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Luo S, Wu F, Jin Y, Liu D. The Potential Hepatocyte Differentiation Targets and MSC Proliferation by FH1. J Cell Mol Med 2025; 29:e70601. [PMID: 40346964 PMCID: PMC12064995 DOI: 10.1111/jcmm.70601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 03/24/2025] [Accepted: 04/30/2025] [Indexed: 05/12/2025] Open
Abstract
The main cause of acute liver failure (ALF) is hepatocellular necrosis, which induces liver repair dysfunction and leads to high mortality. In recent years, studies have increasingly shown that stem cell-derived hepatocyte-like cells (HLCs) can be used for treatment in animal models of ALF. Notably, a hepatocyte differentiation strategy based on the small-molecule compound functional hit 1 (FH1) successfully replaces HGF to promote the maturation of HLCs, but the underlying mechanism is still unclear. In this study, we used network pharmacology analysis to clarify the important role of the HGF/c-Met signalling pathway in FH1-induced hepatocyte (FH1-iHeps) differentiation. After FH1 was added to mesenchymal stem/stromal cells (MSCs), proliferation and cell cycle progression were rescued by treatment with a tyrosine kinase (c-Met) inhibitor. Additionally, c-Met signalling in MSCs was significantly increased by treatment with FH1, as shown by the increased c-Met, p-p38, p-AKT and p-ERK1/2 protein levels. FH1-iHeps efficiently improved the liver function of mice with acute liver injury and prolonged their lifespan. These data provide new insight into the mechanisms regulating the stemness properties of human umbilical cord-derived stem cells (hUC-MSCs) and reveal a previously unrecognised link between FH1 and c-Met in directing hepatocyte differentiation.
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Affiliation(s)
- Sang Luo
- Department of Beijing National Biochip Research Center Sub‐Center in Ningxia, Institute of Medical SciencesGeneral Hospital of Ningxia Medical UniversityYinchuanChina
| | - Fang Wu
- Ningxia Regional Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Regional High Incidence DiseaseYinchuanChina
| | - Yiran Jin
- Department of Beijing National Biochip Research Center Sub‐Center in Ningxia, Institute of Medical SciencesGeneral Hospital of Ningxia Medical UniversityYinchuanChina
| | - Dan Liu
- Department of Beijing National Biochip Research Center Sub‐Center in Ningxia, Institute of Medical SciencesGeneral Hospital of Ningxia Medical UniversityYinchuanChina
- Key Laboratory of Ministry of Education for Fertility Preservation and MaintenanceNingxia Medical UniversityYinchuanChina
- Department of GynecologyGeneral Hospital of Ningxia Medical UniversityYinchuanChina
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2
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Ramzan F, Salim A, Hussain A, Khan I. Unleashing the Healing Power of Mesenchymal Stem Cells for Osteochondral Abnormalities. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2024. [DOI: 10.1007/s40883-024-00356-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 07/25/2024] [Accepted: 08/31/2024] [Indexed: 01/11/2025]
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3
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Budzynska K, Siemionow M, Stawarz K, Chambily L, Siemionow K. Chimeric Cell Therapies as a Novel Approach for Duchenne Muscular Dystrophy (DMD) and Muscle Regeneration. Biomolecules 2024; 14:575. [PMID: 38785982 PMCID: PMC11117592 DOI: 10.3390/biom14050575] [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: 04/02/2024] [Revised: 05/06/2024] [Accepted: 05/11/2024] [Indexed: 05/25/2024] Open
Abstract
Chimerism-based strategies represent a pioneering concept which has led to groundbreaking advancements in regenerative medicine and transplantation. This new approach offers therapeutic potential for the treatment of various diseases, including inherited disorders. The ongoing studies on chimeric cells prompted the development of Dystrophin-Expressing Chimeric (DEC) cells which were introduced as a potential therapy for Duchenne Muscular Dystrophy (DMD). DMD is a genetic condition that leads to premature death in adolescent boys and remains incurable with current methods. DEC therapy, created via the fusion of human myoblasts derived from normal and DMD-affected donors, has proven to be safe and efficacious when tested in experimental models of DMD after systemic-intraosseous administration. These studies confirmed increased dystrophin expression, which correlated with functional and morphological improvements in DMD-affected muscles, including cardiac, respiratory, and skeletal muscles. Furthermore, the application of DEC therapy in a clinical study confirmed its long-term safety and efficacy in DMD patients. This review summarizes the development of chimeric cell technology tested in preclinical models and clinical studies, highlighting the potential of DEC therapy in muscle regeneration and repair, and introduces chimeric cell-based therapies as a promising, novel approach for muscle regeneration and the treatment of DMD and other neuromuscular disorders.
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Affiliation(s)
- Katarzyna Budzynska
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, IL 60607, USA; (K.B.); (K.S.); (L.C.); (K.S.)
| | - Maria Siemionow
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, IL 60607, USA; (K.B.); (K.S.); (L.C.); (K.S.)
- Chair and Department of Traumatology, Orthopaedics, and Surgery of the Hand, Poznan University of Medical Sciences, 61-545 Poznan, Poland
| | - Katarzyna Stawarz
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, IL 60607, USA; (K.B.); (K.S.); (L.C.); (K.S.)
| | - Lucile Chambily
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, IL 60607, USA; (K.B.); (K.S.); (L.C.); (K.S.)
| | - Krzysztof Siemionow
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, IL 60607, USA; (K.B.); (K.S.); (L.C.); (K.S.)
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Song Y, Lu Z, Shu W, Xiang Z, Wang Z, Wei X, Xu X. Arouse potential stemness: Intrinsic and acquired stem cell therapeutic strategies for advanced liver diseases. CELL INSIGHT 2023; 2:100115. [PMID: 37719773 PMCID: PMC10502372 DOI: 10.1016/j.cellin.2023.100115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 08/10/2023] [Accepted: 08/10/2023] [Indexed: 09/19/2023]
Abstract
Liver diseases are a major health issue, and prolonged liver injury always progresses. Advanced liver disorders impair liver regeneration. Millions of patients die yearly worldwide, even with the available treatments of liver transplantation and artificial liver support system. With its abundant cell resources and significant differentiative potential, stem cell therapy is a viable treatment for various disorders and offers hope to patients waiting for orthotopic liver transplantation. Considering such plight, stem cell therapeutic strategies deliver hope to the patients. Moreover, we conclude intrinsic and acquired perspectives based on stem cell sources. The properties and therapeutic uses of these stem cells' specific types or sources were then reviewed. Owing to the recent investigations of the above cells, a safe and effective therapy will emerge for advanced liver diseases soon.
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Affiliation(s)
- Yisu Song
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People’s Hospital Zhejiang University School of Medicine Hangzhou, Zhejiang, 310006, China
- Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
| | - Zhengyang Lu
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People’s Hospital Zhejiang University School of Medicine Hangzhou, Zhejiang, 310006, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
- Zhejiang Chinese Medical University, Hangzhou, 310053, PR China
| | - Wenzhi Shu
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People’s Hospital Zhejiang University School of Medicine Hangzhou, Zhejiang, 310006, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
| | - Ze Xiang
- Zhejiang University School of Medicine, Hangzhou, China
| | - Zhengxin Wang
- Department of General Surgery, Huashan Hospital, Fudan University Shanghai, 200040, China
| | - Xuyong Wei
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People’s Hospital Zhejiang University School of Medicine Hangzhou, Zhejiang, 310006, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
| | - Xiao Xu
- Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
- Institute of Organ Transplantation, Zhejiang University, Hangzhou, 310003, China
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5
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Dittmar T, Sieler M, Hass R. Why do certain cancer cells alter functionality and fuse? Biol Chem 2023; 404:951-960. [PMID: 37246410 DOI: 10.1515/hsz-2023-0162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/11/2023] [Indexed: 05/30/2023]
Abstract
Cancer cell fusion represents a rare event. However, the surviving cancer hybrid cells after a post-hybrid selection process (PHSP) can overgrow other cancer cells by exhibiting a proliferation advantage and/or expression of cancer stem-like properties. Addition of new tumor properties during hetero-fusion of cancer cells e.g. with mesenchymal stroma-/stem-like cells (MSC) contribute to enhanced tumor plasticity via acquisition of new/altered functionalities. This provides new avenues for tumor development and metastatic behavior. Consequently, the present review article will also address the question as to whether cancer cell fusion represents a general and possibly evolutionary-conserved program or rather a random process?
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Affiliation(s)
- Thomas Dittmar
- Institute of Immunology, Center for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Stockumer Str. 10, D-58448 Witten, Germany
| | - Mareike Sieler
- Institute of Immunology, Center for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Stockumer Str. 10, D-58448 Witten, Germany
| | - Ralf Hass
- Department of Obstetrics and Gynecology, Biochemistry and Tumor Biology Laboratory, Hannover Medical School, D-30625 Hannover, Germany
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6
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Dittmar T, Hass R. Intrinsic signalling factors associated with cancer cell-cell fusion. Cell Commun Signal 2023; 21:68. [PMID: 37016404 PMCID: PMC10071245 DOI: 10.1186/s12964-023-01085-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 02/21/2023] [Indexed: 04/06/2023] Open
Abstract
Cellular fusion e.g. between cancer cells and normal cells represents a stepwise process that is tightly regulated. During a pre-hybrid preparation program somatic cells and/or cancer cells are promoted to a pro-fusogenic state as a prerequisite to prepare a fusion process. A pro-fusogenic state requires significant changes including restructure of the cytoskeleton, e.g., by the formation of F-actin. Moreover, distinct plasma membrane lipids such as phosphatidylserine play an important role during cell fusion. In addition, the expression of distinct fusogenic factors such as syncytins and corresponding receptors are of fundamental importance to enable cellular mergers. Subsequent hybrid formation and fusion are followed by a post-hybrid selection process. Fusion among normal cells is important and often required during organismal development. Cancer cells fusion appears more rarely and is associated with the generation of new cancer hybrid cell populations. These cancer hybrid cells contribute to an elevated tumour plasticity by altered metastatic behaviour, changes in therapeutic and apoptotic responses, and even in the formation of cancer stem/ initiating cells. While many parts within this multi-step cascade are still poorly understood, this review article predominantly focusses on the intracellular necessities for fusion among cancer cells or with other cell populations of the tumour microenvironment. Video Abstract.
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Affiliation(s)
- Thomas Dittmar
- Institute of Immunology, Centre for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Stockumer Str. 10, 58448, Witten, Germany.
| | - Ralf Hass
- Biochemistry and Tumor Biology Laboratory, Department of Obstetrics and Gynaecology, Hannover Medical School, 30625, Hannover, Germany.
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7
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Cre recombinase expression cooperates with homozygous FLT3 internal tandem duplication knockin mouse model to induce acute myeloid leukemia. Leukemia 2023; 37:741-750. [PMID: 36739348 PMCID: PMC10079527 DOI: 10.1038/s41375-023-01832-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 01/17/2023] [Accepted: 01/20/2023] [Indexed: 02/06/2023]
Abstract
Murine models offer a valuable tool to recapitulate genetically defined subtypes of AML, and to assess the potential of compound mutations and clonal evolution during disease progression. This is of particular importance for difficult to treat leukemias such as FLT3 internal tandem duplication (ITD) positive AML. While conditional gene targeting by Cre recombinase is a powerful technology that has revolutionized biomedical research, consequences of Cre expression such as lack of fidelity, toxicity or off-target effects need to be taken into consideration. We report on a transgenic murine model of FLT3-ITD induced disease, where Cre recombinase expression alone, and in the absence of a conditional allele, gives rise to an aggressive leukemia phenotype. Here, expression of various Cre recombinases leads to polyclonal expansion of FLT3ITD/ITD progenitor cells, induction of a differentiation block and activation of Myc-dependent gene expression programs. Our report is intended to alert the scientific community of potential risks associated with using this specific mouse model and of unexpected effects of Cre expression when investigating cooperative oncogenic mutations in murine models of cancer.
