP double-positive cells in the cirrhotic livers. A significant decrease in the liver fibrosis areas was observed in group A. Splenectomy enhanced the repopulation of bone marrow cells into the cirrhotic liver and improved the liver microenvironment via expression of MMP9 secreted from repopulating GFP-positive cells. Next, we performed a clinical trial to compare the effect of splenectomy on the efficacy of ABMi therapy. Cirrhotic patients who underwent splenectomy before ABMi therapy tended to have a greater improvement in liver function. CONCLUSION ABMi therapy with splenectomy may be an effective therapeutic modality for cirrhosis.
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Affiliation(s)
- Takuya Iwamoto
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan
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Mendt M, Cardier JE. Stromal-derived factor-1 and its receptor, CXCR4, are constitutively expressed by mouse liver sinusoidal endothelial cells: implications for the regulation of hematopoietic cell migration to the liver during extramedullary hematopoiesis. Stem Cells Dev 2012; 21:2142-51. [PMID: 22121892 DOI: 10.1089/scd.2011.0565] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Stromal-derived factor (SDF)-1 is the main regulating factor for trafficking/homing of hematopoietic stem cells (HSC) to the bone marrow (BM). It is possible that this chemokine may also play a fundamental role in regulating the migration of HSC to several organs during extramedullary hematopoiesis. Because liver sinusoidal endothelial cells (LSEC) constitute an extramedullary niche for HSC, it is possible that these cells represent one of the main cellular sources of SDF-1 at the liver. Here, we show that LSEC express SDF-1 at the mRNA and protein level. Biological assays showed that conditioned medium from LSEC (LSEC-CM) stimulated the migration of BM progenitor lineage-negative (BM/Lin⁻) cells. This effect was significantly reduced by AMD3100, indicating that the SDF-1/CXCR4 axis is involved in the stimulatory migrating effect induced by LSEC-CM. Early localization of HSC in SDF-1-expressing LSEC microenvironment together with increased levels of this chemokine in hepatic homogenates was found in an experimental model of liver extramedullary hematopoiesis. Flow cytometry studies showed that LSEC express the CXCR4 receptor. Functional assays showed that activation of this receptor by SDF-1 stimulated the migration of LSEC and increased the expression of PECAM-1. Our findings suggest that LSEC through the production of SDF-1 may constitute a fundamental niche for regulation of HSC migration to the liver. To our knowledge, this is the first report showing that LSEC not only express and secrete SDF-1, but also its receptor CXCR4.
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Affiliation(s)
- Mayela Mendt
- Unidad de Terapia Celular-Laboratorio de Patología Celular y Molecular, Centro de Medicina Experimental, Instituto Venezolano de Investigaciones Científicas-IVIC, Apartado, Caracas, Venezuela
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Kawai K, Xue F, Takahara T, Kudo H, Yata Y, Zhang W, Sugiyama T. Matrix metalloproteinase-9 contributes to the mobilization of bone marrow cells in the injured liver. Cell Transplant 2012; 21:453-464. [PMID: 22793053 DOI: 10.3727/096368911x605367] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Effective mobilization of hematopoietic stem cells (HSCs) in injured organs has not been established. Matrix metalloproteinase-9 (MMP-9) is known to release HSCs from bone marrow (BM) into the peripheral blood, but its role in the recruitment of HSCs to injured organs is unclear. In this study we tried to clarify the role of the host MMP-9 in trafficking of HSCs toward the injured liver, especially the relation of MMP-9 with the chemokine receptor 4 (CXCR4)-chemokine ligand 12 (CXCL12) axis, and to examine whether MMP-9 deficiency affects BM cell trafficking to the injured liver in mice. In vitro, we investigated the effect of MMP-9 on migration activity and CXCR4 expression on lineage-negative (Lin(-)) BM cells. In vivo, we induced acute and chronic liver injury in MMP-9 knockout (KO) and control mice by inoculation of carbon tetrachloride, followed by transplantation of Lin(-) BM cells obtained from enhanced green fluorescent protein (EGFP)-transgenic mice, and counted the BM cells mobilized in the injured liver. In a migration assay, active MMP-9, but not proMMP-9, increased the number of migrated Lin(-) BM cells, which was inhibited by tissue inhibitor of metalloproteinase-1 or a MMP inhibitor. This chemoattractant function by MMP-9 was synergistic when cotreated with CXCL12. CXCR4 expression on Lin(-) BM cells was dose- and time-dependently increased by active MMP-9. At the same time, treatment with MMP-9 enhanced CXCL12 expression, and CXCL12 reciprocally increased MMP-9 expression in BM cells. In in vivo studies, many EGFP(+) cells were seen in control recipient mice. In contrast, few EGFP(+) cells were observed in MMP-9 KO mice. BM cells tended to differentiate into desmin(+) cells. In conclusion, MMP-9 contributes to the mobilization of BM cells in the injured liver by upregulating the expression of CXCR4 on Lin(-) BM cells and attracting BM cells along its gradient of CXCL12. Therefore, host MMP-9 plays an important role in BM cell migration in the injured liver.
