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Bakhshandeh B, Ranjbar N, Abbasi A, Amiri E, Abedi A, Mehrabi M, Dehghani Z, Pennisi CP. Recent progress in the manipulation of biochemical and biophysical cues for engineering functional tissues. Bioeng Transl Med 2023; 8:e10383. [PMID: 36925674 PMCID: PMC10013802 DOI: 10.1002/btm2.10383] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 06/28/2022] [Accepted: 07/16/2022] [Indexed: 11/11/2022] Open
Abstract
Tissue engineering (TE) is currently considered a cutting-edge discipline that offers the potential for developing treatments for health conditions that negatively affect the quality of life. This interdisciplinary field typically involves the combination of cells, scaffolds, and appropriate induction factors for the regeneration and repair of damaged tissue. Cell fate decisions, such as survival, proliferation, or differentiation, critically depend on various biochemical and biophysical factors provided by the extracellular environment during developmental, physiological, and pathological processes. Therefore, understanding the mechanisms of action of these factors is critical to accurately mimic the complex architecture of the extracellular environment of living tissues and improve the efficiency of TE approaches. In this review, we recapitulate the effects that biochemical and biophysical induction factors have on various aspects of cell fate. While the role of biochemical factors, such as growth factors, small molecules, extracellular matrix (ECM) components, and cytokines, has been extensively studied in the context of TE applications, it is only recently that we have begun to understand the effects of biophysical signals such as surface topography, mechanical, and electrical signals. These biophysical cues could provide a more robust set of stimuli to manipulate cell signaling pathways during the formation of the engineered tissue. Furthermore, the simultaneous application of different types of signals appears to elicit synergistic responses that are likely to improve functional outcomes, which could help translate results into successful clinical therapies in the future.
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Affiliation(s)
- Behnaz Bakhshandeh
- Department of Biotechnology, College of ScienceUniversity of TehranTehranIran
| | - Nika Ranjbar
- Department of Biotechnology, College of ScienceUniversity of TehranTehranIran
| | - Ardeshir Abbasi
- Department of Immunology, Faculty of Medical SciencesTarbiat Modares UniversityTehranIran
| | - Elahe Amiri
- Department of Life Science Engineering, Faculty of New Sciences and TechnologyUniversity of TehranTehranIran
| | - Ali Abedi
- Department of Life Science Engineering, Faculty of New Sciences and TechnologyUniversity of TehranTehranIran
| | - Mohammad‐Reza Mehrabi
- Department of Microbial Biotechnology, School of Biology, College of ScienceUniversity of TehranTehranIran
| | - Zahra Dehghani
- Department of Biotechnology, College of ScienceUniversity of TehranTehranIran
| | - Cristian Pablo Pennisi
- Regenerative Medicine Group, Department of Health Science and TechnologyAalborg UniversityAalborgDenmark
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2
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Radaszkiewicz KA, Beckerová D, Woloszczuková L, Radaszkiewicz TW, Lesáková P, Blanářová OV, Kubala L, Humpolíček P, Pachernik J. 12-O-Tetradecanoylphorbol-13-acetate increases cardiomyogenesis through PKC/ERK signaling. Sci Rep 2020; 10:15922. [PMID: 32985604 PMCID: PMC7522207 DOI: 10.1038/s41598-020-73074-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Accepted: 08/31/2020] [Indexed: 12/21/2022] Open
Abstract
12-O-Tetradecanoylphorbol-13-acetate (TPA) is the most widely used diacylglycerol (DAG) mimetic agent and inducer of protein kinase C (PKC)-mediated cellular response in biomedical studies. TPA has been proposed as a pluripotent cell differentiation factor, but results obtained have been inconsistent. In the present study we show that TPA can be applied as a cardiomyogenesis-promoting factor for the differentiation of mouse embryonic stem (mES) cells in vitro. The mechanism of TPA action is mediated by the induction of extracellular signal-regulated kinase (ERK) activity and the subsequent phosphorylation of GATA4 transcription factor. Interestingly, general mitogens (FGF, EGF, VEGF and serum) or canonical WNT signalling did not mimic the effect of TPA. Moreover, on the basis of our results, we postulate that a TPA-sensitive population of cardiac progenitor cells exists at a certain time point (after days 6–8 of the differentiation protocol) and that the proposed treatment can be used to increase the multiplication of ES cell-derived cardiomyocytes.
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Affiliation(s)
| | - Deborah Beckerová
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Lucie Woloszczuková
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
| | | | - Petra Lesáková
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Olga Vondálová Blanářová
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Lukáš Kubala
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.,Department of Free Radical Pathophysiology, Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic
| | - Petr Humpolíček
- Centre of Polymer Systems and Faculty of Technology, Tomas Bata University in Zlin, 760 01, Zlin, Czech Republic
| | - Jiří Pachernik
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
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Nemade H, Acharya A, Chaudhari U, Nembo E, Nguemo F, Riet N, Abken H, Hescheler J, Papadopoulos S, Sachinidis A. Cyclooxygenases Inhibitors Efficiently Induce Cardiomyogenesis in Human Pluripotent Stem Cells. Cells 2020; 9:cells9030554. [PMID: 32120775 PMCID: PMC7140528 DOI: 10.3390/cells9030554] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 01/28/2020] [Accepted: 02/26/2020] [Indexed: 12/12/2022] Open
Abstract
Application of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is limited by the challenges in their efficient differentiation. Recently, the Wingless (Wnt) signaling pathway has emerged as the key regulator of cardiomyogenesis. In this study, we evaluated the effects of cyclooxygenase inhibitors on cardiac differentiation of hPSCs. Cardiac differentiation was performed by adherent monolayer based method using 4 hPSC lines (HES3, H9, IMR90, and ES4SKIN). The efficiency of cardiac differentiation was evaluated by flow cytometry and RT-qPCR. Generated hPSC-CMs were characterised using immunocytochemistry, electrophysiology, electron microscopy, and calcium transient measurements. Our data show that the COX inhibitors Sulindac and Diclofenac in combination with CHIR99021 (GSK-3 inhibitor) efficiently induce cardiac differentiation of hPSCs. In addition, inhibition of COX using siRNAs targeted towards COX-1 and/or COX-2 showed that inhibition of COX-2 alone or COX-1 and COX-2 in combination induce cardiomyogenesis in hPSCs within 12 days. Using IMR90-Wnt reporter line, we showed that inhibition of COX-2 led to downregulation of Wnt signalling activity in hPSCs. In conclusion, this study demonstrates that COX inhibition efficiently induced cardiogenesis via modulation of COX and Wnt pathway and the generated cardiomyocytes express cardiac-specific structural markers as well as exhibit typical calcium transients and action potentials. These cardiomyocytes also responded to cardiotoxicants and can be relevant as an in vitro cardiotoxicity screening model.
