Regenerative Medicine
- Salivary glands regenerate after radiation injury through SOX2‐mediated secretory cell replacement
- Elaine Emmerson1,3,†,
- Alison J May1,†,
- Lionel Berthoin1,
- Noel Cruz‐Pacheco1,
- Sara Nathan1,
- Aaron J Mattingly1,
- Jolie L Chang2,
- William R Ryan2,
- Aaron D Tward2 and
- Sarah M Knox (sarah.knox{at}ucsf.edu)*,1
- 1Program in Craniofacial Biology, Department of Cell and Tissue Biology, University of California, San Francisco, CA, USA
- 2Department of Otolaryngology, University of California, San Francisco, CA, USA
- 3Present Address: The MRC Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh, UK
- ↵*Corresponding author. Tel: +1 415 502 0811; E‐mail: sarah.knox{at}ucsf.edu
↵† These authors contributed equally to this work as first authors
Salivary glands regenerate after radiation injury through SOX2‐mediated secretory acinar cell replacement as shown using genetic lineage tracing and ablation methods, in combination with in vivo and ex vivo gamma radiation‐induced damage models.
Synopsis
Salivary glands regenerate after radiation injury through SOX2‐mediated secretory acinar cell replacement as shown using genetic lineage tracing and ablation methods, in combination with in vivo and ex vivo gamma radiation‐induced damage models.
SOX2+ stem cells are essential to acinar cell replacement in the sublingual gland (SLG) during homeostasis and after radiation‐induced damage.
SOX2‐mediated acinar cell replacement is contingent on neuronal muscarinic signalling.
In the absence of nerves, a muscarinic mimetic can drive SOX2‐mediated regeneration.
SOX2 function is essential for SLG regeneration following radiation‐induced injury.
SOX2 along with parasympathetic nerves are diminished in human salivary gland biopsies following irradiation therapy and SOX2 and the acinar lineage are upregulated in response to muscarinic activation.
EMBO Mol Med (2018) 10: e8051
- Received May 18, 2017.
- Revision received December 14, 2017.
- Accepted December 18, 2017.
- © 2018 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.
- Regenerating human epithelia with cultured stem cells: feeder cells, organoids and beyond
- Robert E Hynds1,2,3,
- Paola Bonfanti (p.bonfanti{at}ucl.ac.uk)*,3,4,5 and
- Sam M Janes (s.janes{at}ucl.ac.uk)*,1
- 1Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK
- 2CRUK Lung Cancer Centre of Excellence, UCL Cancer Institute, University College London, London, UK
- 3The Francis Crick Institute, London, UK
- 4Great Ormond Street Institute of Child Health, University College London, London, UK
- 5Institute of Immunity and Transplantation, University College London, London, UK
- ↵*
Corresponding author. Tel: +44 20 3796 3531; E‐mail: p.bonfanti{at}ucl.ac.uk
Corresponding author. Tel: +44 20 3108 7746; E‐mail: s.janes{at}ucl.ac.uk
In this timely review article, Paola Bonfanti, Robert Hynds and Sam Janes provide an insightful discussion and chronological overview of stem cells and regenerative medicine.
EMBO Mol Med (2018) 10: 139–150
- Received June 30, 2017.
- Revision received September 26, 2017.
- Accepted November 29, 2017.
- © 2017 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.