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Pozzobon M, D’Agostino S, Roubelakis MG, Cargnoni A, Gramignoli R, Wolbank S, Gindraux F, Bollini S, Kerdjoudj H, Fenelon M, Di Pietro R, Basile M, Borutinskaitė V, Piva R, Schoeberlein A, Eissner G, Giebel B, Ponsaerts P. General consensus on multimodal functions and validation analysis of perinatal derivatives for regenerative medicine applications. Front Bioeng Biotechnol 2022; 10:961987. [PMID: 36263355 PMCID: PMC9574482 DOI: 10.3389/fbioe.2022.961987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Accepted: 07/01/2022] [Indexed: 11/26/2022] Open
Abstract
Perinatal tissues, such as placenta and umbilical cord contain a variety of somatic stem cell types, spanning from the largely used hematopoietic stem and progenitor cells to the most recently described broadly multipotent epithelial and stromal cells. As perinatal derivatives (PnD), several of these cell types and related products provide an interesting regenerative potential for a variety of diseases. Within COST SPRINT Action, we continue our review series, revising and summarizing the modalities of action and proposed medical approaches using PnD products: cells, secretome, extracellular vesicles, and decellularized tissues. Focusing on the brain, bone, skeletal muscle, heart, intestinal, liver, and lung pathologies, we discuss the importance of potency testing in validating PnD therapeutics, and critically evaluate the concept of PnD application in the field of tissue regeneration. Hereby we aim to shed light on the actual therapeutic properties of PnD, with an open eye for future clinical application. This review is part of a quadrinomial series on functional/potency assays for validation of PnD, spanning biological functions, such as immunomodulation, anti-microbial/anti-cancer, anti-inflammation, wound healing, angiogenesis, and regeneration.
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Affiliation(s)
- Michela Pozzobon
- Department of Women’s and Children’s Health, University of Padova, Padova, Italy
| | - Stefania D’Agostino
- Department of Women’s and Children’s Health, University of Padova, Padova, Italy
| | - Maria G. Roubelakis
- Laboratory of Biology, Medical School of Athens, National and Kapodistrian University of Athens, Athens, Greece
| | - Anna Cargnoni
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | - Roberto Gramignoli
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Susanne Wolbank
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, The Research Center in Cooperation with AUVA Trauma Research Center, Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Florelle Gindraux
- Service de Chirurgie Orthopédique, Traumatologique et plastique, CHU Besançon, Laboratoire de Nanomédecine, Imagerie, Thérapeutique EA 4662, University Bourgogne Franche-Comté, Besançon, France
| | - Sveva Bollini
- Department of Experimental Medicine (DIMES), School of Medical and Pharmaceutical Sciences, University of Genova, Genova, Italy
| | - Halima Kerdjoudj
- University of Reims Champagne Ardenne, EA 4691 BIOS “Biomatériaux et Inflammation en Site Osseux”, UFR d’Odontologie, Reims, France
| | | | - Roberta Di Pietro
- Department of Medicine and Ageing Sciences, Section of Biomorphology, G. d'Annunzio University of Chieti-Pescara, Chieti, Italy
| | - Mariangela Basile
- Department of Medicine and Ageing Sciences, Section of Biomorphology, G. d'Annunzio University of Chieti-Pescara, Chieti, Italy
| | - Veronika Borutinskaitė
- Department of Molecular Cell Biology, Institute of Biochemistry, Vilnius University, Vilnius, Lithuania
| | - Roberta Piva
- Department of Neuroscience and Rehabilitation, University of Ferrara, Ferrara, Italy
| | - Andreina Schoeberlein
- Department of Obstetrics and Feto-maternal Medicine, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Guenther Eissner
- Systems Biology Ireland, School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
| | - Bernd Giebel
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Peter Ponsaerts
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium
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Yao L, Hu X, Dai K, Yuan M, Liu P, Zhang Q, Jiang Y. Mesenchymal stromal cells: promising treatment for liver cirrhosis. Stem Cell Res Ther 2022; 13:308. [PMID: 35841079 PMCID: PMC9284869 DOI: 10.1186/s13287-022-03001-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 05/13/2022] [Indexed: 11/11/2022] Open
Abstract
Liver fibrosis is a wound-healing process that occurs in response to severe injuries and is hallmarked by the excessive accumulation of extracellular matrix or scar tissues within the liver. Liver fibrosis can be either acute or chronic and is induced by a variety of hepatotoxic causes, including lipid deposition, drugs, viruses, and autoimmune reactions. In advanced fibrosis, liver cirrhosis develops, a condition for which there is no successful therapy other than liver transplantation. Although liver transplantation is still a viable option, numerous limitations limit its application, including a lack of donor organs, immune rejection, and postoperative complications. As a result, there is an immediate need for a different kind of therapeutic approach. Recent research has shown that the administration of mesenchymal stromal cells (MSCs) is an attractive treatment modality for repairing liver injury and enhancing liver regeneration. This is accomplished through the cell migration into liver sites, immunoregulation, hepatogenic differentiation, as well as paracrine mechanisms. MSCs can also release a huge variety of molecules into the extracellular environment. These molecules, which include extracellular vesicles, lipids, free nucleic acids, and soluble proteins, exert crucial roles in repairing damaged tissue. In this review, we summarize the characteristics of MSCs, representative clinical study data, and the potential mechanisms of MSCs-based strategies for attenuating liver cirrhosis. Additionally, we examine the processes that are involved in the MSCs-dependent modulation of the immune milieu in liver cirrhosis. As a result, our findings lend credence to the concept of developing a cell therapy treatment for liver cirrhosis that is premised on MSCs. MSCs can be used as a candidate therapeutic agent to lengthen the survival duration of patients with liver cirrhosis or possibly reverse the condition in the near future.
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Affiliation(s)
- Lichao Yao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Xue Hu
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Kai Dai
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Mengqin Yuan
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Pingji Liu
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Qiuling Zhang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Yingan Jiang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China.
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Jahnavi S, Garg V, Vasandan AB, SundarRaj S, Kumar A, Prasanna S J. Lineage reprogramming of human adipose mesenchymal stem cells to immune modulatory i-Heps. Int J Biochem Cell Biol 2022; 149:106256. [PMID: 35772664 DOI: 10.1016/j.biocel.2022.106256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 06/14/2022] [Accepted: 06/24/2022] [Indexed: 11/19/2022]
Abstract
Pluripotent stem cell derived-hepatocytes depict fetal -hepatocyte characteristics/maturity and are immunogenic limiting their applications. Attempts have been made to derive hepatocytes from mesenchymal stem cells using developmental cocktails, epigenetic modulators and small molecules. However, achieving a stable terminally differentiated functional state had been a challenge. Inefficient hepatic differentiation could be due to lineage restrictions set during development. Hence a novel lineage reprogramming approach has been utilized to confer competence to adipose-mesenchymal stem cells (ADMSCs) to efficiently respond to hepatogenic cues and achieve a stable functional hepatic state. Lineage reprogramming involved co-transduction of ADMSCs with hepatic endoderm pioneer Transcription factor (TF)-FOXA2, HHEX-a homeobox gene and HNF4α-master TF indispensable for hepatic state maintenance. Lineage priming was evidenced by endogenous HFN4α promoter demethylation and robust responsiveness to minimal hepatic maturation cues. Induced hepatocytes (i-Heps) exhibited mesenchymal-to-epithelial transition and terminal hepatic signatures. Functional characterisation of i-Heps for hepatic drug detoxification systems, xenobiotic uptake/clearance, metabolic status and hepatotropic virus entry validated acquisition of stable hepatic state and junctional maturity Exhaustive analysis of MSC memory in i-Heps indicated loss of MSC-immunophenotype and terminal differentiation to osteogenic/adipogenic lineages. Importantly, i-Heps suppressed phytohemagglutinin-induced T-cell blasts, inhibited allogenic mixed-lymphocyte reactions (MLRs) and secreted immunomodulatory- indoleamine 2,3-dioxygenase in T-cell blast co-cultures akin to native ADMSCs. In a nutshell, the present study identifies a novel cocktail of TFs that reprogram ADMSCs to stable hepatic state. i-Heps exhibit adult hepatocyte functional maturity with robust immune-modulatory abilities rendering suitability for rigorous drug testing, hepatocyte-pathogen interaction studies and transplantation in allogenic settings.
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Affiliation(s)
- Sowmya Jahnavi
- Manipal Institute of Regenerative Medicine, MAHE, Bangalore, India
| | - Vaishali Garg
- Manipal Institute of Regenerative Medicine, MAHE, Bangalore, India
| | | | - Swathi SundarRaj
- Principal Scientist, Stempeutics Research Pvt. Ltd, Bangalore, India
| | - Anujith Kumar
- Manipal Institute of Regenerative Medicine, MAHE, Bangalore, India
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11
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Generation of Cancer Stem/Initiating Cells by Cell-Cell Fusion. Int J Mol Sci 2022; 23:ijms23094514. [PMID: 35562905 PMCID: PMC9101717 DOI: 10.3390/ijms23094514] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/10/2022] [Accepted: 04/17/2022] [Indexed: 02/04/2023] Open
Abstract
CS/ICs have raised great expectations in cancer research and therapy, as eradication of this key cancer cell type is expected to lead to a complete cure. Unfortunately, the biology of CS/ICs is rather complex, since no common CS/IC marker has yet been identified. Certain surface markers or ALDH1 expression can be used for detection, but some studies indicated that cancer cells exhibit a certain plasticity, so CS/ICs can also arise from non-CS/ICs. Another problem is intratumoral heterogeneity, from which it can be inferred that different CS/IC subclones must be present in the tumor. Cell–cell fusion between cancer cells and normal cells, such as macrophages and stem cells, has been associated with the generation of tumor hybrids that can exhibit novel properties, such as an enhanced metastatic capacity and even CS/IC properties. Moreover, cell–cell fusion is a complex process in which parental chromosomes are mixed and randomly distributed among daughter cells, resulting in multiple, unique tumor hybrids. These, if they have CS/IC properties, may contribute to the heterogeneity of the CS/IC pool. In this review, we will discuss whether cell–cell fusion could also lead to the origin of different CS/ICs that may expand the overall CS/IC pool in a primary tumor.