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Affiliation(s)
- Harshal Nemade
- Institute of Neurophysiology, Faculty of Medicine, University of Cologne, Robert-Koch-Str. 39, 50931 Cologne, Germany; (H.N.); (A.A.); (U.C.); (E.N.); (F.N.); (J.H.); (S.P.)
| | - Aviseka Acharya
- Institute of Neurophysiology, Faculty of Medicine, University of Cologne, Robert-Koch-Str. 39, 50931 Cologne, Germany; (H.N.); (A.A.); (U.C.); (E.N.); (F.N.); (J.H.); (S.P.)
| | - Umesh Chaudhari
- Institute of Neurophysiology, Faculty of Medicine, University of Cologne, Robert-Koch-Str. 39, 50931 Cologne, Germany; (H.N.); (A.A.); (U.C.); (E.N.); (F.N.); (J.H.); (S.P.)
| | - Erastus Nembo
- Institute of Neurophysiology, Faculty of Medicine, University of Cologne, Robert-Koch-Str. 39, 50931 Cologne, Germany; (H.N.); (A.A.); (U.C.); (E.N.); (F.N.); (J.H.); (S.P.)
| | - Filomain Nguemo
- Institute of Neurophysiology, Faculty of Medicine, University of Cologne, Robert-Koch-Str. 39, 50931 Cologne, Germany; (H.N.); (A.A.); (U.C.); (E.N.); (F.N.); (J.H.); (S.P.)
| | - Nicole Riet
- Department I Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of Cologne (UKK), Robert-Koch-Str. 21, 50931 Cologne, Germany;
| | - Hinrich Abken
- Regensburg Centre for Interventional Immunology (RCI), Deptartment Genetic Immunotherapy, University Hospital Regensburg, 93053 Regensburg, Germany;
| | - Jürgen Hescheler
- Institute of Neurophysiology, Faculty of Medicine, University of Cologne, Robert-Koch-Str. 39, 50931 Cologne, Germany; (H.N.); (A.A.); (U.C.); (E.N.); (F.N.); (J.H.); (S.P.)
| | - Symeon Papadopoulos
- Institute of Neurophysiology, Faculty of Medicine, University of Cologne, Robert-Koch-Str. 39, 50931 Cologne, Germany; (H.N.); (A.A.); (U.C.); (E.N.); (F.N.); (J.H.); (S.P.)
| | - Agapios Sachinidis
- Institute of Neurophysiology, Faculty of Medicine, University of Cologne, Robert-Koch-Str. 39, 50931 Cologne, Germany; (H.N.); (A.A.); (U.C.); (E.N.); (F.N.); (J.H.); (S.P.)
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Str. 21, 50931 Cologne, Germany
- Correspondence: ; Tel.: +49-0221-4787373
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Gao L, Dong J, Zhang N, Le Z, Ren W, Li S, Li F, Song J, Wang Q, Dou Z, Park SY, Zhi K. Cyclosporine A Suppresses the Malignant Progression of Oral Squamous Cell Carcinoma in vitro. Anticancer Agents Med Chem 2019; 19:248-255. [PMID: 30378503 DOI: 10.2174/1871520618666181029170605] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2017] [Revised: 02/14/2018] [Accepted: 10/09/2018] [Indexed: 12/15/2022]
Abstract
Background:The Oral Squamous Cell Carcinoma (OSCC) is one of the most frequent cancer types. Failure of treatment of OSCC is potentially lethal because of local recurrence, regional lymph node metastasis, and distant metastasis. Chemotherapy plays a vital role through suppression of tumorigenesis. Cyclosporine A (CsA), an immunosuppressant drug, has been efficiently used in allograft organ transplant recipients to prevent rejection, and also has been used in a subset of patients with autoimmunity related disorders. The present study aims to investigate novel and effective chemotherapeutic drugs to overcome drug-resistance in the treatment of OSCC.Methods:Cells were incubated in the standard way. Cell viability was assayed using the MTT assay. Cell proliferation was determined using colony formation assay. The cell cycle assay was performed using flow cytometry. Apoptosis was assessed using fluorescence-activated cell sorting after stained by the Annexin V-fluorescein isothiocyanate (FITC). Cell migration and invasion were analyzed using wound healing assay and tranwell. The effect of COX-2, c-Myc, MMP-9, MMP-2, and NFATc1 protein expression was determined using Western blot analysis while NFATc1 mRNA expression was determined by RT-PCR.Results:In vitro studies indicated that CsA inhibited partial OSCC growth by inducing cell cycle arrest, apoptosis, and the migration and invasion of OSCC cells. We also demonstrated that CsA could inhibit the expression of NFATc1 and its downstream genes COX-2, c-Myc, MMP-9, and MMP-2 in OSCC cells. Furthermore, we analyzed the expression of NFATc1 in head and neck cancer through the Oncomine database. The data was consistent with the experimental findings.Conclusion:The present study initially demonstrated that CsA could inhibit the progression of OSCC cells and can mediate the signal molecules of NFATc1 signaling pathway, which has strong relationship with cancer development. That explains us CsA has potential to explore the possibilities as a novel chemotherapeutic drug for the treatment of OSCC.
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Affiliation(s)
- Ling Gao
- Key Lab of Oral Clinical Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Jianwei Dong
- Department of Stomatology, Shangluo Central Hospital, Shangluo, Shanxi, China
| | - Nanyang Zhang
- Key Lab of Oral Clinical Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Zhanxian Le
- Fujian Provincial Key Laboratory of Screening for Novel Microbial Products, Fujian Institute of Microbiology, Fuzhou, Fujian, China
| | - Wenhao Ren
- Key Lab of Oral Clinical Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Shaoming Li
- Key Lab of Oral Clinical Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Fan Li
- Key Lab of Oral Clinical Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Jianzhong Song
- Key Lab of Oral Clinical Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Qibo Wang
- Key Lab of Oral Clinical Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Zhichao Dou
- Key Lab of Oral Clinical Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Soo Y. Park
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Keqian Zhi
- Key Lab of Oral Clinical Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
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Acharya A, Brungs S, Lichterfeld Y, Hescheler J, Hemmersbach R, Boeuf H, Sachinidis A. Parabolic, Flight-Induced, Acute Hypergravity and Microgravity Effects on the Beating Rate of Human Cardiomyocytes. Cells 2019; 8:cells8040352. [PMID: 31013958 PMCID: PMC6523861 DOI: 10.3390/cells8040352] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 04/10/2019] [Accepted: 04/12/2019] [Indexed: 12/14/2022] Open
Abstract
Functional studies of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hCMs) under different gravity conditions contribute to aerospace medical research. To study the effects of altered gravity on hCMs, we exposed them to acute hypergravity and microgravity phases in the presence and absence of the β-adrenoceptor isoprenalin (ISO), L-type Ca2+ channel (LTCC) agonist Bay-K8644, or LTCC blocker nifedipine, and monitored their beating rate (BR). These logistically demanding experiments were executed during the 66th Parabolic Flight Campaign of the European Space Agency. The hCM cultures were exposed to 31 alternating hypergravity, microgravity, and hypergravity phases, each lasting 20–22 s. During the parabolic flight experiment, BR and cell viability were monitored using the xCELLigence real-time cell analyzer Cardio Instrument®. Corresponding experiments were performed on the ground (1 g), using an identical set-up. Our results showed that BR continuously increased during the parabolic flight, reaching a 40% maximal increase after 15 parabolas, compared with the pre-parabolic (1 g) phase. However, in the presence of the LTCC blocker nifedipine, no change in BR was observed, even after 31 parabolas. We surmise that the parabola-mediated increase in BR was induced by the LTCC blocker. Moreover, the increase in BR induced by ISO and Bay-K8644 during the pre-parabola phase was further elevated by 20% after 25 parabolas. This additional effect reflects the positive impact of the parabolas in the absence of both agonists. Our study suggests that acute alterations of gravity significantly increase the BR of hCMs via the LTCC.