- CXCL12α/SDF‐1 from perisynaptic Schwann cells promotes regeneration of injured motor axon terminals
- Samuele Negro1,
- Francesca Lessi2,
- Elisa Duregotti1,
- Paolo Aretini2,
- Marco La Ferla2,
- Sara Franceschi2,
- Michele Menicagli2,
- Elisanna Bergamin1,
- Egle Radice3,
- Marcus Thelen3,
- Aram Megighian1,
- Marco Pirazzini1,
- Chiara M Mazzanti (c.mazzanti{at}fondazionepisascienza.org)*,2,
- Michela Rigoni (michela.rigoni{at}unipd.it)*,1 and
- Cesare Montecucco (cesare.montecucco{at}unipd.it)*,1,4
- 1Department of Biomedical Sciences, University of Padua, Padua, Italy
- 2Laboratory of Genomics, Pisa Science Foundation, Pisa, Italy
- 3Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland
- 4CNR Institute of Neuroscience, Padua, Italy
- ↵*
Corresponding author. Tel: +39 050974061; E‐mail: c.mazzanti{at}fondazionepisascienza.org
Corresponding author. Tel: +39 0498276077; E‐mail: michela.rigoni{at}unipd.it
Corresponding author. Tel: +39 0498276058; E‐mail: cesare.montecucco{at}unipd.it
Motor axon terminal degeneration induces perisynaptic Schwann cells to release the chemokine CXCL12, which binds to neuronal CXCR4 receptors promoting axonal growth to reform a functional neuromuscular junction.
Synopsis
Motor axon terminal degeneration induces perisynaptic Schwann cells to release the chemokine CXCL12α, which binds to neuronal CXCR4 receptors promoting axonal growth to reform a functional neuromuscular junction.
The levels of both CXCL12α mRNA and the encoded protein increase in perisynaptic Schwann cells upon nerve terminal degeneration induced by the spider toxin α‐latrotoxin.
In vivo neutralization of the chemokine by a specific antibody or inhibition of its receptor CXCR4 delay neuromuscular junction functional recovery after neurodegeneration.
In vivo administration of recombinant CXCL12α accelerates neuroregeneration most likely by promoting the growth of motor axons.
EMBO Mol Med (2017) 9: 1000–1010
- Received October 26, 2016.
- Revision received May 3, 2017.
- Accepted May 8, 2017.
- © 2017 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.
- Transient transcription factor (OSKM) expression is key towards clinical translation of in vivo cell reprogramming
de Lázaro, Cossu and Kostarelos comment on the prospects of short‐term in vivo OSKM induction to initiate cell reprogramming and enhance tissue regeneration, while avoiding the threat of generating teratomas.
- © 2017 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.
- The transcription factor GATA4 promotes myocardial regeneration in neonatal mice
- Mona Malek Mohammadi1,
- Badder Kattih1,
- Andrea Grund1,
- Natali Froese1,
- Mortimer Korf‐Klingebiel1,
- Anna Gigina1,
- Ulrike Schrameck1,
- Carsten Rudat2,
- Qiangrong Liang3,
- Andreas Kispert2,4,
- Kai C Wollert1,4,
- Johann Bauersachs1,4 and
- Joerg Heineke (heineke.joerg{at}mh-hannover.de)*,1,4
- 1Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover, Germany
- 2Institut für Molekularbiologie, Medizinische Hochschule Hannover, Hannover, Germany
- 3Department of Biomedical Sciences, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY, USA
- 4Cluster of Excellence REBIRTH, Medizinische Hochschule Hannover, Hannover, Germany
- ↵*Corresponding author. Tel: +49 511 532 3079; Fax: +49 511 532 5412; E‐mail: heineke.joerg{at}mh-hannover.de
Why heart regeneration in mice is no longer possible after the age of 7 days remains unknown. Here, the robust downregulation of cardiac GATA4 levels occurring around the same time is shown to be at least in part responsible for this phenomenon.
Synopsis
Why heart regeneration in mice is no longer possible after the age of 7 days remains unknown. Here, the robust downregulation of cardiac GATA4 levels occurring around the same time is shown to be at least in part responsible for this phenomenon.
Cardiac GATA4 expression is strongly downregulated (by about 70–80%) between postnatal day 1 (P1) and P7 in parallel with the loss of regenerative capacity of the heart.
Reconstitution of cardiac GATA4 levels by adenoviral gene transfer after P7 enhances cardiac regeneration after cryoinjury by promoting cardiomyocyte proliferation and angiogenesis.
Cardiomyocyte‐specific ablation of GATA4 decreases neonatal heart regeneration.