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Zhang L, Ma XJN, Fei YY, Han HT, Xu J, Cheng L, Li X. Stem cell therapy in liver regeneration: Focus on mesenchymal stem cells and induced pluripotent stem cells. Pharmacol Ther 2022; 232:108004. [PMID: 34597754 DOI: 10.1016/j.pharmthera.2021.108004] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 08/11/2021] [Accepted: 09/23/2021] [Indexed: 02/07/2023]
Abstract
The liver has the ability to repair itself after injury; however, a variety of pathological changes in the liver can affect its ability to regenerate, and this could lead to liver failure. Mesenchymal stem cells (MSCs) are considered a good source of cells for regenerative medicine, as they regulate liver regeneration through different mechanisms, and their efficacy has been demonstrated by many animal experiments and clinical studies. Induced pluripotent stem cells, another good source of MSCs, have also made great progress in the establishment of organoids, such as liver disease models, and in drug screening. Owing to the recent developments in MSCs and induced pluripotent stem cells, combined with emerging technologies including graphene, nano-biomaterials, and gene editing, precision medicine and individualized clinical treatment may be realized in the near future.
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Affiliation(s)
- Lu Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China; The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Xiao-Jing-Nan Ma
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Yuan-Yuan Fei
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China
| | - Heng-Tong Han
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Jun Xu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Lu Cheng
- Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China
| | - Xun Li
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China; Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Hepatopancreatobiliary Surgery Institute of Gansu Province, Lanzhou 730000, PR China; The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China.
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Extraembryonic Mesenchymal Stromal/Stem Cells in Liver Diseases: A Critical Revision of Promising Advanced Therapy Medicinal Products. Cells 2022; 11:cells11071074. [PMID: 35406638 PMCID: PMC8997603 DOI: 10.3390/cells11071074] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/17/2022] [Accepted: 03/21/2022] [Indexed: 02/04/2023] Open
Abstract
Liver disorders have been increasing globally in recent years. These diseases are associated with high morbidity and mortality rates and impose high care costs on the health system. Acute liver failure, chronic and congenital liver diseases, as well as hepatocellular carcinoma have been limitedly treated by whole organ transplantation so far. But novel treatments for liver disorders using cell-based approaches have emerged in recent years. Extra-embryonic tissues, including umbilical cord, amnion membrane, and chorion plate, contain multipotent stem cells. The pre-sent manuscript discusses potential application of extraembryonic mesenchymal stromal/stem cells, focusing on the management of liver diseases. Extra-embryonic MSC are characterized by robust and constitutive anti-inflammatory and anti-fibrotic properties, indicating as therapeutic agents for inflammatory conditions such as liver fibrosis or advanced cirrhosis, as well as chronic inflammatory settings or deranged immune responses.
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14
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Yang Y, Zhao Y, Zhang L, Zhang F, Li L. The Application of Mesenchymal Stem Cells in the Treatment of Liver Diseases: Mechanism, Efficacy, and Safety Issues. Front Med (Lausanne) 2021; 8:655268. [PMID: 34136500 PMCID: PMC8200416 DOI: 10.3389/fmed.2021.655268] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 04/15/2021] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cell (MSC) transplantation is a novel treatment for liver diseases due to the roles of MSCs in regeneration, fibrosis inhibition and immune regulation. However, the mechanisms are still not completely understood. Despite the significant efficacy of MSC therapy in animal models and preliminary clinical trials, issues remain. The efficacy and safety of MSC-based therapy in the treatment of liver diseases remains a challenging issue that requires more investigation. This article reviews recent studies on the mechanisms of MSCs in liver diseases and the associated challenges and suggests potential future applications.
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Affiliation(s)
- Ya Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yalei Zhao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lingjian Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Fen Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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15
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Aquino JB, Sierra R, Montaldo LA. Diverse cellular origins of adult blood vascular endothelial cells. Dev Biol 2021; 477:117-132. [PMID: 34048734 DOI: 10.1016/j.ydbio.2021.05.010] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 04/26/2021] [Accepted: 05/14/2021] [Indexed: 12/11/2022]
Abstract
During embryonic stages, vascular endothelial cells (ECs) originate from the mesoderm, at specific extraembryonic and embryonic regions, through a process called vasculogenesis. In the adult, EC renewal/replacement mostly depend on local resident ECs or endothelial progenitor cells (EPCs). Nevertheless, contribution from circulating ECs/EPCs was also reported. In addition, cells lacking from EC/EPC markers with in vitro extended plasticity were shown to originate endothelial-like cells (ELCs). Most of these cells consist of mesenchymal stromal progenitors, which would eventually get mobilized from the bone marrow after injury. Based on that, current knowledge on different mouse and human bone marrow stromal cell (BM-SC) subpopulations, able to contribute with mesenchymal stromal/stem cells (MSCs), is herein reviewed. Such analyses underline an unexpected heterogeneity among sinusoidal LepR+ stromal/CAR cells. For instance, in a recent report a subgroup of LepR+ stromal/CAR progenitors, which express GLAST and is traced in Wnt1Cre;R26RTom mice, was found to contribute with ELCs in vivo. These GLAST + Wnt1+ BM-SCs were shown to get mobilized to the peripheral blood and to contribute with liver regeneration. Other sources of ELCs, such as adipose, neural and dental pulp tissues, were also published. Finally, mechanisms likely involved in the enhanced cellular plasticity properties of bone marrow/adipose tissue stromal cells, able to originate ELCs, are assessed. In the future, strategies to analyze the in vivo expression profile of stromal cells, with MSC properties, in combination with screening of active genomic regions at the single cell-level, during early postnatal development and/or after injury, will likely help understanding properties of these ELC sources.
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Affiliation(s)
- Jorge B Aquino
- CONICET-Universidad Austral, Instituto de Investigaciones en Medicina Traslacional (IIMT), Developmental Biology & Regenerative Medicine Laboratory, Argentina.
| | - Romina Sierra
- CONICET-Universidad Austral, Instituto de Investigaciones en Medicina Traslacional (IIMT), Developmental Biology & Regenerative Medicine Laboratory, Argentina
| | - Laura A Montaldo
- CONICET-Universidad Austral, Instituto de Investigaciones en Medicina Traslacional (IIMT), Developmental Biology & Regenerative Medicine Laboratory, Argentina
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16
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Cwykiel J, Jundzill A, Klimczak A, Madajka-Niemeyer M, Siemionow M. Donor Recipient Chimeric Cells Induce Chimerism and Extend Survival of Vascularized Composite Allografts. Arch Immunol Ther Exp (Warsz) 2021; 69:13. [PMID: 33970329 PMCID: PMC8110509 DOI: 10.1007/s00005-021-00614-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 04/08/2021] [Indexed: 11/30/2022]
Abstract
This study evaluated the efficacy of donor recipient chimeric cell (DRCC) therapy created by fusion of donor and recipient derived bone marrow cells (BMC) in chimerism and tolerance induction in a rat vascularized composite allograft (VCA) model. Twenty-four VCA (groin flaps) from MHC-mismatched ACI (RT1a) donors were transplanted to Lewis (RT1l) recipients. Rats were randomly divided into (n = 6/group): Group 1—untreated controls, Groups 2—7-day immunosuppression controls, Group 3—DRCC, and Group 4—DRCC with 7-day anti-αβTCR monoclonal antibody and cyclosporine A protocol. DRCC created by polyethylene glycol-mediated fusion of ACI and Lewis BMC were cultured and transplanted (2–4 × 106) to VCA recipients via intraosseous delivery route. Flow cytometry assessed peripheral blood chimerism while fluorescent microscopy and PCR tested the presence of DRCC in the recipient’s blood, bone marrow (BM), and lymphoid organs at the study endpoint (VCA rejection). No complications were observed after DRCC intraosseous delivery. Group 4 presented the longest average VCA survival (79.3 ± 30.9 days) followed by Group 2 (53.3 ± 13.6 days), Group 3 (18 ± 7.5 days), and Group 1 (8.5 ± 1 days). The highest chimerism level was detected in Group 4 (57.9 ± 6.2%) at day 7 post-transplant. The chimerism declined at day 21 post-transplant and remained at 10% level during the entire follow-up period. Single dose of DRCC therapy induced long-term multilineage chimerism and extended VCA survival. DRCC introduces a novel concept of customized donor-recipient cell-based therapy supporting solid organ and VCA transplants.
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Affiliation(s)
- Joanna Cwykiel
- Department of Orthopaedics, University of Illinois At Chicago, Molecular Biology Research Building, 900 S. Ashland Ave. Room# 3356, Chicago, IL, 60607, USA.,Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Arkadiusz Jundzill
- Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH, USA.,Chair of Urology, Department of Regenerative Medicine, Nicolaus Copernicus University in Torun, Ludwik Rydygier Medical College in Bydgoszcz, Bydgoszcz, Poland.,Department of Plastic, Reconstructive and Aesthetic Surgery, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Bydgoszcz, Poland
| | - Aleksandra Klimczak
- Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH, USA.,Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | | | - Maria Siemionow
- Department of Orthopaedics, University of Illinois At Chicago, Molecular Biology Research Building, 900 S. Ashland Ave. Room# 3356, Chicago, IL, 60607, USA. .,Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH, USA. .,Department of Surgery, Poznan University of Medical Sciences, Poznan, Poland.
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17
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Cwykiel J, Madajka-Niemeyer M, Siemionow M. Development of Donor Recipient Chimeric Cells of bone marrow origin as a novel approach for tolerance induction in transplantation. Stem Cell Investig 2021; 8:8. [PMID: 33969113 DOI: 10.21037/sci-2020-044] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 03/03/2021] [Indexed: 12/14/2022]
Abstract
Background Cell therapies and chimerism-based strategies are currently the most successful approach for tolerance induction in transplantation. This study aimed to establish and characterize novel Donor Recipient Chimeric Ccell (DRCC) therapy of bone marrow (BM) origin presenting donor-recipient phenotype to support tolerance induction. Methods Ex vivo fusions of fully MHC-mismatched BM cells from ACI (RT1a) and Lewis (RT1l) rats were performed using polyethylene-glycol (PEG). The creation of rat DRCC was tested by flow cytometry (FC), confocal microscopy and PCR. FC characterized DRCC's phenotype (CD3, CD4, CD8, CD45, CD90, CD11b/c, CD45RA, OX-82, or CD4/CD25) and apoptosis, while mixed lymphocyte reaction assessed DRCC's immunogenicity and colony forming unit assay tested DRCC's differentiation and proliferation. DRCC's polyploidy was evaluated using Hoechst33342 staining and COMET assay tested genotoxicity of fusion procedure. ELISA analyzed the secretion of IL-2, IL-4, IL-10, TGFß1, IFNγ and TNFα by DRCC at day 1, 5 and 14 post-fusion. The DRCC's phenotype after long-term culturing was assessed by reverse-transcription PCR. Results The chimeric state of DRCC was confirmed. Fusion did not change the expression of hematopoietic markers compared to BM controls. Although an increased number of early and late apoptotic (Annexin V+/Sytox blue- and Annexin V+/Sytox blue+, respectively) DRCC was detected at 24h post-fusion, the number significantly decreased at day 5 (38.4%±3.1% and 22.6%±2.5%, vs. 28.3%±2.5% and 13.9%±2.6%, respectively, P<0.05). DRCC presented decreased immunogenicity, increased expression of IL-10 and TGFβ1 and proliferative potential comparable to BM controls. The average percentage of tetraploid DRCC was 3.1%±0.2% compared to 0.96%±0.1% in BM controls. The lack of damage to the DRCC's DNA content supported the DRCC's safety. In culture, DRCC maintained proliferation for up to 28 days while preserving hematopoietic profile. Conclusions This study confirmed feasibility of DRCC creation via ex vivo PEG mediated fusion. The created DRCC revealed pro-tolerogenic properties indicating potential immunomodulatory effect of DRCC therapy when applied in vivo to support tolerance induction in solid organ and vascularized composite allograft transplantation.
