Stem Cells
- Atrial‐like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial‐selective pharmacology
- Harsha D Devalla*,1,
- Verena Schwach1,
- John W Ford2,
- James T Milnes2,
- Said El‐Haou2,
- Claire Jackson2,
- Konstantinos Gkatzis1,
- David A Elliott3,
- Susana M Chuva de Sousa Lopes1,4,
- Christine L Mummery1,
- Arie O Verkerk5 and
- Robert Passier*,1
- 1Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, The Netherlands
- 2Xention Ltd, Cambridge, UK
- 3Murdoch Childrens Research Institute Royal Children's Hospital, Melbourne, Vic., Australia
- 4Department for Reproductive Medicine, Ghent University Hospital, Ghent, Belgium
- 5Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- ↵*
Corresponding author. Tel: +31 71 5269528; Fax: +31 71 5268289; E‐mail: h.d.devalla{at}lumc.nl
Corresponding author. Tel: +31 71 5269359; Fax: +31 71 5268289; E‐mail: r.passier{at}lumc.nl
Newly generated human embryonic stem cell‐derived atrial‐like cardiomyocytes resemble human atrial cardiomyocytes and prove to be a valuable model for pre‐clinical drug screenings to identify effective atrial‐selective compounds against atrial fibrillation.
Synopsis
Newly generated human embryonic stem cell‐derived atrial‐like cardiomyocytes resemble human atrial cardiomyocytes and prove to be a valuable model for pre‐clinical drug screenings to identify effective atrial‐selective compounds against atrial fibrillation.
Exogenous addition of retinoic acid drives differentiating human embryonic stem cells towards atrial‐like cardiomyocytes.
COUP‐TFI and COUP‐TFII are induced during atrial differentiation.
COUP‐TF transcription factors regulate atrial‐specific ion channel genes.
hESC‐atrial CMs respond to drugs targeting atrial‐selective ion channels.
EMBO Mol Med (2015) 7: 394–410
- Received October 17, 2014.
- Revision received January 18, 2015.
- Accepted January 23, 2015.
- © 2015 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Deletion of the von Hippel–Lindau gene causes sympathoadrenal cell death and impairs chemoreceptor‐mediated adaptation to hypoxia
- David Macías1,2,3,
- Mary Carmen Fernández‐Agüera1,2,3,
- Victoria Bonilla‐Henao1,2,3 and
- José López‐Barneo*,1,2,3
- 1Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
- 2Departamento de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain
- 3Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- ↵*Corresponding author. Tel: +34 955 923007; E‐mail: lbarneo{at}us.es
Instead of tumorigenesis, Vhl inactivation in rodent catecholaminergic cells in vivo causes atrophy of the adrenal medulla, carotid body (CB) and sympathetic ganglia. Hypoxia‐induced adult CB neurogenesis is inhibited and Vhl‐KO mice cannot acclimatize to hypoxia.
Synopsis
Instead of tumorigenesis, Vhl inactivation in rodent catecholaminergic cells in vivo causes atrophy of the adrenal medulla, carotid body (CB) and sympathetic ganglia. Hypoxia‐induced adult CB neurogenesis is inhibited and Vhl‐KO mice cannot acclimatize to hypoxia.
Contrary to generally held beliefs Vhl is not a tumor suppressor gene in all cells.
Vhl‐deficiency in mouse sympathoadrenal cells does not result in the appearance of tumors.
Pheochromocytomas in man could be associated with gain‐of‐function mutations in VHL.
Animals lacking Vhl exhibit atrophy of the CB and adrenal medulla and present a striking intolerance to systemic hypoxia that could give rise to death.
EMBO Mol Med (2014) 6: 1577–1592
- Received April 8, 2014.
- Revision received October 15, 2014.
- Accepted October 20, 2014.
