Stem Cells
- Lost in translation: pluripotent stem cell‐derived hematopoiesis
- 1RG Reprogramming and Gene Therapy, REBIRTH Cluster of Excellence Hannover Medical School, Hannover, Germany
- 2Institute of Experimental Hematology Hannover Medical School, Hannover, Germany
- 3Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
- 4JRG Translational Hematology of Congenital Diseases, REBIRTH Cluster of Excellence Hannover Medical School, Hannover, Germany
- ↵*Corresponding author. Tel: +49 511 532 5266; Fax: +49 511 532 5234; E‐mail: lachmann.nico{at}mh-hannover.de
↵† These authors contributed equally to this work
This review highlights recent developments in the field of pluripotent stem cell differentiation toward hematopoietic stem/progenitor cells and cytokines as factors controlling primitive and definitive hematopoietic development.
EMBO Mol Med (2015) 7: 1388–1402
- Received March 31, 2015.
- Revision received May 29, 2015.
- Accepted June 22, 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.
- Antisense‐mediated exon skipping: a therapeutic strategy for titin‐based dilated cardiomyopathy
- Michael Gramlich*,1,2,†,
- Luna Simona Pane3,†,
- Qifeng Zhou1,†,
- Zhifen Chen3,
- Marta Murgia4,5,
- Sonja Schötterl1,
- Alexander Goedel3,
- Katja Metzger1,
- Thomas Brade3,
- Elvira Parrotta3,6,
- Martin Schaller7,
- Brenda Gerull8,
- Ludwig Thierfelder9,
- Annemieke Aartsma‐Rus10,
- Siegfried Labeit11,
- John J Atherton12,
- Julie McGaughran13,
- Richard P Harvey2,14,
- Daniel Sinnecker3,
- Matthias Mann4,
- Karl‐Ludwig Laugwitz3,15,
- Meinrad Paul Gawaz1 and
- Alessandra Moretti*,3,15
- 1Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany
- 2Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia
- 3I. Medical Department – Cardiology, Klinikum rechts der Isar – Technische Universität München, Munich, Germany
- 4Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
- 5Department of Biomedical Sciences, University of Padova, Padua, Italy
- 6Department of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, Catanzaro, Italy
- 7Department of Dermatology, Eberhard Karls University, Tübingen, Germany
- 8Libin Cardiovascular Institute of Alberta and University of Calgary, Calgary, AB, Canada
- 9Max Delbrueck Center for Molecular Medicine, Berlin, Germany
- 10Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
- 11Institute for Integrative Pathophysiology, Universitätsmedizin Mannheim, Mannheim, Germany
- 12Department of Cardiology, Royal Brisbane and Women's Hospital and University of Queensland School of Medicine, Brisbane, Australia
- 13Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Qld, Australia
- 14St Vincent's Clinical School, University of New South Wales, Kensington, NSW, Australia
- 15DZHK (German Centre for Cardiovascular Research) – partner site Munich Heart Alliance, Munich, Germany
- ↵*
Corresponding author. Tel: +49 7071 29 80642; Fax: +49 7071 29 4550; E‐mail: michael.gramlich{at}med.uni-tuebingen.de
Corresponding author. Tel: +49 89 4140 6907; Fax: +49 89 4140 4901; E‐mail: amoretti{at}med1.med.tum.de
-
↵† These authors contributed equally to this work
Truncating mutations in the giant sarcomeric protein titin (TTN) are a major cause for inherited forms of dilated cardiomyopathy (DCM). Antisense oligonucleotides (AON)‐mediated exon skipping is shown here to be a promising strategy as potential treatment option for DCM.
Synopsis
Truncating mutations in the giant sarcomeric protein titin (TTN) are a major cause for inherited forms of dilated cardiomyopathy (DCM). Antisense oligonucleotides (AON)‐mediated exon skipping is shown here to be a promising strategy as potential treatment option for DCM.
Reframing TTN transcript by AON‐mediated exon skipping improved myofibril formation and stability in patient‐specific iPSC‐derived cardiomyocytes harboring a A‐band TTN truncating mutation.