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Affiliation(s)
- Aviseka Acharya
- Institute of Neurophysiology, Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
| | - Sonja Brungs
- German Aerospace Center, Institute of Aerospace Medicine, Gravitational Biology, Linder Hoehe, 51147 Cologne, Germany.
| | - Yannick Lichterfeld
- German Aerospace Center, Institute of Aerospace Medicine, Gravitational Biology, Linder Hoehe, 51147 Cologne, Germany.
| | - Jürgen Hescheler
- Institute of Neurophysiology, Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
| | - Ruth Hemmersbach
- German Aerospace Center, Institute of Aerospace Medicine, Gravitational Biology, Linder Hoehe, 51147 Cologne, Germany.
| | - Helene Boeuf
- INSERM (French National Institute of Health and Medical Research), U1026-Biotis, Université de Bordeaux, 33076 Bordeaux, France.
| | - Agapios Sachinidis
- Institute of Neurophysiology, Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
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Ashwini A, Naganur SS, Smitha B, Sheshadri P, Prasanna J, Kumar A. Cyclosporine A-Mediated IL-6 Expression Promotes Neural Induction in Pluripotent Stem Cells. Mol Neurobiol 2017. [PMID: 28623616 DOI: 10.1007/s12035-017-0633-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Differentiation of pluripotent stem cells (PSCs) to neural lineages has gathered huge attention in both basic research and regenerative medicine. The major hurdle lies in the efficiency of differentiation and identification of small molecules that facilitate neurogenesis would partly circumvent this limitation. The small molecule Cyclosporine A (CsA), a commonly used immunosuppressive drug, has been shown to enhance in vivo neurogenesis. To extend the information to in vitro neurogenesis, we examined the effect of CsA on neural differentiation of PSCs. We found CsA to increase the expression of neural progenitor genes during early neural differentiation. Gene silencing approach revealed CsA-mediated neural induction to be dependent on blocking the Ca2+-activated phosphatase calcineurin (Cn) signaling. Similar observation with FK506, an independent inhibitor of Cn, further strengthened the necessity of blocking Cn for enhanced neurogenesis. Surprisingly, mechanistic insight revealed Cn-inhibition dependent upregulation of IL-6 protein to be necessary for CsA-mediated neurogenesis. Together, these findings provide a comprehensive understanding of the role of CsA in neurogenesis, thus suggesting a method for obtaining large numbers of neural progenitors from PSCs for possible transplantation.
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Affiliation(s)
- Ashwathnarayan Ashwini
- School of Regenerative Medicine, Manipal University, Allalasandra, GKVK post, Yelahanka, Bangalore, 560065, India
| | - Sushma S Naganur
- School of Regenerative Medicine, Manipal University, Allalasandra, GKVK post, Yelahanka, Bangalore, 560065, India
| | - Bhaskar Smitha
- School of Regenerative Medicine, Manipal University, Allalasandra, GKVK post, Yelahanka, Bangalore, 560065, India
| | - Preethi Sheshadri
- School of Regenerative Medicine, Manipal University, Allalasandra, GKVK post, Yelahanka, Bangalore, 560065, India
| | - Jyothi Prasanna
- School of Regenerative Medicine, Manipal University, Allalasandra, GKVK post, Yelahanka, Bangalore, 560065, India
| | - Anujith Kumar
- School of Regenerative Medicine, Manipal University, Allalasandra, GKVK post, Yelahanka, Bangalore, 560065, India.
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Hübscher D, Kaiser D, Elsner L, Monecke S, Dressel R, Guan K. The Tumorigenicity of Multipotent Adult Germline Stem Cells Transplanted into the Heart Is Affected by Natural Killer Cells and by Cyclosporine A Independent of Its Immunosuppressive Effects. Front Immunol 2017; 8:67. [PMID: 28220117 PMCID: PMC5292627 DOI: 10.3389/fimmu.2017.00067] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Accepted: 01/16/2017] [Indexed: 12/18/2022] Open
Abstract
Transplantation of stem cells represents an upcoming therapy for many degenerative diseases. For clinical use, transplantation of pluripotent stem cell-derived cells should lead to integration of functional grafts without immune rejection or teratoma formation. Our previous studies showed that the risk of teratoma formation is highly influenced by the immune system of the recipients. In this study, we have observed a higher teratoma formation rate when undifferentiated so-called multipotent adult germline stem cells (maGSCs) were transplanted into the heart of T, B, and natural killer (NK) cell-deficient RAG2−/−γc−/− mice than in RAG2−/− mice, which still have NK cells. Notably, in both strains, the teratoma formation rate was significantly reduced by the immunosuppressive drug cyclosporine A (CsA). Thus, CsA had a profound effect on teratoma formation independent of its immunosuppressive effects. The transplantation into RAG2−/− mice led to an activation of NK cells, which reached the maximum 14 days after transplantation and was not affected by CsA. The in vivo-activated NK cells efficiently killed YAC-1 and also maGSC target cells. This NK cell activation was confirmed in C57BL/6 wild-type mice whether treated with CsA or not. Sham operations in wild-type mice indicated that the inflammatory response to open heart surgery rather than the transplantation of maGSCs activated the NK cell system. An activation of NK cells during the transplantation of stem cell-derived in vitro differentiated grafts might be clinically beneficial by reducing the risk of teratoma formation by residual pluripotent cells.
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Affiliation(s)
- Daniela Hübscher
- Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany
| | - Diana Kaiser
- Department of Cardiology and Pneumology, University Medical Center Göttingen , Göttingen , Germany
| | - Leslie Elsner
- Institute of Cellular and Molecular Immunology, University Medical Center Göttingen , Göttingen , Germany
| | - Sebastian Monecke
- DZHK (German Center for Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany; Institute of Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany
| | - Ralf Dressel
- DZHK (German Center for Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany; Institute of Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany
| | - Kaomei Guan
- Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; Institute of Pharmacology and Toxicology, Technische Universität Dresden, Dresden, Germany
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Affiliation(s)
- Dennis Schade
- Department
of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse
6, 44227 Dortmund, Germany
| | - Alleyn T. Plowright
- Department
of Medicinal Chemistry, Cardiovascular and Metabolic Diseases Innovative
Medicines, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden
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9
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Kim WH, Jung DW, Williams DR. Making cardiomyocytes with your chemistry set: Small molecule-induced cardiogenesis in somatic cells. World J Cardiol 2015; 7:125-133. [PMID: 25810812 PMCID: PMC4365307 DOI: 10.4330/wjc.v7.i3.125] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2014] [Revised: 01/05/2015] [Accepted: 01/20/2015] [Indexed: 02/06/2023] Open
Abstract
Cell transplantation is an attractive potential therapy for heart diseases. For example, myocardial infarction (MI) is a leading cause of mortality in many countries. Numerous medical interventions have been developed to stabilize patients with MI and, although this has increased survival rates, there is currently no clinically approved method to reverse the loss of cardiac muscle cells (cardiomyocytes) that accompanies this disease. Cell transplantation has been proposed as a method to replace cardiomyocytes, but a safe and reliable source of cardiogenic cells is required. An ideal source would be the patients’ own somatic tissue cells, which could be converted into cardiogenic cells and transplanted into the site of MI. However, these are difficult to produce in large quantities and standardized protocols to produce cardiac cells would be advantageous for the research community. To achieve these research goals, small molecules represent attractive tools to control cell behavior. In this editorial, we introduce the use of small molecules in stem cell research and summarize their application to the induction of cardiogenesis in non-cardiac cells. Exciting new developments in this field are discussed, which we hope will encourage cardiac stem cell biologists to further consider employing small molecules in their culture protocols.
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10
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Choi SC, Lee H, Choi JH, Kim JH, Park CY, Joo HJ, Park JH, Hong SJ, Yu CW, Lim DS. Cyclosporin A induces cardiac differentiation but inhibits hemato-endothelial differentiation of P19 cells. PLoS One 2015; 10:e0117410. [PMID: 25629977 PMCID: PMC4309530 DOI: 10.1371/journal.pone.0117410] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Accepted: 12/22/2014] [Indexed: 01/11/2023] Open
Abstract
Little is known about the mechanisms underlying the effects of Cyclosporin A (CsA) on the fate of stem cells, including cardiomyogenic differentiation. Therefore, we investigated the effects and the molecular mechanisms behind the actions of CsA on cell lineage determination of P19 cells. CsA induced cardiomyocyte-specific differentiation of P19 cells, with the highest efficiency at a concentration of 0.32 μM during embryoid body (EB) formation via activation of the Wnt signaling pathway molecules, Wnt3a, Wnt5a, and Wnt8a, and the cardiac mesoderm markers, Mixl1, Mesp1, and Mesp2. Interestingly, cotreatment of P19 cells with CsA plus dimethyl sulfoxide (DMSO) during EB formation significantly increases cardiac differentiation. In contrast, mRNA expression levels of hematopoietic and endothelial lineage markers, including Flk1 and Er71, were severely reduced in CsA-treated P19 cells. Furthermore, expression of Flk1 protein and the percentage of Flk1+ cells were severely reduced in 0.32 μM CsA-treated P19 cells compared to control cells. CsA significantly modulated mRNA expression levels of the cell cycle molecules, p53 and Cyclins D1, D2, and E2 in P19 cells during EB formation. Moreover, CsA significantly increased cell death and reduced cell number in P19 cells during EB formation. These results demonstrate that CsA induces cardiac differentiation but inhibits hemato-endothelial differentiation via activation of the Wnt signaling pathway, followed by modulation of cell lineage-determining genes in P19 cells during EB formation.