- © 2014 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- RARRES3 suppresses breast cancer lung metastasis by regulating adhesion and differentiation
- Mònica Morales1,†,
- Enrique J Arenas1,†,
- Jelena Urosevic1,
- Marc Guiu1,
- Esther Fernández1,
- Evarist Planet2,
- Robert Bryn Fenwick3,
- Sonia Fernández‐Ruiz4,
- Xavier Salvatella3,5,
- David Reverter6,
- Arkaitz Carracedo4,7,8,
- Joan Massagué9,10 and
- Roger R Gomis*,1,5
- 1Oncology Program, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
- 2Biostatistics and Bioinformatics Unit, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
- 3Joint BSC‐IRB Research Programme in Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
- 4CIC bioGUNE Bizkaia Tecnology park, Derio, Spain
- 5Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
- 6Departament de Bioquímica i de Biologia Molecular, Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
- 7Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), Bilbao, Spain
- 8Ikerbasque Basque Foundation for Science, Bilbao, Spain
- 9Cancer Biology and Genetics Program, Memorial Sloan‐Kettering Cancer Center, New York, NY, USA
- 10Howard Hughes Medical Institute, Chevy Chase, MD, USA
- ↵*Corresponding author. Tel: +34 934039959; Fax: +34 934034848; E‐mail: roger.gomis{at}irbbarcelona.org
-
↵† The authors equally contributed to the work.
Loss of RARRES3 facilitates breast cancer cell extravasation, lung extracellular matrix adherence, and lung colonization. Furthermore, RARRES3 levels in the primary tumor may predict risk of relapse and might help identify therapy‐resistant tumors.
Synopsis
Loss of RARRES3 facilitates breast cancer cell extravasation, lung extracellular matrix adherence, and lung colonization. Furthermore, RARRES3 levels in the primary tumor may predict risk of relapse and might help identify therapy‐resistant tumors.
Low expression levels of RARRES3 in ER‐negative primary breast tumors identify patients at high risk of developing lung metastasis.
RARRES3 suppresses lung metastasis in ER‐negative breast cancer cells.
RARRES3 depletion facilitates the adhesion of breast cancer cells to lung parenchyma and metastasis initiation.
Loss of RARRES3 phospholipase A1/A2 activity impairs tumor cell differentiation and is crucial for metastasis initiation.
EMBO Mol Med (2014) 6: 865–881
- Received November 18, 2013.
- Revision received April 3, 2014.
- Accepted April 23, 2014.
- © 2014 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Targeted gene therapy and cell reprogramming in Fanconi anemia
- Paula Rio1,2,†,
- Rocio Baños1,2,†,
- Angelo Lombardo3,†,
- Oscar Quintana‐Bustamante1,2,
- Lara Alvarez1,2,
- Zita Garate1,2,
- Pietro Genovese3,
- Elena Almarza1,2,
- Antonio Valeri1,2,
- Begoña Díez1,2,
- Susana Navarro1,2,
- Yaima Torres4,
- Juan P Trujillo2,5,
- Rodolfo Murillas6,
- Jose C Segovia1,2,
- Enrique Samper4,
- Jordi Surralles5,
- Philip D Gregory7,
- Michael C Holmes7,
- Luigi Naldini*,3,8 and
- Juan A Bueren*,1,2
- 1Division of Hematopoietic Innovative Therapies, CIEMAT/CIBERER, Madrid, Spain
- 2Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS‐FJD, UAM), Madrid, Spain
- 3San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy
- 4NIMGenetics SL, Madrid, Spain
- 5Universidad Autónoma Barcelona/CIBERER, Barcelona, Spain
- 6Division of Epithelial Biomedicine, CIEMAT/CIBERER, Madrid, Spain
- 7Sangamo BioSciences Inc., Richmond, CA, USA
- 8Vita Salute San Raffaele University, Milan, Italy
- ↵*
Corresponding author. Tel: +34 913 466 518; Fax: +34 913 466 484; E‐mail: juan.bueren{at}ciemat.es
Corresponding author. Tel: +02 2643 4681; Fax: +02 2643 4621; E‐mail: naldini.luigi{at}hsr.it
-
↵† These authors contributed equally to this work.
This study shows for the first time the possibility of performing targeted gene therapy in a z‐repair deficiency syndrome, known as Fanconi anemia. By reprogramming targeted cells, asymptomatic gene‐edited iPSCs and hematopoietic progenitor cells are generated.
Synopsis
This study shows for the first time the possibility of performing targeted gene therapy in a DNA‐repair deficiency syndrome, known as Fanconi anemia. By reprogramming targeted cells, asymptomatic gene‐edited iPSCs and hematopoietic progenitor cells are generated.