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Affiliation(s)
- Joanna Cwykiel
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, IL, USA.,Department of Plastic Surgery, Cleveland Clinic, Cleveland, Ohio, USA
| | | | - Maria Siemionow
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, IL, USA.,Department of Plastic Surgery, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Surgery, Poznan University of Medical Sciences, Poznan, Poland
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18
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Hu WC. The Central THαβ Immunity Associated Cytokine: IL-10 Has a Strong Anti-Tumor Ability Toward Established Cancer Models In Vivo and Toward Cancer Cells In Vitro. Front Oncol 2021; 11:655554. [PMID: 33912464 PMCID: PMC8072451 DOI: 10.3389/fonc.2021.655554] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 03/15/2021] [Indexed: 11/17/2022] Open
Abstract
Immunotherapy is a promising new approach for cancer treatment. In this study, I propose to use the THαβ-mediated immune response for cancer treatment. The THαβ-mediated immune response is activated by IL-10 and IL-15. Thus, I used IL-10 and-15 as therapeutic agents in the 4T1 cell line, which is a mouse cell line of breast cancer, and the NXS2 cell line, which is a mouse cell line of neuroblastoma. Cells from 4T1 and NXS2 were subcutaneously inoculated in wild type BALB/c female mice and AJ mice, respectively, and administered cytokines or an antibody treatment at various dosages. My results showed that IL-10 and IL-15 administration led to reduction in tumor volume and increase in survival. However, traditional TH1 cytokine IFN-γ administration led to increase in tumor volume and decline in survival. Antibody treatment in conjunction with IL-10 was not significantly better than IL-10, due to the expression of GD2 on immune cells. Moreover, an anti-GD2 antibody inhibited the immune cells themselves. Additionally, I found that IL-10 was directly toxic to tumor cells in vitro. Thus, I conclude that the THαβ immunological pathway is a good treatment strategy for cancer.
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Affiliation(s)
- Wan-Chung Hu
- Genomics Research Center, Academia Sinica, Taipei, Taiwan.,Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
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19
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Dörnen J, Sieler M, Weiler J, Keil S, Dittmar T. Cell Fusion-Mediated Tissue Regeneration as an Inducer of Polyploidy and Aneuploidy. Int J Mol Sci 2020; 21:E1811. [PMID: 32155721 PMCID: PMC7084716 DOI: 10.3390/ijms21051811] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 02/28/2020] [Accepted: 03/04/2020] [Indexed: 12/20/2022] Open
Abstract
The biological phenomenon of cell fusion plays a crucial role in several physiological processes, including wound healing and tissue regeneration. Here, it is assumed that bone marrow-derived stem cells (BMSCs) could adopt the specific properties of a different organ by cell fusion, thereby restoring organ function. Cell fusion first results in the production of bi- or multinucleated hybrid cells, which either remain as heterokaryons or undergo ploidy reduction/heterokaryon-to-synkaryon transition (HST), thereby giving rise to mononucleated daughter cells. This process is characterized by a merging of the chromosomes from the previously discrete nuclei and their subsequent random segregation into daughter cells. Due to extra centrosomes concomitant with multipolar spindles, the ploidy reduction/HST could also be associated with chromosome missegregation and, hence, induction of aneuploidy, genomic instability, and even putative chromothripsis. However, while the majority of such hybrids die or become senescent, aneuploidy and genomic instability appear to be tolerated in hepatocytes, possibly for stress-related adaption processes. Likewise, cell fusion-induced aneuploidy and genomic instability could also lead to a malignant conversion of hybrid cells. This can occur during tissue regeneration mediated by BMSC fusion in chronically inflamed tissue, which is a cell fusion-friendly environment, but is also enriched for mutagenic reactive oxygen and nitrogen species.
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Affiliation(s)
| | | | | | | | - Thomas Dittmar
- Institute of Immunology, Center for Biomedical Education and Research (ZBAF), Witten/Herdecke University, 58448 Witten, Germany; (J.D.); (M.S.); (J.W.); (S.K.)
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20
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Maliken BD, Kanisicak O, Karch J, Khalil H, Fu X, Boyer JG, Prasad V, Zheng Y, Molkentin JD. Gata4-Dependent Differentiation of c-Kit +-Derived Endothelial Cells Underlies Artefactual Cardiomyocyte Regeneration in the Heart. Circulation 2019; 138:1012-1024. [PMID: 29666070 PMCID: PMC6125755 DOI: 10.1161/circulationaha.118.033703] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Supplemental Digital Content is available in the text. Background: Although c-Kit+ adult progenitor cells were initially reported to produce new cardiomyocytes in the heart, recent genetic evidence suggests that such events are exceedingly rare. However, to determine if these rare events represent true de novo cardiomyocyte formation, we deleted the necessary cardiogenic transcription factors Gata4 and Gata6 from c-Kit–expressing cardiac progenitor cells. Methods: Kit allele–dependent lineage tracing and fusion analysis were performed in mice following simultaneous Gata4 and Gata6 cell type–specific deletion to examine rates of putative de novo cardiomyocyte formation from c-Kit+ cells. Bone marrow transplantation experiments were used to define the contribution of Kit allele–derived hematopoietic cells versus Kit lineage–dependent cells endogenous to the heart in contributing to apparent de novo lineage-traced cardiomyocytes. A Tie2CreERT2 transgene was also used to examine the global impact of Gata4 deletion on the mature cardiac endothelial cell network, which was further evaluated with select angiogenesis assays. Results: Deletion of Gata4 in Kit lineage–derived endothelial cells or in total endothelial cells using the Tie2CreERT2 transgene, but not from bone morrow cells, resulted in profound endothelial cell expansion, defective endothelial cell differentiation, leukocyte infiltration into the heart, and a dramatic increase in Kit allele–dependent lineage-traced cardiomyocytes. However, this increase in labeled cardiomyocytes was an artefact of greater leukocyte-cardiomyocyte cellular fusion because of defective endothelial cell differentiation in the absence of Gata4. Conclusions: Past identification of presumed de novo cardiomyocyte formation in the heart from c-Kit+ cells using Kit allele lineage tracing appears to be an artefact of labeled leukocyte fusion with cardiomyocytes. Deletion of Gata4 from c-Kit+ endothelial progenitor cells or adult endothelial cells negatively impacted angiogenesis and capillary network integrity.
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Affiliation(s)
- Bryan D Maliken
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (B.D.M., O.K., J.K., H.K., X.F., J.G.B., V.P., Y.Z., J.D.M.)
| | - Onur Kanisicak
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (B.D.M., O.K., J.K., H.K., X.F., J.G.B., V.P., Y.Z., J.D.M.)
| | - Jason Karch
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (B.D.M., O.K., J.K., H.K., X.F., J.G.B., V.P., Y.Z., J.D.M.)
| | - Hadi Khalil
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (B.D.M., O.K., J.K., H.K., X.F., J.G.B., V.P., Y.Z., J.D.M.)
| | | | - Justin G Boyer
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (B.D.M., O.K., J.K., H.K., X.F., J.G.B., V.P., Y.Z., J.D.M.).,Howard Hughes Medical Institute, Cincinnati Children's Hospital Research Foundation, OH (J.G.B., J.D.M)
| | - Vikram Prasad
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (B.D.M., O.K., J.K., H.K., X.F., J.G.B., V.P., Y.Z., J.D.M.)
| | - Yi Zheng
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (B.D.M., O.K., J.K., H.K., X.F., J.G.B., V.P., Y.Z., J.D.M.)
| | - Jeffery D Molkentin
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (B.D.M., O.K., J.K., H.K., X.F., J.G.B., V.P., Y.Z., J.D.M.).,Howard Hughes Medical Institute, Cincinnati Children's Hospital Research Foundation, OH (J.G.B., J.D.M)
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21
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Myerson D, Parkin RK. Donor-derived hepatocytes in human hematopoietic cell transplant recipients: evidence of fusion. Virchows Arch 2018; 474:365-374. [PMID: 30539318 DOI: 10.1007/s00428-018-2497-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 11/13/2018] [Accepted: 11/19/2018] [Indexed: 12/12/2022]
Abstract
Reconstitution of hepatocytes by hematopoietic stem cells-a phenomenon which occurs in rodents under highly selective conditions-results from infrequent fusion between incoming myelomonocytes and host hepatocytes, with subsequent proliferation. Human hematopoietic stem cell transplant recipients have been little studied, with some support for transdifferentiation (direct differentiation). We studied routinely obtained autopsy liver tissue of four female hematopoietic cell transplant recipients with male donors, using a highly specific conjoint immunohistochemistry in situ hybridization light microscopic technique. Hepatocyte nuclei were identified by cytokeratin (Cam5.2) staining and evaluated for X and Y chromosome content. Over 1.6 million hepatocytes were assessed for rare instances of donor origin, revealing a Y chromosome in 67. Mixed tetraploids (XXXY) and their nuclear truncation products (XXY, XY, Y) were directly demonstrated, with no detection of the male tetraploids (XXYY) that may result from transdifferentiation with subsequent tetraploidization, nor their unique truncation products (XYY, YY), implicating fusion as the mechanism. To determine whether it is the sole mechanism, we modeled the chromosome distribution based on the same probability of detection of each X chromosome, deriving parameters of sensitivity and female tetraploidy by best fit. We then hypothesized that the distribution of Y chromosome-containing cells could be predicted by a similar model. After modification to account for "clumpy" Y chromosomes, the observed results were in accord with the predicted results (p = 0.6). These results suggest that all the Y-containing cells, including apparent XY cells, derive from mixed tetraploids, consistent with fusion as the sole mechanism.
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Affiliation(s)
- David Myerson
- Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA, 98109, USA. .,Department of Pathology, University of Washington, Seattle, WA, 98195, USA.
| | - Rachael K Parkin
- Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA, 98109, USA
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22
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Pesaresi M, Sebastian-Perez R, Cosma MP. Dedifferentiation, transdifferentiation and cell fusion: in vivo reprogramming strategies for regenerative medicine. FEBS J 2018; 286:1074-1093. [PMID: 30103260 DOI: 10.1111/febs.14633] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 07/01/2018] [Accepted: 08/10/2018] [Indexed: 12/23/2022]
Abstract
Regenerative capacities vary enormously across the animal kingdom. In contrast to most cold-blooded vertebrates, mammals, including humans, have very limited regenerative capacity when it comes to repairing damaged or degenerating tissues. Here, we review the main mechanisms of tissue regeneration, underlying the importance of cell dedifferentiation and reprogramming. We discuss the significance of cell fate and identity changes in the context of regenerative medicine, with a particular focus on strategies aiming at the promotion of the body's self-repairing mechanisms. We also introduce some of the most recent advances that have resulted in complete reprogramming of cell identity in vivo. Lastly, we discuss the main challenges that need to be addressed in the near future to develop in vivo reprogramming approaches with therapeutic potential.