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Affiliation(s)
- Seung-Cheol Choi
- Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Korea
| | - Hyunjoo Lee
- Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Korea
| | - Ji-Hyun Choi
- Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Korea
| | - Jong-Ho Kim
- Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Korea
| | - Chi-Yeon Park
- Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Korea
| | - Hyung-Joon Joo
- Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Korea
| | - Jae-Hyoung Park
- Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Korea
| | - Soon-Jun Hong
- Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Korea
| | - Cheol-Woong Yu
- Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Korea
| | - Do-Sun Lim
- Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Korea
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Meganathan K, Sotiriadou I, Natarajan K, Hescheler J, Sachinidis A. Signaling molecules, transcription growth factors and other regulators revealed from in-vivo and in-vitro models for the regulation of cardiac development. Int J Cardiol 2015; 183:117-28. [PMID: 25662074 DOI: 10.1016/j.ijcard.2015.01.049] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 11/19/2014] [Accepted: 01/25/2015] [Indexed: 02/08/2023]
Abstract
Several in-vivo heart developmental models have been applied to decipher the cardiac developmental patterning encompassing early, dorsal, cardiac and visceral mesoderm as well as various transcription factors such as Gata, Hand, Tin, Dpp, Pnr. The expression of cardiac specific transcription factors, such as Gata4, Tbx5, Tbx20, Tbx2, Tbx3, Mef2c, Hey1 and Hand1 are of fundamental significance for the in-vivo cardiac development. Not only the transcription factors, but also the signaling molecules involved in cardiac development were conserved among various species. Enrichment of the bone morphogenic proteins (BMPs) in the anterior lateral plate mesoderm is essential for the initiation of myocardial differentiation and the cardiac developmental process. Moreover, the expression of a number of cardiac transcription factors and structural genes initiate cardiac differentiation in the medial mesoderm. Other signaling molecules such as TGF-beta, IGF-1/2 and the fibroblast growth factor (FGF) play a significant role in cardiac repair/regeneration, ventricular heart development and specification of early cardiac mesoderm, respectively. The role of the Wnt signaling in cardiac development is still controversial discussed, as in-vitro results differ dramatically in relation to the animal models. Embryonic stem cells (ESC) were utilized as an important in-vitro model for the elucidation of the cardiac developmental processes since they can be easily manipulated by numerous signaling molecules, growth factors, small molecules and genetic manipulation. Finally, in the present review the dynamic role of the long noncoding RNA and miRNAs in the regulation of cardiac development are summarized and discussed.
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Affiliation(s)
- Kesavan Meganathan
- Center of Physiology and Pathophysiology, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany
| | - Isaia Sotiriadou
- Center of Physiology and Pathophysiology, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany
| | - Karthick Natarajan
- Center of Physiology and Pathophysiology, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany
| | - Jürgen Hescheler
- Center of Physiology and Pathophysiology, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany
| | - Agapios Sachinidis
- Center of Physiology and Pathophysiology, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany.
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12
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Davies SG, Kennewell PD, Russell AJ, Seden PT, Westwood R, Wynne GM. Stemistry: the control of stem cells in situ using chemistry. J Med Chem 2015; 58:2863-94. [PMID: 25590360 DOI: 10.1021/jm500838d] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
A new paradigm for drug research has emerged, namely the deliberate search for molecules able to selectively affect the proliferation, differentiation, and migration of adult stem cells within the tissues in which they exist. Recently, there has been significant interest in medicinal chemistry toward the discovery and design of low molecular weight molecules that affect stem cells and thus have novel therapeutic activity. We believe that a successful agent from such a discover program would have profound effects on the treatment of many long-term degenerative disorders. Among these conditions are examples such as cardiovascular decay, neurological disorders including Alzheimer's disease, and macular degeneration, all of which have significant unmet medical needs. This perspective will review evidence from the literature that indicates that discovery of such agents is achievable and represents a worthwhile pursuit for the skills of the medicinal chemist.
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Affiliation(s)
- Stephen G Davies
- †Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, U.K
| | - Peter D Kennewell
- †Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, U.K
| | - Angela J Russell
- †Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, U.K.,‡Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, U.K
| | - Peter T Seden
- †Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, U.K
| | - Robert Westwood
- †Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, U.K
| | - Graham M Wynne
- †Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, U.K
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13
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Cyclosporin in cell therapy for cardiac regeneration. J Cardiovasc Transl Res 2014; 7:475-82. [PMID: 24831573 DOI: 10.1007/s12265-014-9570-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Accepted: 04/21/2014] [Indexed: 12/19/2022]
Abstract
Stem cell therapy is a promising strategy in promoting cardiac repair in the setting of ischemic heart disease. Clinical and preclinical studies have shown that cell therapy improves cardiac function. Whether autologous or allogeneic cells should be used, and the need for immunosuppression in non-autologous settings, is a matter of debate. Cyclosporin A (CsA) is frequently used in preclinical trials to reduce cell rejection after non-autologous cell therapy. The direct effect of CsA on the function and survival of stem cells is unclear. Furthermore, the appropriate daily dosage of CsA in animal models has not been established. In this review, we discuss the pros and cons of the use of CsA on an array of stem cells both in vitro and in vivo. Furthermore, we present a small collection of data put forth by our group supporting the efficacy and safety of a specific daily CsA dosage in a pig model.
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14
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Xie M, Cao N, Ding S. Small molecules for cell reprogramming and heart repair: progress and perspective. ACS Chem Biol 2014; 9:34-44. [PMID: 24372513 DOI: 10.1021/cb400865w] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Regenerative medicine for heart failure seeks to replace lost cardiomyocytes. Chemical approaches for producing ample supplies of cells, such as pluripotent stem cells and cardiomyocytes, hold promise as practical means to achieve safe, facile cell-based therapy for cardiac repair and regenerative medicine. In this review, we describe recent advances in the application of small molecules to improve the generation and maintenance of pluripotent stem cells. We also describe new directions in heart repair and regeneration in which chemical approaches may find their application.
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Affiliation(s)
- Min Xie
- The Gladstone Institutes, 1650 Owens Street, San Francisco, California 94158, United States
| | - Nan Cao
- The Gladstone Institutes, 1650 Owens Street, San Francisco, California 94158, United States
| | - Sheng Ding
- The Gladstone Institutes, 1650 Owens Street, San Francisco, California 94158, United States
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15
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Parameswaran S, Kumar S, Verma RS, Sharma RK. Cardiomyocyte culture - an update on the in vitro cardiovascular model and future challenges. Can J Physiol Pharmacol 2013; 91:985-98. [PMID: 24289068 DOI: 10.1139/cjpp-2013-0161] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The success of any work with isolated cardiomyocytes depends on the reproducibility of cell isolation, because the cells do not divide. To date, there is no suitable in vitro model to study human adult cardiac cell biology. Although embryonic stem cells and induced pluripotent stem cells are able to differentiate into cardiomyocytes in vitro, the efficiency of this process is low. Isolation and expansion of human cardiomyocyte progenitor cells from cardiac surgical waste or, alternatively, from fetal heart tissue is another option. However, to overcome various issues related to human tissue usage, especially ethical concerns, researchers use large- and small-animal models to study cardiac pathophysiology. A simple model to study the changes at the cellular level is cultures of cardiomyocytes. Although primary murine cardiomyocyte cultures have their own advantages and drawbacks, alternative strategies have been developed in the last two decades to minimise animal usage and interspecies differences. This review discusses the use of freshly isolated murine cardiomyocytes and cardiomyocyte alternatives for use in cardiac disease models and other related studies.