GATA4 promotes regeneration by inducing regenerative genes in the heart, such as IL‐13, cyclin A2, or IGF‐2R.
EMBO Mol Med (2017) 9: 265–279
- Received May 13, 2016.
- Revision received November 25, 2016.
- Accepted November 30, 2016.
- © 2017 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.
- Reprogramming‐derived gene cocktail increases cardiomyocyte proliferation for heart regeneration
- Yuan‐Yuan Cheng1,2,
- Yu‐Ting Yan1,2,
- David J Lundy2,
- Annie HA Lo2,
- Yu‐Ping Wang2,
- Shu‐Chian Ruan2,
- Po‐Ju Lin2 and
- Patrick CH Hsieh (phsieh{at}ibms.sinica.edu.tw)*,1,2,3
- 1Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
- 2Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
- 3Department of Surgery, Institute of Medical Genomics and Proteomics, Institute of Clinical Medicine, National Taiwan University & Hospital, Taipei, Taiwan
- ↵*Corresponding author. Tel: +886 2 27899170; Fax: +886 2 27858594; E‐mail: phsieh{at}ibms.sinica.edu.tw
The proliferation rate of remnant cardiomyocytes (CMs) is too low for cardiac regeneration after injury. Here, a gene cocktail is defined to induce CMs to efficiently proliferate, while improving cardiac function after myocardial infarction in mice.
Synopsis
The proliferation rate of remnant cardiomyocytes (CMs) is too low for cardiac regeneration after injury. Here, a gene cocktail is defined to induce CMs to efficiently proliferate, while improving cardiac function after myocardial infarction in mice.
The second day prior to the mesenchymal–epithelial transition was identified as the critical time for initiating cardiomyocyte reprogramming.
Microarray data analysis pinpointed a set of up‐regulated genes that were used to derive a reprogramming gene cocktail.
The gene cocktail recipe comprising FoxM1, Id1, and Jnk3‐shRNAs (FIJs) enhances cardiomyocyte proliferation.
Cardiomyocyte cell cycle re‐entry is followed by completed mitosis and cytokinesis to execute a delayed reprogramming.
The FIJs gene cocktail improves heart function after myocardial infarction in a mouse model.
EMBO Mol Med (2017) 9: 251–264
- Received April 28, 2016.
- Revision received November 27, 2016.
- Accepted November 29, 2016.
- © 2016 Academia Sinica. 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.
- Impaired liver regeneration in aged mice can be rescued by silencing Hippo core kinases MST1 and MST2
- Giulio Loforese1,
- Thomas Malinka1,
- Adrian Keogh1,
- Felix Baier1,
- Cedric Simillion2,
- Matteo Montani3,
- Thanos D Halazonetis4,
- Daniel Candinas1 and
- Deborah Stroka (deborah.stroka{at}dkf.unibe.ch)*,1
- 1Department of Clinical Research, Visceral Surgery and Medicine, University of Bern, Bern, Switzerland
- 2Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland
- 3Institute of Pathology, University of Bern, Bern, Switzerland
- 4Department of Molecular Biology, University of Geneva, Geneva, Switzerland
- ↵*Corresponding author. Tel: +41 31 632 2748; E‐mail: deborah.stroka{at}dkf.unibe.ch
Inhibition of the Hippo core kinases MST1 and MST2 with siRNA has the therapeutic potential to improve liver regeneration in age‐related non‐regenerative disorders.
Synopsis
Inhibition of the Hippo core kinases MST1 and MST2 with siRNA has the therapeutic potential to improve liver regeneration in age‐related non‐regenerative disorders.
Hippo pathway proteins are differentially modulated throughout the quiescent, hypertrophic and proliferative phases of liver regeneration.
In aged mice, the modulation of Hippo proteins following partial hepatectomy is altered and liver regeneration is impaired.
siRNA encapsulated into liposomes efficiently targets liver parenchymal cells.
Deletion of the Hippo core kinases MST1 and MST2 partially restores liver regeneration in a non‐regenerative aged mouse model, suggesting them as promising candidates as pharmacological targets to treat non‐regenerative disorders.