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Affiliation(s)
- Martina Pesaresi
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Spain
| | - Ruben Sebastian-Perez
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Spain
| | - Maria Pia Cosma
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Spain.,Universitat Pompeu Fabra (UPF), Barcelona, Spain.,Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
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23
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Lizier M, Castelli A, Montagna C, Lucchini F, Vezzoni P, Faggioli F. Cell fusion in the liver, revisited. World J Hepatol 2018; 10:213-221. [PMID: 29527257 PMCID: PMC5838440 DOI: 10.4254/wjh.v10.i2.213] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 12/28/2017] [Accepted: 02/06/2018] [Indexed: 02/06/2023] Open
Abstract
There is wide agreement that cell fusion is a physiological process in cells in mammalian bone, muscle and placenta. In other organs, such as the cerebellum, cell fusion is controversial. The liver contains a considerable number of polyploid cells: They are commonly believed to originate by genome endoreplication, although the contribution of cell fusion to polyploidization has not been excluded. Here, we address the topic of cell fusion in the liver from a historical point of view. We discuss experimental evidence clearly supporting the hypothesis that cell fusion occurs in the liver, specifically when bone marrow cells were injected into mice and shown to rescue genetic hepatic degenerative defects. Those experiments-carried out in the latter half of the last century-were initially interpreted to show “transdifferentiation”, but are now believed to demonstrate fusion between donor macrophages and host hepatocytes, raising the possibility that physiologically polyploid cells, such as hepatocytes, could originate, at least partially, through homotypic cell fusion. In support of the homotypic cell fusion hypothesis, we present new data generated using a chimera-based model, a much simpler model than those previously used. Cell fusion as a road to polyploidization in the liver has not been extensively investigated, and its contribution to a variety of conditions, such as viral infections, carcinogenesis and aging, remains unclear.
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Affiliation(s)
- Michela Lizier
- Istituto di Ricerca Genetica e Biomedica, CNR, Milan 20138, Italy
- Human Genome Laboratory, Humanitas Clinical and Research Center, IRCCS, Milan 20089, Italy
| | - Alessandra Castelli
- Istituto di Ricerca Genetica e Biomedica, CNR, Milan 20138, Italy
- Human Genome Laboratory, Humanitas Clinical and Research Center, IRCCS, Milan 20089, Italy
| | - Cristina Montagna
- Department of Genetics and Pathology Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, United States
| | - Franco Lucchini
- Centro Ricerche Biotecnologiche, Università Cattolica del Sacro Cuore, Cremona 26100, Italy
| | - Paolo Vezzoni
- Istituto di Ricerca Genetica e Biomedica, CNR, Milan 20138, Italy
- Human Genome Laboratory, Humanitas Clinical and Research Center, IRCCS, Milan 20089, Italy
| | - Francesca Faggioli
- Istituto di Ricerca Genetica e Biomedica, CNR, Milan 20138, Italy
- Human Genome Laboratory, Humanitas Clinical and Research Center, IRCCS, Milan 20089, Italy
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24
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Allen KJ, Cheah DMY, Lee XL, Pettigrew-Buck NE, Vadolas J, Mercer JFB, Ioannou PA, Williamson R. The Potential of Bone Marrow Stem Cells to Correct Liver Dysfunction in a Mouse Model of Wilson's Disease. Cell Transplant 2017; 13:765-73. [PMID: 15690978 DOI: 10.3727/000000004783983341] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Metabolic liver diseases are excellent targets for correction using novel stem cell, hepatocyte, and gene therapies. In this study, the use of bone marrow stem cell transplantation to correct liver disease in the toxic milk (tx) mouse, a murine model for Wilson's disease, was evaluated. Preconditioning with sublethal irradiation, dietary copper loading, and the influence of cell transplantation sites were assessed. Recipient tx mice were sublethally irradiated (4 Gy) prior to transplantation with bone marrow stem cells harvested from normal congenic (DL) littermates. Of 46 transplanted tx mice, 11 demonstrated genotypic repopulation in the liver. Sublethal irradiation was found to be essential for donor cell engraftment and liver repopulation. Dietary copper loading did not improve cell engraftment and repopulation results. Both intravenously and intrasplenically transplanted cells produced similar repopulation successes. Direct evidence of functionality and disease correction following liver repopulation was observed in the 11 mice where liver copper levels were significantly reduced when compared with mice with no liver repopulation. The reversal of copper loading with bone marrow cells is similar to the level of correction seen when normal congenic liver cells are used. Transplantation of bone marrow cells partially corrects the metabolic phenotype in a mouse model for Wilson's disease.
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Affiliation(s)
- Katrina J Allen
- Cell and Gene Therapy Group, Murdoch Childrens Research Institute, Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
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Cellular Origins of Regenerating Nodules and Malignancy in the FAH Model of Liver Injury after Bone Marrow Cell Transplantation. Stem Cells Int 2016; 2016:5791317. [PMID: 26962307 PMCID: PMC4709791 DOI: 10.1155/2016/5791317] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Accepted: 10/04/2015] [Indexed: 12/02/2022] Open
Abstract
In previous reports, we and other groups have shown that proliferating hepatocytes are formed by the fusion of donor hematopoietic cells with host hepatocytes in the Fah−/− model. Thus, it would be interesting to determine whether cell fusion occurs during malignancy. However, it is difficult to demonstrate such processes using this model. Therefore, we established a new strain to study the processes of regenerating nodules and malignancy and their origins. The FAH−/− mouse model was crossed with the ROSAnZ strain and their offspring was genotyped for FAH−/− and ROSAnZ mutations to create a new strain (Fah−/−-ROSAnZ). Using this strain as recipients, we performed bone marrow transplantation experiments. As a result, we could not demonstrate the presence of any epithelial cells except hepatocytes that were of donor origin in regenerating tissue, and no evidence of cell fusion was found in tumors. The hepatic malignancy was of host origin in these mice. There was higher expression of extracellular matrix proteins and more inflammatory cells in liver tumor nodules than in regenerating normal liver nodules. Hepatocytes generated by fusion with bone marrow cells did not form malignant tumors. Extracellular matrix and inflammatory cells had significantly accumulated in liver tumors.
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Mahajan V, Gaymalov Z, Alakhova D, Gupta R, Zucker IH, Kabanov AV. Horizontal gene transfer from macrophages to ischemic muscles upon delivery of naked DNA with Pluronic block copolymers. Biomaterials 2015; 75:58-70. [PMID: 26480472 DOI: 10.1016/j.biomaterials.2015.10.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2015] [Revised: 09/30/2015] [Accepted: 10/01/2015] [Indexed: 12/31/2022]
Abstract
Intramuscular administration of plasmid DNA (pDNA) with non-ionic Pluronic block copolymers increases gene expression in injected muscles and lymphoid organs. We studied the role of immune cells in muscle transfection upon inflammation. Local inflammation in murine hind limb ischemia model (MHLIM) drastically increased DNA, RNA and expressed protein levels in ischemic muscles injected with pDNA/Pluronic. The systemic inflammation (MHLIM or peritonitis) also increased expression of pDNA/Pluronic in the muscles. When pDNA/Pluronic was injected in ischemic muscles the reporter gene, Green Fluorescent Protein (GFP) co-localized with desmin(+) muscle fibers and CD11b(+) macrophages (MØs), suggesting transfection of MØs along with the muscle cells. P85 enhanced (∼ 4 orders) transfection of MØs with pDNA in vitro. Moreover, adoptively transferred MØs were shown to pass the transgene to inflamed muscle cells in MHLIM. Using a co-culture of myotubes (MTs) and transfected MØs expressing a reporter gene under constitutive (cmv-luciferase) or muscle specific (desmin-luciferase) promoter we demonstrated that P85 enhances horizontal gene transfer from MØ to MTs. Therefore, MØs can play an important role in muscle transfection with pDNA/Pluronic during inflammation, with both inflammation and Pluronic contributing to the increased gene expression. pDNA/Pluronic has potential for therapeutic gene delivery in muscle pathologies that involve inflammation.
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Affiliation(s)
- Vivek Mahajan
- Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA
| | - Zagit Gaymalov
- Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA; Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA
| | - Daria Alakhova
- Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA
| | - Richa Gupta
- Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA
| | - Irving H Zucker
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA
| | - Alexander V Kabanov
- Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA; Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA; Laboratory of Chemical Design of Bionanomaterials, Faculty of Chemistry, M.V. Lomonosov Moscow State University, 119899 Moscow, Russia.
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Li L, Zeng Z, Qi Z, Wang X, Gao X, Wei H, Sun R, Tian Z. Natural Killer Cells-Produced IFN-γ Improves Bone Marrow-Derived Hepatocytes Regeneration in Murine Liver Failure Model. Sci Rep 2015; 5:13687. [PMID: 26345133 PMCID: PMC4561890 DOI: 10.1038/srep13687] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2015] [Accepted: 08/03/2015] [Indexed: 02/07/2023] Open
Abstract
Bone-marrow transplantation (BMT) can repopulate the liver through BM-derived hepatocyte (BMDH) generation, although the underlying mechanism remains unclear. Using fumarylacetoacetate hydrolase-deficient (Fah(-/-)) mice as a liver-failure model, we confirmed that BMDHs were generated by fusion of BM-derived CD11b(+)F4/80(+)myelomonocytes with resident Fah(-/-) hepatocytes. Hepatic NK cells became activated during BMDH generation and were the major IFN-γ producers. Indeed, both NK cells and IFN-γ were required for BMDH generation since WT, but not NK-, IFN-γ-, or IFN-γR1-deficient BM transplantation successfully generated BMDHs and rescued survival in Fah(-/-) hosts. BM-derived myelomonocytes were determined to be the IFN-γ-responding cells. The IFN-γ-IFN-γR interaction contributed to the myelomonocyte-hepatocyte fusion process, as most of the CD11b(+) BMDHs in mixed BM chimeric Fah(-/-) hosts transplanted with a 1:1 ratio of CD45.1(+) WT and CD45.2(+) Ifngr1(-/-) BM cells were of CD45.1(+) WT origin. Confirming these findings in vitro, IFN-γ dose-dependently promoted the fusion of GFP(+) myelomonocytes with Fah(-/-) hepatocytes due to a direct effect on myelomonocytes; similar results were observed using activated NK cells. In conclusion, BMDH generation requires NK cells to facilitate myelomonocyte-hepatocyte fusion in an IFN-γ-dependent manner, providing new insights for treating severe liver failure.
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Affiliation(s)
- Lu Li
- Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Zhutian Zeng
- Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Ziping Qi
- Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Xin Wang
- The Key Laboratory of National Education Ministry for Mammalian Reproductive Biology and Biotechnology, Inner Mongolia University, Hohhot 010070, China
| | - Xiang Gao
- Model Animal Research Center, Nanjing University, Nanjing 210061, China
| | - Haiming Wei
- Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Rui Sun
- Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Zhigang Tian
- Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
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Porada CD, Atala AJ, Almeida-Porada G. The hematopoietic system in the context of regenerative medicine. Methods 2015; 99:44-61. [PMID: 26319943 DOI: 10.1016/j.ymeth.2015.08.015] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Revised: 07/06/2015] [Accepted: 08/23/2015] [Indexed: 12/16/2022] Open
Abstract
Hematopoietic stem cells (HSC) represent the prototype stem cell within the body. Since their discovery, HSC have been the focus of intensive research, and have proven invaluable clinically to restore hematopoiesis following inadvertent radiation exposure and following radio/chemotherapy to eliminate hematologic tumors. While they were originally discovered in the bone marrow, HSC can also be isolated from umbilical cord blood and can be "mobilized" peripheral blood, making them readily available in relatively large quantities. While their ability to repopulate the entire hematopoietic system would already guarantee HSC a valuable place in regenerative medicine, the finding that hematopoietic chimerism can induce immunological tolerance to solid organs and correct autoimmune diseases has dramatically broadened their clinical utility. The demonstration that these cells, through a variety of mechanisms, can also promote repair/regeneration of non-hematopoietic tissues as diverse as liver, heart, and brain has further increased their clinical value. The goal of this review is to provide the reader with a brief glimpse into the remarkable potential HSC possess, and to highlight their tremendous value as therapeutics in regenerative medicine.