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Affiliation(s)
- Sreejit Parameswaran
- a Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 0W8, Canada
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16
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Oh SW, Kim B, Jeon S, Go DM, Kim MK, Baek K, Oh GT, Kim DY. Identification and characterization of CW108F, a novel β-carboline compound that promotes cardiomyogenesis of stem cells. Life Sci 2013; 93:409-15. [PMID: 23892198 DOI: 10.1016/j.lfs.2013.07.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Revised: 06/27/2013] [Accepted: 07/10/2013] [Indexed: 11/16/2022]
Abstract
AIMS The aim of this study was to identify new compounds that induce cardiomyocyte differentiation of stem cells through cell-based screening and investigate lineage specificity and mechanisms in vitro. MAIN METHODS Embryoid bodies (EBs) formed from TC-1/KH2 mouse embryonic stem cells (ESCs) carrying the gene for enhanced green fluorescent protein (EGFP) under the control of the α-myosin heavy chain (MHC) promoter were treated with test compounds. The number of cardiomyocyte-like (EGFP-expressing) cells in EBs was determined by fluorescence-activated cell sorting. Cardiomyocyte differentiation was further confirmed using lineage-specific biochemical assays and by investigating the expression of cardiomyocyte-specific and "stemness"-associated genes. Nuclear factor-kappaB (NF-κB) signaling activity was measured in A549 cells using a reporter-gene assay. KEY FINDINGS A β-carboline compound, designated CW108F, increased the number of mouse ESCs expressing α-MHC promoter-driven EGFP and the proportion of beating EBs. CW108F also increased expression of MHC in P19 stem cells, but did not induce osteogenesis of MC3T3-E1 cells, suggesting lineage-specific activity toward cardiomyocytes. CW108F upregulated expression of cardiac-specific GATA-4 and atrial natriuretic factor (ANF) genes in TC-1/KH2 cells, but downregulated expression of the stemness genes, Oct-4 and brachyury. CW108F inhibited NF-κB transcriptional activity, an effect that might contribute to its cardiomyogenesis-promoting activity. SIGNIFICANCE The results of this study suggest that the novel β-carboline, CW108F, promotes the differentiation of ESCs into cardiomyocytes and may be useful for investigating molecular pathways of cardiomyogenesis and generating cardiomyocytes from ESCs.
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Affiliation(s)
- Se-Woong Oh
- Central Research Institute, JW Pharmaceutical Corporation, Hwaseong-City, Gyeonggi-Do 445-380, Republic of Korea
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17
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Lairson LL, Lyssiotis CA, Zhu S, Schultz PG. Small molecule-based approaches to adult stem cell therapies. Annu Rev Pharmacol Toxicol 2013; 53:107-25. [PMID: 23294307 DOI: 10.1146/annurev-pharmtox-011112-140300] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
There is considerable interest in the development of stem cell-based strategies for the treatment of a broad range of human diseases, including neurodegenerative, autoimmune, cardiovascular, and musculoskeletal diseases. To date, such regenerative approaches have focused largely on the development of cell transplantation therapies using cells derived from pluripotent embryonic stem cells (ESCs). Although there have been exciting preliminary reports describing the efficacy of ESC-derived replacement therapies, approaches involving ex vivo manipulated ESCs are hindered by issues of mutation, immune rejection, and ethical controversy. An alternative approach involves direct in vivo modulation or ex vivo expansion of endogenous adult stem cell populations using drug-like small molecules. Here we describe chemical approaches to the regulation of somatic stem cell biology that are yielding new biological insights and that may ultimately lead to innovative new medicines.
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Affiliation(s)
- Luke L Lairson
- Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
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18
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Kawaguchi N, Nakanishi T. Cardiomyocyte regeneration. Cells 2013; 2:67-82. [PMID: 24709645 PMCID: PMC3972659 DOI: 10.3390/cells2010067] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2012] [Revised: 12/25/2012] [Accepted: 01/05/2013] [Indexed: 01/14/2023] Open
Abstract
The heart was initially believed to be a terminally differentiated organ; once the cardiomyocytes died, no recovery could be made to replace the dead cells. However, around a decade ago, the concept of cardiac stem cells (CSCs) in adult hearts was proposed. CSCs differentiate into cardiomyocytes, keeping the heart functioning. Studies have proved the existence of stem cells in the heart. These somatic stem cells have been studied for use in cardiac regeneration. Moreover, recently, induced pluripotent stem cells (iPSCs) were invented, and methodologies have now been developed to induce stable cardiomyocyte differentiation and purification of mature cardiomyocytes. A reprogramming method has also been applied to direct reprogramming using cardiac fibroblasts into cardiomyocytes. Here, we address cardiomyocyte differentiation of CSCs and iPSCs. Furthermore, we describe the potential of CSCs in regenerative biology and regenerative medicine.
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Affiliation(s)
- Nanako Kawaguchi
- Department of Pediatric Cardiology, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
| | - Toshio Nakanishi
- Department of Pediatric Cardiology, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
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19
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Otaka S, Nagura S, Koike C, Okabe M, Yoshida T, Fathy M, Yanagi K, Misaki T, Nikaido T. Selective isolation of nanog-positive human amniotic mesenchymal cells and differentiation into cardiomyocytes. Cell Reprogram 2013; 15:80-91. [PMID: 23298400 DOI: 10.1089/cell.2012.0028] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Adult cardiomyocytes have little ability to regenerate, thus cardiac regeneration therapy represents a potential method for treating severe heart failure. Human amniotic mesenchymal cells (hAMCs) have the potential to be a useful cell source for cardiac regeneration therapy. We attempted to isolate stem cells from hAMCs and differentiate them into cardiomyocytes. Nanog promoter-Cre plasmid and cytomegalovirus (CMV) promoter-loxP-STOP-loxP-Red-puro(r) plasmid were co-transfected into immortalized hAMCs (iHAMs). Nanog-positive iHAMs were treated with 5-azacytidine (5-aza), trichostatin A (TA), activin A (AA), and bone morphogenetic protein-4 (BMP-4), or co-cultured with murine fetal cardiomyocytes for cardiomyocytes differentiation. Isolated Nanog-positive iHAMs were analyzed by quantitative RT-PCR and immunofluorescent staining before and after differentiation. Expression of Nanog, Oct3/4, Sox2, and Klf4 was significantly higher in Nanog-positive than in Nanog-negative iHAMs. Nanog-positive iHAMs were stained for Nanog and Oct3/4 in the nucleus. Nanog-positive iHAMs treated with 5-aza expressed Nkx2.5, GATA-4, human atrial natriuretic peptide (hANP), cardiac troponin T (cTnT), myocin light chain (Mlc)-2a, Mlc-2v, β-myosin heavy chain (β-MHC), hyperpolarization-activated cyclic nucleotide gated channels (HCN)-4, and inwardly rectifying potassium channels (Kir)-2.1. Although Nanog-positive iHAMs treated with TA, AA, or BMP-4 expressed several cardiac markers, no contraction was observed. Co-cultured Nanog-positive iHAMs with murine fetal cardiomyocytes spontaneously contracted in a synchronized manner and expressed the cardiac markers. In conclusion, Nanog-positive hAMCs with characteristics of stem cells were isolated and differentiated into cardiomyocyte-like cells, suggesting that these isolated hAMCs could be a useful cell source for cardiac regeneration therapy.