Systemic application of AON improved heart function and prevented DCM in a knock‐in DCM mouse model of the same TTN mutation.
Personalized RNA‐based exon skipping is a promising therapeutic strategy for DCM patients.
EMBO Mol Med (2015) 7: 562–576
- Received January 16, 2015.
- Revision received February 12, 2015.
- Accepted February 17, 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.
- A single epidermal stem cell strategy for safe ex vivo gene therapy
- Stéphanie Droz‐Georget Lathion1,2,
- Ariane Rochat1,2,
- Graham Knott3,
- Alessandra Recchia4,
- Danielle Martinet5,
- Sara Benmohammed6,
- Nicolas Grasset1,2,
- Andrea Zaffalon1,2,
- Nathalie Besuchet Schmutz5,
- Emmanuelle Savioz‐Dayer1,2,
- Jacques Samuel Beckmann5,6,
- Jacques Rougemont7,
- Fulvio Mavilio4,8 and
- Yann Barrandon*,1,2
- 1Department of Experimental Surgery, Lausanne University Hospital (CHUV), Lausanne, Switzerland
- 2Laboratory of Stem Cell Dynamics, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
- 3Interdisciplinary Center for Electron Microscopy, Faculty of Life Sciences EPFL, Lausanne, Switzerland
- 4Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
- 5Service de Génétique Médicale, Lausanne University Hospital (CHUV), Lausanne, Switzerland
- 6Department of Medical Genetics, Université de Lausanne, Lausanne, Switzerland
- 7Bioinformatics and Biostatistics Core Facility, Faculty of Life Sciences EPFL, Lausanne, Switzerland
- 8Genethon, Evry, France
- ↵*Corresponding author. Tel: +41 21 314 24 61; Fax: +41 21 314 24 68; E‐mail: yann.barrandon{at}epfl.ch
First time demonstration of a safe clonal strategy for ex vivo gene therapy before autologous transduced cells are transplanted into patients. Using recessive dystrophic epidermolysis bullosa (RDEB) COL7A1 corrected epidermal cloned stem cells as proof of principle, this strategy proves promising for clinical applications.
Synopsis
First time demonstration of a safe clonal strategy for ex vivo gene therapy before autologous transduced cells are transplanted into patients. Using recessive dystrophic epidermolysis bullosa (RDEB) COL7A1 corrected epidermal cloned stem cells as proof of principle, this strategy proves promising for clinical applications.
Assessment of safety and efficacy of an ex vivo gene therapy product derived from a single epidermal stem cell transduced with a gene of interest.
A clonal strategy was the best method to fulfil stringent safety regulatory requirements for ex vivo gene therapy.
Long‐term regeneration of anchoring fibrils from the progeny of a single genetically corrected epidermal stem cell from a patient with RDEB (type VII collagen deficiency) transplanted onto immunodeficient mice.
EMBO Mol Med (2015) 7: 380–393
- Received June 18, 2014.
- Revision received January 8, 2015.
- Accepted January 21, 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.
- Single stem cell gene therapy for genetic skin disease
Stem cell gene therapy followed by transplantation into damaged regions of the skin has been successfully used to treat genetic skin blistering disorder. Usually, many stem cells are virally transduced to obtain a sufficient number of genetically corrected cells required for successful transplantation, as genetic insertion in every stem cell cannot be precisely defined. In this issue of EMBO Molecular Medicine, Droz‐Georget Lathion et al developed a new strategy for ex vivo single cell gene therapy that allows extensive genomic and functional characterization of the genetically repaired individual cells before they can be used in clinical settings.
See also: S Droz-Georget Lathion et al (April 2015)
In this issue of EMBO Molecular Medicine, Droz‐Georget Lathion et al developed a new strategy for ex vivo single‐cell gene therapy that allows extensive genomic and functional characterization of the genetically repaired cells before they can be used in clinical settings.
- © 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.
- 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.
Pages