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Affiliation(s)
- Christopher D Porada
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, 391 Technology Way, Winston-Salem, NC 27157-1083, United States.
| | - Anthony J Atala
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, 391 Technology Way, Winston-Salem, NC 27157-1083, United States.
| | - Graça Almeida-Porada
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, 391 Technology Way, Winston-Salem, NC 27157-1083, United States.
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Alejandra MR, Juan AB, Ana SR. Cell therapy for liver diseases: current medicine and future promises. Expert Rev Gastroenterol Hepatol 2015; 9:837-50. [PMID: 25747732 DOI: 10.1586/17474124.2015.1016913] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Liver diseases are a major health problem worldwide since they usually represent the main causes of death in most countries, causing excessive costs to public health systems. Nowadays, there are no efficient current therapies for most hepatic diseases and liver transplant is infrequent due to the availability of organs, cost and risk of transplant rejection. Therefore, alternative therapies for liver diseases have been developed, including cell-based therapies. Stem cells (SCs) are characterized by their self-renewing capacity, unlimited proliferation and differentiation under certain conditions into tissue- or organ-specific cells with special functions. Cell-based therapies for liver diseases have been successful in experimental models, showing anti-inflammatory, antifibrogenic and regenerative effects. Nowadays, clinical trials using SCs for liver pathologies are increasing in number, and those that have reached publication have achieved favorable effects, encouraging us to think that SCs will have a potential clinical use in a short time.
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Affiliation(s)
- Meza-Ríos Alejandra
- Department of Molecular Biology and Genomics, Health Sciences University Center, Institute for Molecular Biology and Gene Therapy, University of Guadalajara, Sierra Mojada 950, Colonia Independencia, Guadalajara, Jalisco 44340, México
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Liu WH, Song FQ, Ren LN, Guo WQ, Wang T, Feng YX, Tang LJ, Li K. The multiple functional roles of mesenchymal stem cells in participating in treating liver diseases. J Cell Mol Med 2015; 19:511-520. [PMID: 25534251 PMCID: PMC4369809 DOI: 10.1111/jcmm.12482] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Accepted: 10/07/2014] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are a group of stem cells derived from the mesodermal mesenchyme. MSCs can be obtained from a variety of tissues, including bone marrow, umbilical cord tissue, umbilical cord blood, peripheral blood and adipose tissue. Under certain conditions, MSCs can differentiate into many cell types both in vitro and in vivo, including hepatocytes. To date, four main strategies have been developed to induce the transdifferentiation of MSCs into hepatocytes: addition of chemical compounds and cytokines, genetic modification, adjustment of the micro-environment and alteration of the physical parameters used for culturing MSCs. Although the phenomenon of transdifferentiation of MSCs into hepatocytes has been described, the detailed mechanism is far from clear. Generally, the mechanism is a cascade reaction whereby stimulating factors activate cellular signalling pathways, which in turn promote the production of transcription factors, leading to hepatic gene expression. Because MSCs can give rise to hepatocytes, they are promising to be used as a new treatment for liver dysfunction or as a bridge to liver transplantation. Numerous studies have confirmed the therapeutic effects of MSCs on hepatic fibrosis, cirrhosis and other liver diseases, which may be related to the differentiation of MSCs into functional hepatocytes. In addition to transdifferentiation into hepatocytes, when MSCs are used to treat liver disease, they may also inhibit hepatocellular apoptosis and secrete various bioactive molecules to promote liver regeneration. In this review, the capacity and molecular mechanism of MSC transdifferentiation, and the therapeutic effects of MSCs on liver diseases are thoroughly discussed.
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Affiliation(s)
- Wei-hui Liu
- General Surgery Center, Chengdu Military General HospitalChengdu, Sichuan Province, China
| | - Fu-qiang Song
- Experimental Medical Center, Chengdu Military General HospitalChengdu, Sichuan Province, China
| | - Li-na Ren
- General Surgery Center, Chengdu Military General HospitalChengdu, Sichuan Province, China
| | - Wen-qiong Guo
- Nursing College, Chengdu Medical SchoolChengdu, Sichuan Province, China
| | - Tao Wang
- General Surgery Center, Chengdu Military General HospitalChengdu, Sichuan Province, China
| | - Ya-xing Feng
- Experimental Medical Center, Chengdu Military General HospitalChengdu, Sichuan Province, China
| | - Li-jun Tang
- General Surgery Center, Chengdu Military General HospitalChengdu, Sichuan Province, China
| | - Kun Li
- Experimental Medical Center, Chengdu Military General HospitalChengdu, Sichuan Province, China
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Moghadasali R, Azarnia M, Hajinasrollah M, Arghani H, Nassiri SM, Molazem M, Vosough A, Mohitmafi S, Najarasl M, Ajdari Z, Yazdi RS, Bagheri M, Ghanaati H, Rafiei B, Gheisari Y, Baharvand H, Aghdami N. Intra-renal arterial injection of autologous bone marrow mesenchymal stromal cells ameliorates cisplatin-induced acute kidney injury in a rhesus Macaque mulatta monkey model. Cytotherapy 2014; 16:734-49. [PMID: 24801377 DOI: 10.1016/j.jcyt.2014.01.004] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Revised: 12/26/2013] [Accepted: 01/08/2014] [Indexed: 12/29/2022]
Abstract
BACKGROUND Clinically, acute kidney injury (AKI) is a potentially devastating condition for which no specific therapy improves efficacy of the repair process. Bone marrow mesenchymal stromal cells (BM-MSCs) are proven to be beneficial for the renal repair process after AKI in different experimental rodent models, but their efficacy in large animals and humans remains unknown. This study aims to assess the effect of autologous rhesus Macaque mulatta monkey BM-MSC transplantation in cisplatin-induced AKI. METHODS We chose a model of AKI induced by intravenous administration of 5 mg/kg cisplatin. BM-MSCs were transplanted through intra-arterial injection. The animals were followed for survival, biochemistry analysis and pathology. RESULTS Transplantation of 5 × 10(6) cells/kg ameliorated renal function during the first week, as shown by significantly lower serum creatinine and urea values and higher urine creatinine and urea clearance without hyponatremia, hyperkalemia, proteinuria and polyuria up to 84 d compared with the vehicle and control groups. The superparamagnetic iron oxide nanoparticle-labeled cells were found in both the glomeruli and tubules. BM-MSCs markedly accelerated Foxp3+ T-regulatory cells in response to cisplatin-induced damage, as revealed by higher numbers of Foxp3+ cells within the tubuli of these monkeys compared with cisplatin-treated monkeys in the control and vehicle groups. CONCLUSIONS These data demonstrate that BM-MSCs in this unique large-animal model of cisplatin-induced AKI exhibited recovery and protective properties.
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Affiliation(s)
- Reza Moghadasali
- Department of Biology, Kharazmi University, Tehran, Iran; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Department of Regenerative Medicine at the Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mahnaz Azarnia
- Department of Biology, Kharazmi University, Tehran, Iran
| | - Mostafa Hajinasrollah
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Hassan Arghani
- Urology and Nephrology Research Center, Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Mahdi Nassiri
- Department of Clinical Pathology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Mohammad Molazem
- Department of Veterinary Radiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Ahmad Vosough
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Soroush Mohitmafi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Department of Clinical Sciences, Faculty of Veterinary Medicine, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Mostafa Najarasl
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Zahra Ajdari
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Reza Salman Yazdi
- Department of Andrology at the Reproductive Biomedicine Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Mohsen Bagheri
- Department of Andrology at the Reproductive Biomedicine Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Hossein Ghanaati
- Advanced Diagnostic and Interventional Radiology Research Center (ADIR), Tehran University of Medical Sciences, Tehran, Iran
| | - Behrooz Rafiei
- Advanced Diagnostic and Interventional Radiology Research Center (ADIR), Tehran University of Medical Sciences, Tehran, Iran
| | - Yousof Gheisari
- Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hossein Baharvand
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Department of Regenerative Medicine at the Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Department of Developmental Biology, University of Science and Culture, ACECR, Tehran, Iran
| | - Nasser Aghdami
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Department of Regenerative Medicine at the Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
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Siemionow MZ. A systematic review and meta-analysis on the prevalence of Dupuytren disease in the general population of Western countries. Plast Reconstr Surg 2014. [PMID: 24263394 PMCID: PMC7121457 DOI: 10.1007/978-1-4471-6335-0_72] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Dupuytren disease is a fibroproliferative disease of palmar fascia of the hand. Its prevalence has been the subject of several reviews; however, an accurate description of the prevalence range in the general population--and of the relation between age and disease--is lacking. METHODS Embase and PubMed were searched using database-specific Medical Subject Headings; titles and abstracts were searched for the words "Dupuytren," "incidence," and "prevalence." Two reviewers independently assessed the articles using inclusion and exclusion criteria, and rated the included studies with a quality assessment instrument. In a meta-analysis, the median prevalence, as a function of age by sex, was estimated, accompanied by 95 percent prediction intervals. The observed heterogeneity in prevalence was investigated with respect to study quality and geographic location. RESULTS Twenty-three of 199 unique identified articles were included. The number of participants ranged from 37 to 97,537, and age ranged from 18 to 100 years. Prevalence varied from 0.6 to 31.6 percent. The quality of studies differed but could not explain the heterogeneity among studies. Mean prevalence was estimated as 12, 21, and 29 percent at ages 55, 65, and 75 years, respectively, based on the relation between age and prevalence determined from 10 studies. CONCLUSIONS The authors describe a prevalence range of Dupuytren disease in the general population of Western countries. The relation between age and prevalence of Dupuytren disease is given according to sex, including 95 percent prediction intervals. It is possible to determine disease prevalence at a certain age for the total population, and for men and women separately.
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Affiliation(s)
- Maria Z. Siemionow
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, Illinois 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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Qi Z, Li L, Wang X, Gao X, Wang X, Wei H, Zhang J, Sun R, Tian Z. Bone marrow transplantation concurrently reconstitutes donor liver and immune system across host species barrier in mice. PLoS One 2014; 9:e106791. [PMID: 25191899 PMCID: PMC4156390 DOI: 10.1371/journal.pone.0106791] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Accepted: 08/08/2014] [Indexed: 01/12/2023] Open
Abstract
Liver immunopathologic mechanisms during hepatotropic infection, malignant transformation, and autoimmunity are still unclear. Establishing a chimeric mouse with a reconstituted liver and immune system derived from a single donor across species is critical to study regional donor immune responses in recipient liver. Using a strain of mice deficient in tyrosine catabolic enzyme fumarylacetoacetate hydrolase (fah-/-) and bone marrow transplantation (BMT), we reconstituted the donor's hepatocytes and immune cells across host species barrier. Syngeneic, allogeneic or even xenogeneic rat BMT rescued most recipient fah-/- mice against liver failure by donor BM-derived FAH+ hepatocytes. Importantly, immune system developed normally in chimeras, and the immune cells together with organ architecture were intact and functional. Thus, donor BM can across host species barrier and concurrently reconstitutes MHC-identical response between immune cells and hepatocytes, giving rise to a new simple and convenient small animal model to study donor's liver immune response in mice.