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Affiliation(s)
- Shingo Otaka
- Department of Regenerative Medicine, University of Toyama, Japan
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20
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Nguemo F, Fleischmann BK, Gupta MK, Šarić T, Malan D, Liang H, Pfannkuche K, Bloch W, Schunkert H, Hescheler J, Reppel M. The L-type Ca2+ channels blocker nifedipine represses mesodermal fate determination in murine embryonic stem cells. PLoS One 2013; 8:e53407. [PMID: 23320083 PMCID: PMC3539992 DOI: 10.1371/journal.pone.0053407] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2012] [Accepted: 11/28/2012] [Indexed: 01/20/2023] Open
Abstract
Dihydropyridines (DHP), which nifedipine is a member of, preferentially block Ca(2+) channels of different cell types. Moreover, influx of Ca(2+) through L-type Ca(2+) channels (LTCCs) activates Ca(2+) signaling pathways, which in turn contribute to numerous cellular processes. Although LTCCs are expressed in undifferentiated cells, very little is known about its contributions to the transcriptional regulation of mesodermal and cardiac genes. This study aimed to examine the contribution of LTCCs and the effect of nifedipine on the commitment of pluripotent stem cells toward the cardiac lineage in vitro. The murine embryonic stem (ES, cell line D3) and induced pluripotent stem (iPS, cell clone 09) cells were differentiated into enhanced green fluorescence protein (EGFP) expressing spontaneously beating cardiomyocytes (CMs). Early treatment of differentiating cells with 10 µM nifedipine led to a significant inhibition of the cardiac mesoderm formation and cardiac lineage commitment as revealed by gene regulation analysis. This was accompanied by the inhibition of spontaneously occurring Ca(2+) transient and reduction of LTCCs current density (I(CaL)) of differentiated CMs. In addition, nifedipine treatment instigated a pronounced delay of the spontaneous beating embryoid body (EB) and led to a poor surface localization of L-type Ca(2+) channel α(1C) (Ca(V)1.2) subunits. Contrary late incubation of pluripotent stem cells with nifedipine was without any impact on the differentiation process and did not affect the derived CMs function. Our data indicate that nifedipine blocks the determined path of pluripotent stem cells to cardiomyogenesis by inhibition of mesodermal commitment at early stages of differentiation, thus the proper upkeep Ca(2+) concentration and pathways are essentially required for cardiac gene expression, differentiation and function.
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Affiliation(s)
- Filomain Nguemo
- Institute of Neurophysiology, University of Cologne, Cologne, Germany
| | - Bernd K. Fleischmann
- Institute of Physiology I, Life and Brain Center, University of Bonn, Bonn, Germany
| | - Manoj K. Gupta
- Institute of Neurophysiology, University of Cologne, Cologne, Germany
| | - Tomo Šarić
- Institute of Neurophysiology, University of Cologne, Cologne, Germany
| | - Daniela Malan
- Institute of Physiology I, Life and Brain Center, University of Bonn, Bonn, Germany
| | - Huamin Liang
- Department of Physiology, Huazhong University of Science and Technology, Tongji Medical College, Wuhan, China
| | - Kurt Pfannkuche
- Institute of Neurophysiology, University of Cologne, Cologne, Germany
| | - Wilhelm Bloch
- Department of Molecular and Cellular Sport Medicine, German Sport University, Cologne, Germany
| | | | - Jürgen Hescheler
- Institute of Neurophysiology, University of Cologne, Cologne, Germany
| | - Michael Reppel
- Institute of Neurophysiology, University of Cologne, Cologne, Germany
- Department of Cardiology, Medical University of Lübeck, Lübeck, Germany
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Abstract
Regenerative medicine seeks to understand tissue development and homeostasis and build on that knowledge to enhance regeneration of injured tissues. By replenishing lost functional tissues and cells, regenerative medicine could change the treatment paradigm for a broad range of degenerative and ischemic diseases. Multipotent cells hold promise as potential building blocks for regenerating lost tissues, but successful tissue regeneration will depend on comprehensive control of multipotent cells-differentiation into a target cell type, delivery to a desired tissue, and integration into a durable functional structure. At each step of this process, proteins and small molecules provide essential signals and, in some cases, may themselves act as effective therapies. Identifying these signals is thus a fundamental goal of regenerative medicine. In this review we discuss current progress using proteins and small molecules to regulate tissue regeneration, both in combination with cellular therapies and as monotherapy.
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Affiliation(s)
- Eric M Green
- Harvard Stem Cell Institute and the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, Massachusetts 02139, USA
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22
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Oh SW, Lee JB, Kim B, Jeon S, Kim MK, Nam KH, Ha JR, Bhatia M, Oh GT, Kim DY. Peptidomimetic small-molecule compounds promoting cardiogenesis of stem cells. Arch Pharm Res 2012; 35:1979-88. [DOI: 10.1007/s12272-012-1115-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2012] [Revised: 07/14/2012] [Accepted: 08/23/2012] [Indexed: 12/15/2022]
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23
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Jung DW, Williams DR. Reawakening atlas: chemical approaches to repair or replace dysfunctional musculature. ACS Chem Biol 2012; 7:1773-90. [PMID: 23043623 DOI: 10.1021/cb3003368] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Muscle diseases are major health concerns. For example, ischemic heart disease is the third most common cause of death. Cell therapy is an attractive approach for treating muscle diseases, although this is hampered by the need to generate large numbers of functional muscle cells. Small molecules have become established as attractive tools for modulating cell behavior and, in this review, we discuss the recent, rapid research advances made in the development of small molecule methods to facilitate the production of functional cardiac, skeletal, and smooth muscle cells. We also describe how new developments in small molecule strategies for muscle disease aim to induce repair and remodelling of the damaged tissues in situ. Recent progress has been made in developing small molecule cocktails that induce skeletal muscle regeneration, and these are discussed in a broader context, because a similar phenomenon occurs in the early stages of salamander appendage regeneration. Although formidable technical hurdles still remain, these new advances in small molecule-based methodologies should provide hope that cell therapies for patients suffering from muscle disease can be developed in the near future.
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Affiliation(s)
- Da-Woon Jung
- New Drug Targets Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-Dong,
Buk-Gu, Gwangju 500-712, Republic of Korea
| | - Darren R. Williams
- New Drug Targets Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-Dong,
Buk-Gu, Gwangju 500-712, Republic of Korea
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24
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Liu J, Zhang Z, Liu Y, Guo C, Gong Y, Yang S, Ma M, Li Z, Gao WQ, He Z. Generation, characterization, and potential therapeutic applications of cardiomyocytes from various stem cells. Stem Cells Dev 2012; 21:2095-110. [PMID: 22428725 DOI: 10.1089/scd.2012.0031] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Heart failure is one of the leading causes of death worldwide. Myocardial cell transplantation emerges as a novel therapeutic strategy for heart failure, but this approach has been hampered by severe shortage of human cardiomyocytes. We have recently induced mouse embryonic stem cells to differentiate into embryoid bodies and eventually, cardiomyocytes. Here, we address recent advancements in cardiomyocyte differentiation from cardiac stem cells and pluripotent stem cells. We highlight the methodologies, using growth factors, endoderm-like cell cocultures, small molecules, and biomaterials, in directing the differentiation of pluripotent stem cells into cardiomyocytes. The characterization and identification of pluripotent stem cell-derived cardiomyocytes by morphological, phenotypic, and functional features are also discussed. Notably, increasing evidence demonstrates that cardiomyocytes may be generated from the stem cells of several tissues outside the cardiovascular system, including skeletal muscles, bone marrow, testes, placenta, amniotic fluid, and adipose tissues. We further address the potential applications of cardiomyocytes derived from various kinds of stem cells. The differentiation of stem cells into functional cardiomyocytes, especially from an extra-cardiac stem cell source, would circumvent the scarcity of heart donors and human cardiomyocytes, and, most importantly, it would offer an ideal and promising cardiomyocyte source for cell therapy and tissue engineering in treating heart failure.