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Affiliation(s)
- Kengo Kawai
- Third Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan
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Intrahepatic transplantation of CD34+ cord blood stem cells into newborn and adult NOD/SCID mice induce differential organ engraftment. Tissue Cell 2011; 44:80-6. [PMID: 22197619 DOI: 10.1016/j.tice.2011.11.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2011] [Revised: 11/15/2011] [Accepted: 11/17/2011] [Indexed: 11/21/2022]
Abstract
In vivo studies concerning the function of human hematopoietic stem cells (HSC) are limited by relatively low levels of engraftment and the failure of the engrafted HSC preparations to differentiate into functional immune cells after systemic application. In the present paper we describe the effect of intrahepatically transplanted CD34(+) cells from cord blood into the liver of newborn or adult NOD/SCID mice on organ engraftment and differentiation. Analyzing the short and long term time dependency of human cell recruitment into mouse organs after cell transplantation in the liver of newborn and adult NOD/SCID mice by RT-PCR and FACS analysis, a significantly high engraftment was found after transplantation into liver of newborn NOD/SCID mice compared to adult mice, with the highest level of 35% human cells in bone marrow and 4.9% human cells in spleen at day 70. These human cells showed CD19 B-cell, CD34 and CD38 hematopoietic and CD33 myeloid cell differentiation, but lacked any T-cell differentiation. HSC transplantation into liver of adult NOD/SCID mice resulted in minor recruitment of human cells from mouse liver to other mouse organs. The results indicate the usefulness of the intrahepatic application route into the liver of newborn NOD/SCID mice for the investigation of hematopoietic differentiation potential of CD34(+) cord blood stem cell preparations.
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Kilpatrick LA, Zhu J, Lee FS, Lang H. Role of stromal cell-derived factor-1 expression in the injured mouse auditory nerve. Otolaryngol Head Neck Surg 2011; 145:1007-15. [PMID: 21947792 DOI: 10.1177/0194599811416778] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVE The degeneration of hair cells and spiral ganglion neurons (SGNs) is an important pathologic process in the development of sensorineural hearing loss. In a murine model, predictable and reproducible damage to SGNs occurs through the application of ouabain to the round window. Recent evidence has shown that the chemokine stromal cell-derived factor-1 (SDF-1) is a potent chemoattractant of hematopoietic stem cells (HSCs) and provides trophic support to injured tissues during development and maturation. The hypothesis for the current study is that expression of SDF-1 plays an important role in protecting SGNs and preventing further degeneration in the setting of cochlear injury. STUDY DESIGN Prospective, controlled. SETTING Academic research laboratory. SUBJECT AND METHODS Auditory brainstem response (ABR) and the expression of SDF-1 mRNA and protein were examined 1, 3, 7, 14, and 30 days after application of ouabain in 35 adult mice. RESULTS Following ouabain application, real-time reverse-transcription polymerase chain reaction for SDF demonstrates increased mRNA expression following ouabain injury in nontransplanted mice. A significant increase in SDF protein expression was also observed using immunolabeling techniques and Western blot analysis. CONCLUSIONS SDF-1 expression is increased in the auditory nerve following cochlear injury. Further knowledge about the cochlear microenvironment, including SDF-1, is critical to maximizing HSC engraftment in the injured cochlea and providing a therapeutic option for sensorineural hearing loss.
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Affiliation(s)
- Lauren A Kilpatrick
- Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
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Jansen van Vuren P, Tiemessen CT, Paweska JT. Anti-nucleocapsid protein immune responses counteract pathogenic effects of Rift Valley fever virus infection in mice. PLoS One 2011; 6:e25027. [PMID: 21949840 PMCID: PMC3174991 DOI: 10.1371/journal.pone.0025027] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2011] [Accepted: 08/25/2011] [Indexed: 12/31/2022] Open
Abstract
The known virulence factor of Rift Valley fever virus (RVFV), the NSs protein, counteracts the antiviral effects of the type I interferon response. In this study we evaluated the expression of several genes in the liver and spleen involved in innate and adaptive immunity of mice immunized with a RVFV recombinant nucleocapsid protein (recNP) combined with Alhydrogel adjuvant and control animals after challenge with wild type RVFV. Mice immunized with recNP elicited an earlier IFNβ response after challenge compared to non-immunized controls. In the acute phase of liver infection in non-immunized mice there was a massive upregulation of type I and II interferon, accompanied by high viral titers, and the up- and downregulation of several genes involved in the activation of B- and T-cells, indicating that both humoral and cellular immunity is modulated during RVFV infection. Various genes involved in pro-inflammatory responses and with pro-apoptotic effects were strongly upregulated and anti-apoptotic genes were downregulated in liver of non-immunized mice. Expression of many genes involved in B- and T-cell immunity were downregulated in spleen of non-immunized mice but normal in immunized mice. A strong bias towards apoptosis and inflammation in non-immunized mice at an acute stage of liver infection associated with suppression of several genes involved in activation of humoral and cellular immunity in spleen, suggests that RVFV evades the host immune response in more ways than only by inhibition of type I interferon, and that immunopathology of the liver plays a crucial role in RVF disease progression.