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Affiliation(s)
- Ziping Qi
- Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
| | - Lu Li
- Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
- Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China
| | - Xuefu Wang
- Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
| | - Xiang Gao
- Model Animal Research Center, Nanjing University, Nanjing, China
| | - Xin Wang
- Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Haiming Wei
- Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
- Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China
| | - Jian Zhang
- School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Rui Sun
- Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
- Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China
| | - Zhigang Tian
- Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
- Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang, China
- * E-mail:
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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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A systematic review and meta-analysis on the prevalence of Dupuytren disease in the general population of Western countries. Plast Reconstr Surg 2014; 133:593-603. [PMID: 24263394 DOI: 10.1097/01.prs.0000438455.37604.0f] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Dupuytren disease is a fibroproliferative disease of palmar fascia of the hand. Its prevalence has been the subject of several reviews; however, an accurate description of the prevalence range in the general population--and of the relation between age and disease--is lacking. METHODS Embase and PubMed were searched using database-specific Medical Subject Headings; titles and abstracts were searched for the words "Dupuytren," "incidence," and "prevalence." Two reviewers independently assessed the articles using inclusion and exclusion criteria, and rated the included studies with a quality assessment instrument. In a meta-analysis, the median prevalence, as a function of age by sex, was estimated, accompanied by 95 percent prediction intervals. The observed heterogeneity in prevalence was investigated with respect to study quality and geographic location. RESULTS Twenty-three of 199 unique identified articles were included. The number of participants ranged from 37 to 97,537, and age ranged from 18 to 100 years. Prevalence varied from 0.6 to 31.6 percent. The quality of studies differed but could not explain the heterogeneity among studies. Mean prevalence was estimated as 12, 21, and 29 percent at ages 55, 65, and 75 years, respectively, based on the relation between age and prevalence determined from 10 studies. CONCLUSIONS The authors describe a prevalence range of Dupuytren disease in the general population of Western countries. The relation between age and prevalence of Dupuytren disease is given according to sex, including 95 percent prediction intervals. It is possible to determine disease prevalence at a certain age for the total population, and for men and women separately.
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Kochat V, Baligar P, Maiwall R, Mukhopadhyay A. Bone marrow stem-cell therapy for genetic and chronic liver diseases. Hepatol Int 2014. [DOI: 10.1007/s12072-013-9499-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Gentric G, Desdouets C. Polyploidization in liver tissue. THE AMERICAN JOURNAL OF PATHOLOGY 2013; 184:322-31. [PMID: 24140012 DOI: 10.1016/j.ajpath.2013.06.035] [Citation(s) in RCA: 143] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/02/2013] [Revised: 06/17/2013] [Accepted: 06/20/2013] [Indexed: 12/14/2022]
Abstract
Polyploidy (alias whole genome amplification) refers to organisms containing more than two basic sets of chromosomes. Polyploidy was first observed in plants more than a century ago, and it is known that such processes occur in many eukaryotes under a variety of circumstances. In mammals, the development of polyploid cells can contribute to tissue differentiation and, therefore, possibly a gain of function; alternately, it can be associated with development of disease, such as cancer. Polyploidy can occur because of cell fusion or abnormal cell division (endoreplication, mitotic slippage, or cytokinesis failure). Polyploidy is a common characteristic of the mammalian liver. Polyploidization occurs mainly during liver development, but also in adults with increasing age or because of cellular stress (eg, surgical resection, toxic exposure, or viral infections). This review will explore the mechanisms that lead to the development of polyploid cells, our current state of understanding of how polyploidization is regulated during liver growth, and its consequence on liver function.
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Affiliation(s)
- Géraldine Gentric
- French Institute of Health and Medical Research (INSERM), U1016, Cochin Institute, Department of Development, Reproduction and Cancer, Paris, France; French National Centre for Scientific Research (CNRS), UMR 8104, Paris, France; Paris Descartes University, Sorbonne Paris Cité, Paris, France
| | - Chantal Desdouets
- French Institute of Health and Medical Research (INSERM), U1016, Cochin Institute, Department of Development, Reproduction and Cancer, Paris, France; French National Centre for Scientific Research (CNRS), UMR 8104, Paris, France; Paris Descartes University, Sorbonne Paris Cité, Paris, France.
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Fukata M, Ishikawa F, Najima Y, Yamauchi T, Saito Y, Takenaka K, Miyawaki K, Shimazu H, Shimoda K, Kanemaru T, Nakamura KI, Odashiro K, Nagafuji K, Harada M, Akashi K. Contribution of bone marrow-derived hematopoietic stem/progenitor cells to the generation of donor-marker⁺ cardiomyocytes in vivo. PLoS One 2013; 8:e62506. [PMID: 23667482 PMCID: PMC3647070 DOI: 10.1371/journal.pone.0062506] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2011] [Accepted: 03/26/2013] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Definite identification of the cell types and the mechanism relevant to cardiomyogenesis is essential for effective cardiac regenerative medicine. We aimed to identify the cell populations that can generate cardiomyocytes and to clarify whether generation of donor-marker(+) cardiomyocytes requires cell fusion between BM-derived cells and recipient cardiomyocytes. METHODOLOGY/PRINCIPAL FINDINGS Purified BM stem/progenitor cells from green fluorescence protein (GFP) mice were transplanted into C57BL/6 mice or cyan fluorescence protein (CFP)-transgenic mice. Purified human hematopoietic stem cells (HSCs) from cord blood were transplanted into immune-compromised NOD/SCID/IL2rγ(null) mice. GFP(+) cells in the cardiac tissue were analyzed for the antigenecity of a cardiomyocyte by confocal microscopy following immunofluorescence staining. GFP(+) donor-derived cells, GFP(+)CFP(+) fused cells, and CFP(+) recipient-derived cells were distinguished by linear unmixing analysis. Hearts of xenogeneic recipients were evaluated for the expression of human cardiomyocyte genes by real-time quantitative polymerase chain reaction. In C57BL/6 recipients, Lin(-/low)CD45(+) hematopoietic cells generated greater number of GFP(+) cardiomyocytes than Lin(-/low)CD45(-) mesenchymal cells (37.0+/-23.9 vs 0.00+/-0.00 GFP(+) cardiomyocytes per a recipient, P = 0.0095). The number of transplanted purified HSCs (Lin(-/low)Sca-1(+) or Lin(-)Sca-1(+)c-Kit(+) or CD34(-)Lin(-)Sca-1(+)c-Kit(+)) showed correlation to the number of GFP(+) cardiomyocytes (P<0.05 in each cell fraction), and the incidence of GFP(+) cardiomyocytes per injected cell dose was greatest in CD34(-)Lin(-)Sca-1(+)c-Kit(+) recipients. Of the hematopoietic progenitors, total myeloid progenitors generated greater number of GFP(+) cardiomyocytes than common lymphoid progenitors (12.8+/-10.7 vs 0.67+/-1.00 GFP(+) cardiomyocytes per a recipient, P = 0.0021). In CFP recipients, all GFP(+) cardiomyocytes examined coexpressed CFP. Human troponin C and myosin heavy chain 6 transcripts were detected in the cardiac tissue of some of the xenogeneic recipients. CONCLUSIONS/SIGNIFICANCE Our results indicate that HSCs resulted in the generation of cardiomyocytes via myeloid intermediates by fusion-dependent mechanism. The use of myeloid derivatives as donor cells could potentially allow more effective cell-based therapy for cardiac repair.
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Affiliation(s)
- Mitsuhiro Fukata
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka, Japan
- * E-mail: (MF); (FI)
| | - Fumihiko Ishikawa
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka, Japan
- Laboratory for Human Disease Models, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan
- * E-mail: (MF); (FI)
| | - Yuho Najima
- Laboratory for Human Disease Models, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan
| | - Takuji Yamauchi
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka, Japan
| | - Yoriko Saito
- Laboratory for Human Disease Models, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan
| | - Katsuto Takenaka
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka, Japan
| | - Kohta Miyawaki
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka, Japan
| | - Hideki Shimazu
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka, Japan
| | - Kazuya Shimoda
- Department of Gastroenterology and Hematology, Faculty of Medicine, Miyazaki University, Miyazaki, Japan
| | | | - Kei-ichiro Nakamura
- Second Department of Anatomy, Kurume University School of Medicine, Kurume, Japan
| | - Keita Odashiro
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka, Japan
| | - Koji Nagafuji
- Division of Hematology and Oncology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Mine Harada
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka, Japan
| | - Koichi Akashi
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka, Japan
- Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan
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Mukhopadhyay A. Perspective on liver regeneration by bone marrow-derived stem cells-a scientific realization or a paradox. Cytotherapy 2013; 15:881-92. [PMID: 23623692 DOI: 10.1016/j.jcyt.2013.02.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2012] [Revised: 12/27/2012] [Accepted: 02/09/2013] [Indexed: 12/11/2022]
Abstract
Bone marrow (BM)-derived stem cells are reported to have cellular plasticity, which provoked many investigators to use of these cells in the regeneration of nonhematopoietic tissues. However, adult stem cell plasticity contradicts our classic understanding on progressive restriction of the developmental potential of a cell type. Many alternate mechanisms have been proposed to explain this phenomenon; the working hypotheses for elucidating the cellular plasticity of BM-derived stem cells are on the basis of direct differentiation and/or fusion between donor and recipient cells. This review dissects the different outcomes of the investigations on liver regeneration, which were performed with the use of BM-derived stem cells in experimental animals, and reveals some critical factors to explain cellular plasticity. It has been hypothesized that the competent BM-derived stem/progenitor cells, under the influence of liver-regenerating cues, can directly differentiate into hepatic cells. This differentiation takes place as a result of genetic reprogramming, which may be possible in the chemically induced acute liver injury model or at the stage of fetal liver development. Cellular plasticity emerges as an important phenomenon in cell-based therapies for the treatment of many liver diseases in which tissue regeneration is necessary.
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Affiliation(s)
- Asok Mukhopadhyay
- Stem Cell Biology & Center for Molecular Medicine, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India.
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Abstract
Metastasis involves the spread of cancer cells from the primary tumor to surrounding tissues and to distant organs and is the primary cause of cancer morbidity and mortality. In order to complete the metastatic cascade, cancer cells must detach from the primary tumor, intravasate into the circulatory and lymphatic systems, evade immune attack, extravasate at distant capillary beds, and invade and proliferate in distant organs. Currently, several hypotheses have been advanced to explain the origin of cancer metastasis. These involve an epithelial mesenchymal transition, an accumulation of mutations in stem cells, a macrophage facilitation process, and a macrophage origin involving either transformation or fusion hybridization with neoplastic cells. Many of the properties of metastatic cancer cells are also seen in normal macrophages. A macrophage origin of metastasis can also explain the long-standing "seed and soil" hypothesis and the absence of metastasis in plant cancers. The view of metastasis as a macrophage metabolic disease can provide novel insight for therapeutic management.
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Affiliation(s)
- Thomas N Seyfried
- Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA.