Fanconi anemia cells of the FA‐A subtype have been efficiently targeted with zinc finger nucleases and a donor construct harboring the therapeutic FANCA gene.
The specific insertion of FANCA in the AAVS1 “safe harbor locus” of FA‐A fibroblasts efficiently corrected the genetic instability characteristic of these cells.
The reprogramming and re‐differentiation of gene‐edited FA‐A fibroblasts generated disease‐free hematopoietic progenitors.
EMBO Mol Med (2014) 6: 835–848
- Received August 9, 2013.
- Revision received April 16, 2014.
- Accepted April 17, 2014.
- © 2014 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Stimulation of endogenous cardioblasts by exogenous cell therapy after myocardial infarction
- Konstantinos Malliaras1,
- Ahmed Ibrahim1,
- Eleni Tseliou1,
- Weixin Liu1,
- Baiming Sun1,
- Ryan C Middleton1,
- Jeffrey Seinfeld1,
- Lai Wang1,
- Behrooz G Sharifi1 and
- Eduardo Marbán*,1
- ↵*Corresponding author. Tel: +1 310 423 7557; Fax: +1 310 423 7637; E‐mail: Eduardo.Marban{at}csmc.edu
This study reports the isolation and characterization of endogenous cardiomyocyte progenitors in the adult mammalian heart and specifies strategies that could be used for therapeutic stimulation of innate progenitor cell‐mediated cardiac regeneration.
Synopsis
This study reports the isolation and characterization of endogenous cardiomyocyte progenitors in the adult mammalian heart and specifies strategies that could be used for therapeutic stimulation of innate progenitor cell‐mediated cardiac regeneration.
The normal adult mouse heart contains endogenous cardioblasts.
Myocardial infarction leads to cardioblast activation at the site of injury.
Activated cardioblasts express cardiac transcription factors and sarcomeric proteins, contract spontaneously, and differentiate into mature cardiomyocytes.
Activated cardioblasts do not arise from hematogenous seeding, cardiomyocyte dedifferentiation, or mere expansion of a preformed progenitor pool.
Exogenous cell therapy with cardiosphere‐derived cells, through the secretion of SDF1, amplifies innate cardioblast‐mediated tissue regeneration.
EMBO Mol Med (2014) 6: 760–777
- Received October 30, 2013.
- Revision received March 18, 2014.
- Accepted March 27, 2014.
- © 2014 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Delayed transplantation of precursor cell‐derived astrocytes provides multiple benefits in a rat model of Parkinsons
- Christoph Proschel*,1,2,
- Jennifer L Stripay1,3,
- Chung‐Hsuan Shih1,4,
- Joshua C Munger5 and
- Mark D Noble1,2
- 1Department for Biomedical Genetics, University of Rochester, Rochester, NY, USA
- 2Stem Cell and Regenerative Medicine Institute University of Rochester, Rochester, NY, USA
- 3Neuroscience Graduate Program, University of Rochester, Rochester, NY, USA
- 4Department of Pathology, University of Rochester, Rochester, NY, USA
- 5Department of Biochemistry and Biophysics, University of Rochester, Rochester, NY, USA
- ↵*Corresponding author. Tel: +1 585 208 6654; Fax: +1 585 273 1450; E‐mail: chris_proschel{at}urmc.rochester.edu
In vitro‐generated astrocytes GDAsBMP transplantation is the first example of a multimodal single therapeutic cell therapy approach with the potential to promote recovery of multiple neuron populations of relevance to Parkinson's Disease in a rat model.
Synopsis
In vitro‐generated astrocytes GDAsBMP transplantation is the first example of a multimodal single therapeutic cell therapy approach with the potential to promote recovery of multiple neuron populations of relevance to Parkinson's Disease in a rat model.
Transplantation of GDAsBMP provides a successful astrocyte‐based multimodal treatment in a model of Parkinson's Disease without the need for prior genetic modification of cells or the use of neuron transplants to restore function.
Recovery of multiple neuronal populations, including tyrosine hydroxylase expressing, dopaminergic neurons and parvalbumin+ GABAergic interneurons, was caused by post‐symptomatic transplantation of GDAsBMP into a hemiparkinsonian model.