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Affiliation(s)
- Petrus Jansen van Vuren
- Special Pathogens Unit, National Institute for Communicable Diseases of the National Health Laboratory Service, Sandringham, South Africa
- Division Virology and Communicable Diseases Surveillance, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa
| | - Caroline T. Tiemessen
- Division Virology and Communicable Diseases Surveillance, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa
- Cell Biology/AIDS Virus Research Unit, National Institute for Communicable Diseases of the National Health Laboratory Service, Sandringham, South Africa
| | - Janusz T. Paweska
- Special Pathogens Unit, National Institute for Communicable Diseases of the National Health Laboratory Service, Sandringham, South Africa
- Division Virology and Communicable Diseases Surveillance, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa
- * E-mail:
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Herencia C, Rodríguez-Ariza A, Canalejo A, Naranjo A, Briceño FJ, López-Cillero P, De la Mata M, Muñoz-Castañeda JR. Differential bone marrow hematopoietic stem cells mobilization in hepatectomized patients. J Gastrointest Surg 2011; 15:1459-67. [PMID: 21512847 DOI: 10.1007/s11605-011-1541-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2011] [Accepted: 04/05/2011] [Indexed: 01/31/2023]
Abstract
BACKGROUND The involvement of bone marrow hematopoietic stem cells (BMHSC) mobilization during liver regeneration from hepatectomized patients is under debate. The main aim of this study was to investigate the role of BMHSC mobilization after hepatic resection in 33 patients with liver disease. METHODS AND RESULTS Mobilization of CD34(+) BMHSC after 72 h of surgery was found in peripheral blood of some, but not all, of the hepatectomized patients. These CD34(+) cells co-expressed other stem cells markers. The patients without BMHSC mobilization showed high levels of circulating and liver tissue BMHSC (CD34(+) cells) previous to surgery. Therefore, two types of patients: "mobilizers" and "non-mobilizers" were distinguished based on the values of CD34(+) cells before and after surgery. Changes in cytokines involved in the hepatic regeneration (HGF and TGF-β), and in BMHSC mobilization process (SCF, SDF-1, IL-12, or MMP-2), were detected in both groups. In addition, a higher activation previous to surgery of the SDF-1/CXCR4 axis in liver tissue was observed in non mobilizers patients compared to mobilizer patients. CONCLUSION BMHSC mobilization seems to be associated with variations in the levels of cytokines and proteolytic enzymes involved in hepatic regeneration and bone marrow matrix degradation. Hepatectomy may be an insufficient stimulus for BMSHC mobilization. The pre-hepatectomy higher levels CD34(+) cells in peripheral blood and liver, associated to the activation of hepatic SDF-1/CXCR4 axis, suggest a BMHSC mobilization process previous to surgery in non mobilizer patients.
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Affiliation(s)
- Carmen Herencia
- Instituto Maimónides de Investigación Biomédica de Córdoba, (IMIBIC), Hospital Universitario Reina Sofía, Córdoba, Spain
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Mazo IB, Massberg S, von Andrian UH. Hematopoietic stem and progenitor cell trafficking. Trends Immunol 2011; 32:493-503. [PMID: 21802990 DOI: 10.1016/j.it.2011.06.011] [Citation(s) in RCA: 124] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2011] [Revised: 06/17/2011] [Accepted: 06/17/2011] [Indexed: 01/13/2023]
Abstract
Migration of hematopoietic stem cells (HSCs) is essential during embryonic development and throughout adult life. During embryogenesis, trafficking of HSCs is responsible for the sequential colonization of different hematopoietic organs by blood-producing cells. In adulthood, circulation of HSCs maintains homeostasis of the hematopoietic system and participates in innate immune responses. HSC trafficking is also crucial in clinical settings such as bone marrow (BM) and stem cell transplantation. This review provides an overview of the molecular and cellular signals that control and fine-tune trafficking of HSCs and hematopoietic progenitor cells in embryogenesis and during postnatal life. We also discuss the potential clinical utility of therapeutic approaches to modulate HSC trafficking in patients.
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Affiliation(s)
- Irina B Mazo
- Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
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