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Abstract
The liver has an enormous potential to restore the parenchymal tissue loss due to injury. This is accomplished by the proliferation of either the hepatocytes or liver progenitor cells in cases where massive damage prohibits hepatocytes from entering the proliferative response. Under debate is still whether hepatic stem cells are involved in liver tissue maintenance and regeneration or even whether they exist at all. The definition of an adult tissue-resident stem cell comprises basic functional stem cell criteria like the potential of self-renewal, multipotent, i.e. at least bipotent differentiation capacity and serial transplantability featuring the ability of functional tissue repopulation. The relationship between a progenitor and its progeny should exemplify the lineage commitment from the putative stem cell to the differentiated cell. This is mainly assessed by lineage tracing and immunohistochemical identification of markers specific to progenitors and their descendants. Flow cytometry approaches revealed that the liver stem cell population in animals is likely to be heterogeneous giving rise to progeny with different molecular signatures, depending on the stimulus to activate the putative stem cell compartment. The stem cell criteria are met by a variety of cells identified in the fetal and adult liver both under normal and injury conditions. It is the purpose of this review to verify hepatic stem cell candidates in the light of the stem cell definition criteria mentioned. Also from this point of view adult stem cells from non-hepatic tissues such as bone marrow, umbilical cord blood or adipose tissue, have the potential to differentiate into cells featuring functional hepatocyte characteristics. This has great impact because it opens the possibility of generating hepatocyte-like cells from adult stem cells in a sufficient amount and quality for their therapeutical application to treat end-stage liver diseases by stem cell-based hepatocytes in place of whole organ transplantation.
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Affiliation(s)
- Bruno Christ
- Translational Centre for Regenerative Medicine-TRM, University of Leipzig, Philipp-Rosenthal-Straße 55, D-04103 Leipzig, Germany.
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Bone marrow-derived cells contribute to NDEA-induced lung squamous cell carcinoma. Tumour Biol 2012; 34:145-54. [PMID: 23055190 DOI: 10.1007/s13277-012-0522-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2012] [Accepted: 09/09/2012] [Indexed: 01/09/2023] Open
Abstract
Bone marrow-derived stem cells (BMDCs) have the ability to differentiate into lung epithelial cells in response to damage; however, their role in squamous cell carcinoma (SCC) formation is unknown. This study aimed to determine whether BMDC-derived lung epithelial cells could contribute to SCC formation. A model of lung SCC induced with N-nitrosodiethylamine (NDEA) in recipient female mice transplanted with green fluorescent protein (GFP)-positive BMDCs from male donors was established. Incorporation of BMDCs in lung tissue was determined using immunohistochemistry and immunofluorescence to detect GFP expression and fluorescence in situ hybridization to Y chromosomes. BMDC appeared at three stages of lung SCC progression: metaplasia, dysplasia, and carcinoma. There was a significantly higher proportion of GFP-positive (GFP(+)) cells within SCC than was found in metaplasia and dysplasia 16 weeks post-transplantation (both P < 0.017); GFP(+) BMDCs were also observed in clusters within several SCC nests. Furthermore, most GFP(+) cells in SCC were pancytokeratin-positive (PCK(+)) epithelial cells, and some exhibited proliferative activity as determined by Ki67 staining (9.7 ± 3.92 %). The presence of GFP(+)Ki67(+)PCK(+) cells within SCC nests suggested that some donor BMDCs differentiated into proliferating epithelial cells. Finally, analysis of p63 expression, a marker of SCC cells, indicated that the presence of GFP(+)p63(+) cells (green) in inner parts of the SCC. These findings strongly suggest that BMDC-derived lung epithelial cells could participate in lung SCC formation and partially contribute to tumor growth, which might have significant potential implications for both clinical cancer therapy using BMDCs.
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Petrakova OS, Chernioglo ES, Terskikh VV, Kalistratova EN, Vasiliev AV. The use of cellular technologies in treatment of liver pathologies. Acta Naturae 2012; 4:16-30. [PMID: 23150801 PMCID: PMC3491890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Cell techniques find increasing application in modern clinical practice. The II and III phases of clinical trials are already under way for various cellular products used for the restoration of the functions of the cornea, larynx, skin, etc. However, the obtainment of functional cell types specific to different organs and tissues still remains a subject of laboratory research. Liver is one of the most important organs; the problems and prospects of cellular therapy for liver pathologies are currently being actively studied. Cellular therapy of liver pathologies is a complex multistage process requiring a thorough understanding of the molecular mechanisms occurring in liver cells during differentiation and regeneration. An analysis of the current cellular therapy for liver pathologies is presented, the use of various cell types is described, the main molecular mechanisms of hepatocyte differentiation are analyzed, and the challenges and prospects of cell therapy for liver disorders are discussed in this review.
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Affiliation(s)
- O S Petrakova
- Koltzov Institute of Developmental Biology, Russian Academy of Sciences, Vavilova Str., 26, Moscow, Russia, 119334
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Christ B, Stock P. Mesenchymal stem cell-derived hepatocytes for functional liver replacement. Front Immunol 2012; 3:168. [PMID: 22737154 PMCID: PMC3381218 DOI: 10.3389/fimmu.2012.00168] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2012] [Accepted: 06/04/2012] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stem cells represent an alternate cell source to substitute for primary hepatocytes in hepatocyte transplantation because of their multiple differentiation potential and nearly unlimited availability. They may differentiate into hepatocyte-like cells in vitro and maintain specific hepatocyte functions also after transplantation into the regenerating livers of mice or rats both under injury and non-injury conditions. Depending on the underlying liver disease their mode of action is either to replace the diseased liver tissue or to support liver regeneration through their anti-inflammatory and anti-apoptotic as well as their pro-proliferative action.
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Affiliation(s)
- Bruno Christ
- Applied Molecular Hepatology Laboratory, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig Leipzig, Germany
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Kassmer SH, Bruscia EM, Zhang PX, Krause DS. Nonhematopoietic cells are the primary source of bone marrow-derived lung epithelial cells. Stem Cells 2012; 30:491-9. [PMID: 22162244 DOI: 10.1002/stem.1003] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Previous studies have demonstrated that bone marrow (BM)-derived cells differentiate into nonhematopoietic cells of multiple tissues. To date, it remains unknown which population(s) of BM cells are primarily responsible for this engraftment. To test the hypothesis that nonhematopoietic stem cells in the BM are the primary source of marrow-derived lung epithelial cells, either wild-type hematopoietic or nonhematopoietic BM cells were transplanted into irradiated surfactant-protein-C (SPC)-null mice. Donor-derived, SPC-positive type 2 pneumocytes were predominantly detected in the lungs of mice receiving purified nonhematopoietic cells and were absent from mice receiving purified hematopoietic stem and progenitor cells. We conclude that cells contained in the nonhematopoietic fraction of the BM are the primary source of marrow-derived lung epithelial cells. These nonhematopoietic cells may represent a primitive stem cell population residing in adult BM.
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Affiliation(s)
- Susannah H Kassmer
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520-8035, USA.
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Shablii VA, Lukash LL, Lobintseva GS. The role of some donor-host cell interactions under a microenvironmental influence during regeneration processes. CYTOL GENET+ 2012. [DOI: 10.3103/s0095452712030097] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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Christ B, Brückner S. Rodent animal models for surrogate analysis of cell therapy in acute liver failure. Front Physiol 2012; 3:78. [PMID: 22485094 PMCID: PMC3317270 DOI: 10.3389/fphys.2012.00078] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2012] [Accepted: 03/16/2012] [Indexed: 12/27/2022] Open
Abstract
Without therapeutic intervention acute liver failure (ALF) is the consequence of a progredient destruction of the liver parenchyma due to metabolic exhaustion of the hepatocytes. Perivenous hepatocytes are responsible for the detoxification of noxious compounds via the cytochrome P450 enzyme system. Liver transplantation is the only remaining therapeutic option in the end-stage of the disease. Assuming that metabolic capacity could be provided by healthy hepatocytes and thus substitute for the genuine parenchymal cells hepatocyte transplantation since quite some time is considered to be an alternative to whole liver transplantation. While this hypothesis achieved proof-of-concept in animal trials clinical breakthrough is still awaiting success, the reasons of which are ongoing matter of debate. In recent times mesenchymal stem cells (MSC) came into focus as a transplantable cell source to treat ALF. Interestingly, as demonstrated in various rodent animal models their mode of action is rather based on trophic support of hepatocytes remaining in the damaged host parenchyma rather than substitution of tissue loss. Mechanistically, either direct or indirect paracrine effects from the transplanted cells acting pro-proliferative, anti-apoptotic, and anti-inflammatory seem to trigger the regenerative response of the residual healthy hepatocytes in the otherwise lethally injured liver parenchyma. Thus, allogeneic MSC may be the best choice for the treatment of ALF taking advantage of their short-term benefit to sustain the critical phase of the acute insult avoiding long-term immunosuppression.
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Affiliation(s)
- Bruno Christ
- Applied Molecular Hepatology Laboratory, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig Leipzig, Germany
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Liu GM, Zhou C, Xie C, Yang Z, Lv NH. Recent advances in research of gastric cancer stem cells. Shijie Huaren Xiaohua Zazhi 2012; 20:574-579. [DOI: 10.11569/wcjd.v20.i7.574] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is a common malignancy of the digestive tract that has a high mortality and seriously affects people's health. At present, the pathogenesis of gastric cancer is still unclear. According to the cancer stem cell theory, cancer stem cells are malignant cells with the characteristics of normal stem cells, probably formed by the mutation of normal stem cells. Tumor stem cells have been identified in a variety of solid tumors. Recent studies have shown that the location of gastric cancer is consistent with the settlement area of stem cells, indicating that gastric cancer may be a kind of stem cells disease. In this article we will review the existence, origin, identification and separation of cancer stem cells.
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Yamashita T, Fujimiya M, Nagaishi K, Ataka K, Tanaka M, Yoshida H, Tsuchihashi K, Shimamoto K, Miura T. Fusion of bone marrow-derived cells with renal tubules contributes to renal dysfunction in diabetic nephropathy. FASEB J 2011; 26:1559-68. [PMID: 22198389 DOI: 10.1096/fj.11-183194] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Although diabetic nephropathy (DN) is a major cause of end-stage renal disease, the mechanism of dysfunction has not yet been clarified. We previously reported that in diabetes proinsulin-producing bone marrow-derived cells (BMDCs) fuse with hepatocytes and neurons. Fusion cells are polyploidy and produce tumor necrosis factor (TNF)-α, ultimately causing diabetic complications. In this study, we assessed whether the same mechanism is involved in DN. We performed bone marrow transplantation from male GFP-Tg mice to female C57BL/6J mice and produced diabetes by streptozotocin (STZ) or a high-fat diet. In diabetic kidneys, massive infiltration of BMDCs and tubulointerstitial injury were prominent. BMDCs and damaged tubular epithelial cells were positively stained with proinsulin and TNF-α. Cell fusion between BMDCs and renal tubules was confirmed by the presence of Y chromosome. Of tubular epithelial cells, 15.4% contain Y chromosomes in STZ-diabetic mice, 8.6% in HFD-diabetic mice, but only 1.5% in nondiabetic mice. Fusion cells primarily expressed TNF-α and caspase-3 in diabetic kidney. These in vivo findings were confirmed by in vitro coculture experiments between isolated renal tubular cells and BMDCs. It was concluded that cell fusion between BMDCs and renal tubular epithelial cells plays a crucial role in DN.
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Affiliation(s)
- Tomohisa Yamashita
- Second Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan
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