Consistent with high levels of expression of the synaptic modulatory proteins thrombospondin 1 and 2 in GDAsBMP, restored expression of the synaptic protein synaptophysin was also seen in the striatum of transplanted animals.
Multiple factors of interest for the treatment of neurodegenerative disease, including brain‐ and glia‐derived neurotrophic factor, neurturin and IGF1 and‐2, are intrinsically produced by GDAsBMP and are produced at levels far exceeding that seen in their parental precursor cells or in other astrocytes derived from these precursors.
Additional protection against oxidative stress, a process widely involved in CNS pathology, is also provided by increased glutathione production by GDAsBMP.
EMBO Mol Med (2014) 6, 504–518
- Received April 11, 2013.
- Revision received December 13, 2013.
- Accepted December 16, 2013.
- © 2014 The Authors.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Prostaglandin E2 promotes post‐infarction cardiomyocyte replenishment by endogenous stem cells
- Ying‐Chang Hsueh1,2,†,
- Jasmine M F Wu1,2,†,
- Chun‐Keung Yu1,3,
- Kenneth K Wu4 and
- Patrick C H Hsieh*,1,2,5
- 1Institute of Basic Medical Sciences, National Cheng Kung University and Hospital, Tainan, Taiwan
- 2Institute of Clinical Medicine, National Cheng Kung University and Hospital, Tainan, Taiwan
- 3Department of Microbiology and Immunology, National Cheng Kung University and Hospital, Tainan, Taiwan
- 4Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan
- 5Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
- ↵*Corresponding author. Tel: +886 62353535, ext. 3653; Fax: +886 62758781; E‐mail: phsieh{at}mail.ncku.edu.tw
-
↵† These authors contributed equally to this paper.
Although lost cardiomyocytes could be replenished after injury, the efficiency is extremely low. Here, the authors show that PGE2 treatment at a critical time period improves stem cell‐mediated cardiac repair in young mice and restores it in aged animals.
Synopsis
Although lost cardiomyocytes could be replenished after injury, the efficiency is extremely low. Here, the authors show that PGE2 treatment at a critical time period improves stem cell‐mediated cardiac repair in young mice and restores it in aged animals.
Stem cell‐derived cardiomyocyte replenishment occurs within 7 days of injury.
An early inflammatory signal regulates cardiac regeneration after infarction.
PGE2 stimulates cardiomyocyte replenishment mediated by cardiac stem cells.
PGE2 rescues the cardiomyocyte replenishment capacity that is lost in aged mice.
EMBO Mol Med (2014) 6, 496–503
- Received November 18, 2013.
- Revision received December 13, 2013.
- Accepted December 16, 2013.
- © 2014 The Authors.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Sox2 promotes tamoxifen resistance in breast cancer cells
- Marco Piva1,
- Giacomo Domenici1,
- Oihana Iriondo1,
- Miriam Rábano1,
- Bruno M Simões1,
- Valentine Comaills1,
- Inmaculada Barredo2,
- Jose A López‐Ruiz3,
- Ignacio Zabalza2,
- Robert Kypta1,4 and
- Maria d M Vivanco*,1
- 1Cell Biology and Stem Cells Unit, CIC bioGUNE, Bilbao, Spain
- 2Department of Pathology, Galdakao‐Usansolo Hospital, Galdakao, Spain
- 3Servicio de Radiodiagno´stico Preteimagen, Bilbao, Spain
- 4Department of Surgery and Cancer, Imperial College London, London, UK
- ↵*Corresponding author: Tel: +34 944061322; Fax: +34 944061301; E‐mail: mdmvivanco{at}cicbiogune.es
The development of Tam‐resistance in breast cancer is shown to be driven by Sox2‐dependent activation of Wnt signalling in cancer stem cells. Combining hormone therapy and Wnt secretion inhibitors might thus provide a novel strategy to treat breast cancer.
Synopsis
The development of Tam‐resistance in breast cancer is shown to be driven by Sox2‐dependent activation of Wnt signalling in cancer stem cells. Combining hormone therapy and Wnt secretion inhibitors might thus provide a novel strategy to treat breast cancer.
Cancer stem cells play a role in the development of tamoxifen resistance.
Sox2 expression is increased in tamoxifen‐resistant breast cancer cells.