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Affiliation(s)
- Jianfang Liu
- Clinical Stem Cell Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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25
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Kawaguchi N, Hayama E, Furutani Y, Nakanishi T. Prospective in vitro models of channelopathies and cardiomyopathies. Stem Cells Int 2012; 2012:439219. [PMID: 22969812 PMCID: PMC3437306 DOI: 10.1155/2012/439219] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2011] [Revised: 02/17/2012] [Accepted: 03/08/2012] [Indexed: 01/23/2023] Open
Abstract
An in vitro heart disease model is a promising model used for identifying the genes responsible for the disease, evaluating the effects of drugs, and regenerative medicine. We were interested in disease models using a patient-induced pluripotent stem (iPS) cell-derived cardiomyocytes because of their similarity to a patient's tissues. However, as these studies have just begun, we would like to review the literature in this and other related fields and discuss the path for future models of molecular biology that can help to diagnose and cure diseases, and its involvement in regenerative medicine. The heterogeneity of iPS cells and/or differentiated cardiomyocytes has been recognized as a problem. An in vitro heart disease model should be evaluated using molecular biological analyses, such as mRNA and micro-RNA expression profiles and proteomic analysis.
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Affiliation(s)
- Nanako Kawaguchi
- Department of Pediatric Cardiology, Tokyo Women's Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Emiko Hayama
- Department of Pediatric Cardiology, Tokyo Women's Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Yoshiyuki Furutani
- Department of Pediatric Cardiology, Tokyo Women's Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Toshio Nakanishi
- Department of Pediatric Cardiology, Tokyo Women's Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
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26
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Suter DM, Preynat-Seauve O, Tirefort D, Feki A, Krause KH. Phenazopyridine induces and synchronizes neuronal differentiation of embryonic stem cells. J Cell Mol Med 2011; 13:3517-27. [PMID: 20196783 PMCID: PMC4516505 DOI: 10.1111/j.1582-4934.2009.00660.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Embryonic stem (ES) cells are powerful tools to understand mechanisms of neuronal differentiation and to engineer neurons for in vitro studies and cell therapy. We developed a screening approach to identify small organic molecules driving neuronal differentiation of ES cells. For this purpose, we used a lentivector carrying a dual luciferase reporter system to engineer an ES cell line which allowed us to screen for small organic molecules enhancing neuronal differentiation. One of them, phenazopyridine, was further analysed in human ES cells. Phenazopyridine: (i) enhanced neuronal differentiation, (ii) increased cell survival, (iii) decreased the amount of non-neuronal and undifferentiated cells and (iv) synchronized the cellular differentiation state. Phenazopyridine allowed the development of a differentiation protocol compatible with the generation of clinical grade neural precursors, which were able differentiate into different neuronal subtypes, astrocytes and oligodendrocytes. In summary, we describe a powerful approach to identify small molecules directing stem cell differentiation. This led to the establishment of a new application for an old drug and the development of a novel clinical grade protocol for neuronal differentiation of ES cells.
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Affiliation(s)
- David M Suter
- Department of Pathology and Immunology, University of Geneva Medical School, Switzerland
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Yuan X, Li W, Ding S. Small molecules in cellular reprogramming and differentiation. PROGRESS IN DRUG RESEARCH. FORTSCHRITTE DER ARZNEIMITTELFORSCHUNG. PROGRES DES RECHERCHES PHARMACEUTIQUES 2011; 67:253-66. [PMID: 21141734 DOI: 10.1007/978-3-7643-8989-5_13] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Recent advances in somatic cell reprogramming and directed differentiation make it possible to generate patient-specific pluripotent cells and further derive functional tissue-specific cells for biomedical research and future therapies. Chemical compounds targeting enzymes or signaling proteins are powerful tools to regulate and reveal complex cellular processes and have been identified and applied to controlling cell fate and function, including stem cell maintenance, differentiation, and reprogramming. Not only are small molecules useful in generating desired cell types in vitro for various applications, but also such small molecules could be further developed as conventional therapeutics to target patient's own cells residing in different tissues/organs for treating degenerative diseases, injuries, and cancer. Here, we will review recent studies of small molecules in controlling cell fate.
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Affiliation(s)
- Xu Yuan
- Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
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28
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Lyssiotis CA, Lairson LL, Boitano AE, Wurdak H, Zhu S, Schultz PG. Chemical Control of Stem Cell Fate and Developmental Potential. Angew Chem Int Ed Engl 2010; 50:200-42. [DOI: 10.1002/anie.201004284] [Citation(s) in RCA: 112] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Affiliation(s)
- Costas A. Lyssiotis
- Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA), Fax: (+1) 858‐784‐9440
| | - Luke L. Lairson
- The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121 (USA)
| | - Anthony E. Boitano
- The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121 (USA)
| | - Heiko Wurdak
- Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA), Fax: (+1) 858‐784‐9440
| | - Shoutian Zhu
- Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA), Fax: (+1) 858‐784‐9440
| | - Peter G. Schultz
- Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA), Fax: (+1) 858‐784‐9440
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Lyssiotis CA, Lairson LL, Boitano AE, Wurdak H, Zhu S, Schultz PG. Chemische Kontrolle des Schicksals und Entwicklungspotenzials von Stammzellen. Angew Chem Int Ed Engl 2010. [DOI: 10.1002/ange.201004284] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Affiliation(s)
- Costas A. Lyssiotis
- Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA), Fax: (+1) 858‐784‐9440
| | - Luke L. Lairson
- The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121 (USA)
| | - Anthony E. Boitano
- The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121 (USA)
| | - Heiko Wurdak
- Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA), Fax: (+1) 858‐784‐9440
| | - Shoutian Zhu
- Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA), Fax: (+1) 858‐784‐9440
| | - Peter G. Schultz
- Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA), Fax: (+1) 858‐784‐9440
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30
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Modulation of embryonic stem cell fate and somatic cell reprogramming by small molecules. Reprod Biomed Online 2010; 21:26-36. [PMID: 20462797 DOI: 10.1016/j.rbmo.2010.03.021] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2009] [Revised: 12/14/2009] [Accepted: 03/03/2010] [Indexed: 12/19/2022]
Abstract
Embryonic stem cells (ESC) are pluripotent cells and have the ability to self-renew in vitro and to differentiate into cells representing all three germ layers. They provide enormous opportunities for basic research, regenerative medicine as well as drug discovery. The mechanisms that govern ESC fate are not completely understood, so a better understanding and control of ESC self-renewal and differentiation are pivotal for therapeutic applications. In contrast to growth factors and genetic manipulations, small molecules offer great advantages in modulating ESC fate. For instance, they could be conveniently identified through high-throughput screening, work across multiple signalling pathways and affect epigenetic modifications as well. This review focuses on the recent progress in the use of small molecules to regulate ESC self-renewal, differentiation and somatic cell reprogramming.
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31
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Suter DM, Preynat-Seauve O, Tirefort D, Feki A, Krause KH. Phenazopyridine induces and synchronizes neuronal differentiation of embryonic stem cells. J Cell Mol Med 2010. [DOI: 10.1111/j.1582-4934.2008.00660.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
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Berkessel A, Seelig B, Schwengberg S, Hescheler J, Sachinidis A. Chemically Induced Cardiomyogenesis of Mouse Embryonic Stem Cells. Chembiochem 2009; 11:208-17. [DOI: 10.1002/cbic.200900345] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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33
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Zhang F, Pasumarthi KBS. Embryonic stem cell transplantation: promise and progress in the treatment of heart disease. BioDrugs 2009; 22:361-74. [PMID: 18998754 DOI: 10.2165/0063030-200822060-00003] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Cardiovascular diseases remain the leading cause of death worldwide, and the burden is equally shared between men and women around the globe. Cardiomyocytes that die in response to disease processes or aging are replaced by scar tissue instead of new muscle cells. Although recent reports suggest an intrinsic capacity for the mammalian myocardium to regenerate via endogenous stem/progenitor cells, the magnitude of such a response appears to be minimal and has yet to be realized fully in cardiovascular patients. Despite the advances in pharmacotherapy and new biomedical technologies, the prognosis for patients diagnosed with end-stage heart failure appears to be grave. While heart transplantation is a viable option, this life-saving intervention suffers from an acute shortage of cardiac organ donors. In view of these existing issues, donor cell transplantation is emerging as a promising strategy to regenerate diseased myocardium. Studies from multiple laboratories have shown that transplantation of donor cells (e.g. fetal cardiomyocytes, skeletal myoblasts, smooth muscle cells, and adult stem cells) can improve the function of diseased hearts over a short period of time (1-4 weeks). While long-term follow-up studies are warranted, it is generally perceived that the beneficial effects of transplanted cells are mainly due to increased angiogenesis or favorable scar remodeling in the engrafted myocardium. Although skeletal myoblasts and bone marrow stem cells hold the highest potential for implementation of autologous therapies, initial results from phase I trials are not promising. In contrast, transplantation of fetal cardiomyocytes has been shown to confer protection against the induction of ventricular tachycardia in experimental myocardial injury models. Furthermore, results from multiple laboratories suggest that fetal cardiomyocytes can couple functionally with host myocytes, stimulate formation of new blood vessels, and improve myocardial function. While it is neither practical nor ethical to test the potential of fetal cardiomyocytes in clinical trials, embryonic stem (ES) cells serve as a novel source for generation of unlimited quantities of cardiomyocytes for myocardial repair. The initial success in the application of ES cells to partially repair and improve myocardial function in experimental models of heart disease has been quite promising. However, multiple hurdles need to be crossed before the potential benefits of ES cells can be translated to the clinic. In this review, we summarize the current knowledge of cardiomyocyte derivation and enrichment from ES-cell cultures and provide a brief survey of factors increasing cardiomyogenic induction in both mouse and human ES cultures. Subsequently, we summarize the current state of research using mouse and human ES cells for the treatment of heart disease in various experimental models. Furthermore, we discuss the challenges that need to be overcome prior to the successful clinical utilization of ES-derived cardiomyocytes for the treatment of end-stage heart disease. While we are optimistic that the researchers in this field will sail across the hurdles, we also suggest that a more cautious approach to the validation of ES cardiomyocytes in experimental models would certainly prevent future disappointments, as seen with skeletal myoblast studies.
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Affiliation(s)
- Feixiong Zhang
- Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada
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Cyclosporin-A potently induces highly cardiogenic progenitors from embryonic stem cells. Biochem Biophys Res Commun 2008; 379:115-20. [PMID: 19094963 DOI: 10.1016/j.bbrc.2008.12.019] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2008] [Accepted: 12/08/2008] [Indexed: 11/20/2022]
Abstract
Though cardiac progenitor cells should be a suitable material for cardiac regeneration, efficient ways to induce cardiac progenitors from embryonic stem (ES) cells have not been established. Extending our systematic cardiovascular differentiation method of ES cells, here we show efficient and specific expansion of cardiomyocytes and highly cardiogenic progenitors from ES cells. An immunosuppressant, cyclosporin-A (CSA), showed a novel effect specifically acting on mesoderm cells to drastically increase cardiac progenitors as well as cardiomyocytes by 10-20 times. Approximately 200 cardiomyocytes could be induced from one mouse ES cell using this method. Expanded progenitors successfully integrated into scar tissue of infracted heart as cardiomyocytes after cell transplantation to rat myocardial infarction model. CSA elicited specific induction of cardiac lineage from mesoderm in a novel mesoderm-specific, NFAT independent fashion. This simple but efficient differentiation technology would be extended to induce pluripotent stem (iPS) cells and broadly contribute to cardiac regeneration.
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Földes G, Harding SE, Ali NN. Cardiomyocytes from embryonic stem cells: towards human therapy. Expert Opin Biol Ther 2008; 8:1473-83. [DOI: 10.1517/14712598.8.10.1473] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Chen K, Wu L, Wang ZZ. Extrinsic regulation of cardiomyocyte differentiation of embryonic stem cells. J Cell Biochem 2008; 104:119-28. [PMID: 17979183 DOI: 10.1002/jcb.21604] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Cardiovascular disease is one of leading causes of death throughout the U.S. and the world. The damage of cardiomyocytes resulting from ischemic injury is irreversible and leads to the development of progressive heart failure, which is characterized by the loss of functional cardiomyocytes. Because cardiomyocytes are unable to regenerate in the adult heart, cell-based therapy of transplantation provides a potential alternative approach to replace damaged myocardial tissue and restore cardiac function. A major roadblock toward this goal is the lack of donor cells; therefore, it is urgent to identify the cardiovascular cells that are necessary for achieving cardiac muscle regeneration. Pluripotent embryonic stem (ES) cells have enormous potential as a source of therapeutic tissues, including cardiovascular cells; however, the regulatory elements mediating ES cell differentiation to cardiomyocytes are largely unknown. In this review, we will focus on extrinsic factors that play a role in regulating different stages of cardiomyocyte differentiation of ES cells.
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Affiliation(s)
- Kang Chen
- Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
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Kirkton RD, Bursac N. Genetic engineering and stem cells: combinatorial approaches for cardiac cell therapy. IEEE ENGINEERING IN MEDICINE AND BIOLOGY MAGAZINE : THE QUARTERLY MAGAZINE OF THE ENGINEERING IN MEDICINE & BIOLOGY SOCIETY 2008; 27:85-8. [PMID: 18519188 PMCID: PMC2722747 DOI: 10.1109/memb.2008.922356] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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38
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Derive and conquer: sourcing and differentiating stem cells for therapeutic applications. Nat Rev Drug Discov 2008; 7:131-42. [PMID: 18079756 DOI: 10.1038/nrd2403] [Citation(s) in RCA: 106] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Although great progress has been made in the isolation and culture of stem cells, the future of stem-cell-based therapies and their productive use in drug discovery and regenerative medicine depends on two key factors: finding reliable sources of multipotent and pluripotent cells and the ability to control their differentiation to generate desired derivatives. It is essential for clinical applications to establish reliable sources of pathogen-free human embryonic stem cells (ESCs) and develop suitable differentiation techniques. Here, we address some of the problems associated with the sourcing of human ESCs and discuss the current status of stem-cell differentiation technology.
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39
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Emre N, Coleman R, Ding S. A chemical approach to stem cell biology. Curr Opin Chem Biol 2007; 11:252-8. [PMID: 17493865 DOI: 10.1016/j.cbpa.2007.04.024] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2007] [Accepted: 04/30/2007] [Indexed: 11/25/2022]
Abstract
Small molecule libraries have been used successfully to probe several biological systems. Recent work has translated these successes across to the field of stem cell biology. Stem cells hold promise for both modeling of early development as well as having therapeutic potential. Enhanced understanding of the molecular mechanisms that control stem cell fates as well as an improved ability to manipulate cell populations are required. Known mechanistic chemical compounds have been used with stem cells to accomplish these two goals. More recently, through the utilization of high fitness libraries in phenotype-based screens, several small molecules that control self-renewal and differentiation in stem cells have been identified. These small molecules provide useful chemical tools for both basic research and practical applications.
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Affiliation(s)
- Nil Emre
- Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
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