Sox2 inhibition restores cell sensitivity to tamoxifen.
Sox2 is a biomarker for tamoxifen resistance.
Combining hormone therapy with Wnt or Sox2 inhibitors may help prevent breast cancer recurrence.
- Received August 20, 2013.
- Revision received September 20, 2013.
- Accepted September 24, 2013.
- © 2013 The Authors.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Telomerase governs immunomodulatory properties of mesenchymal stem cells by regulating FAS ligand expression
- Chider Chen1,†,
- Kentaro Akiyama2,†,
- Takayoshi Yamaza3,
- Yong‐Ouk You1,
- Xingtian Xu1,
- Bei Li4,
- Yimin Zhao*,4 and
- Songtao Shi*,1
- 1Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA, USA
- 2Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science, Kita‐ku Okayama, Japan
- 3Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, Fukuoka, Japan
- 4School of Stomatology, Fourth Military Medical University, Xi'an Shanxi, China
- ↵*
Corresponding author: Tel: +1 323 442 3038; Fax: +1 323 442 2981; E‐mail: songtaos{at}usc.edu
Corresponding author: Tel: +86 29 8477 6001; Fax +86 29 8322 3047; E‐mail: zhaoym{at}fmmu.edu.cn
-
↵† These authors contributed equally to this study.
Bone marrow mesenchymal stem cells (BMMSC) have therapeutic properties in immune disorders. Telomerase function is shown to not only be critical for BMMSC stemness and osteogenic differentiation, but also to regulate BMMSC‐mediated immune therapies.
Synopsis
Bone marrow mesenchymal stem cells (BMMSC) have therapeutic properties in immune disorders. Telomerase function is shown to not only be critical for BMMSC stemness and osteogenic differentiation, but also to regulate BMMSC‐mediated immune therapies.
Telomerase governs immunomodulatory properties of BMMSCs.
TERT serves as a transcription modulator to regulate FASL expression.
Aspirin increases immunomodulation of BMMSCs through TERT activation.
EMBO Mol Med (2014) 6, 322–334
- Received May 4, 2013.
- Revision received November 10, 2013.
- Accepted November 12, 2013.
- © 2014 The Authors.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Rapid target gene validation in complex cancer mouse models using re‐derived embryonic stem cells
- Ivo J Huijbers1,
- Rahmen Bin Ali1,
- Colin Pritchard1,
- Miranda Cozijnsen1,
- Min‐Chul Kwon1,
- Natalie Proost1,
- Ji‐Ying Song2,
- Hilda de Vries1,
- Jitendra Badhai1,
- Kate Sutherland1,
- Paul Krimpenfort1,
- Ewa M Michalak3,
- Jos Jonkers*,3 and
- Anton Berns*,1
- 1Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- 2Department of Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- 3Division of Molecular Pathology and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- ↵*
Corresponding author. Tel: +31 205121990; Fax: +31 205122011; E‐mail: a.berns{at}nki.nl
Corresponding author. Tel: +31 205122000; Fax: +31 205122050; E‐mail: j.jonkers{at}nki.nl
The GEMM‐ESC approach describes and validates an improved method for generating mouse cancer models directly from embryonic stem cells. This technology speeds up the generation/modification of mouse models, while minimizing cost and breeding efforts.
Synopsis
The GEMM‐ESC approach describes and validates an improved method for generating mouse cancer models directly from embryonic stem cells. This technology speeds up the generation/modification of mouse models, while minimizing cost and breeding efforts.
ESCs cultured in 2i medium show improved pluripotency and display equal genomic stability as ESCs cultured under classic conditions.
Chimeric mice generated from GEMM‐ESCs are equally susceptible to tumors as compared to the parental strain, provided the chimeras display coat color contribution upwards of 70%.
Experimental cohorts are generated on‐demand in less than 4 months without the need for any breeding.
Controlled single copy integration of a transgene in the Col1a1 locus allows for robust reporter and oncogene expression in a mouse model for small cell lung cancer.
Archived ESCs with complex genetic traits can serve as an important resource for the generation of new mouse models of cancer or for the validation of candidate cancer genes.
- Received July 18, 2013.
- Revision received October 22, 2013.
- Accepted October 22, 2013.
- © 2014 The Authors.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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