EMBO Mol Med (2017) 9: 46–60
- Received November 24, 2015.
- Revision received October 24, 2016.
- Accepted October 28, 2016.
- © 2016 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.
- 4‐Aminopyridine promotes functional recovery and remyelination in acute peripheral nerve injury
- Kuang‐Ching Tseng1,2,
- Haiyan Li1,3,
- Andrew Clark3,4,
- Leigh Sundem3,
- Michael Zuscik1,3,
- Mark Noble (mark_noble{at}urmc.rochester.edu)*,5,† and
- John Elfar (openelfar{at}gmail.com)*,1,3,†
- 1Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- 2Department of Chemical Engineering, University of Rochester, Rochester, NY, USA
- 3Department of Orthopaedics & Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA
- 4Department of Biomedical Engineering, University of Rochester, Rochester, NY, USA
- 5Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA
- ↵*
Corresponding author. Tel: +1 585 273 1448; E‐mail: mark_noble{at}urmc.rochester.edu
Corresponding author. Tel: +1 585 273 3157; E‐mail: openelfar{at}gmail.com
↵† These authors contributed equally to this work
4‐aminopyridine, a clinically approved K+ channel blocker, is a novel regenerative agent that enhances endogenous repair processes and may enable improved management and treatment of acute peripheral nerve trauma.
Synopsis
4‐Aminopyridine, a clinically approved K+ channel blocker, is a novel regenerative agent that enhances endogenous repair processes and may enable improved management and treatment of acute peripheral nerve trauma.
Traumatic peripheral nerve damage is a major medical problem without effective treatment options for which diagnostic approaches have been static for decades.
In crush injuries of mouse sciatic nerve, acute treatment with 4‐aminopyridine (4‐AP) accelerated durable functional recovery and promoted remyelination.
4‐AP treatment also enabled distinction between incomplete and complete lesions more rapidly than existing approaches, potentially improving on current strategies for assigning patients to appropriate treatment groups.
Constant daily 4‐AP administration is approved to improve chronic walking disability in multiple sclerosis; therefore, transient use for regenerative purposes offers a promising opportunity for future clinical studies.
EMBO Mol Med (2016) 8: 1409–1420
- Received November 4, 2015.
- Revision received August 25, 2016.
- Accepted September 29, 2016.
- © 2016 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.
- Compassionate use of experimental therapies: who should decide?
- Patricia J Zettler (pzettler{at}gsu.edu)1
In addition to being an example of unsubstantiated hype about regenerative medicine, the controversy around the Italy‐based Stamina Foundation's unproven stem cell therapy represents another chapter in a continuing debate about how to balance patients' requests for early access to experimental medicines with requirements for demonstrating safety and effectiveness. Compassionate use of the Stamina therapy arguably should not have been permitted under Italy's laws, but public pressure was intense and judges ultimately granted access. One lesson from these events is that expert regulatory agencies may be the institutions most competent to make compassionate use decisions and that policies should include more specific criteria for authorizing compassionate use. But even where regulatory agencies make decisions based on clear rules, difficult questions will arise.
In the aftermath of the Stamina case, Patti Zettler discusses the difficult balance between the need to demonstrate safety and effectiveness of new medicines and requests from seriously ill patients for early access to experimental treatments.
- © 2015 The Author. 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.
- Reprogramming and transdifferentiation for cardiovascular development and regenerative medicine: where do we stand?
- 1Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
- 2Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, CA, USA
- 3Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
- 4Max Delbrück Center, Berlin, Germany
- 5Berlin Institute of Health, Berlin, Germany
- ↵*Corresponding author. Tel: +1 650 736 2246; E‐mail: joewu{at}stanford.edu
Comprehensive overview on how reprogramming and transdifferentiation can be exploited to generate induced pluripotent stem cell‐derived cardiomyocytes and induced cardiomyocytes to advance discovery and accelerate translation to the clinic.
EMBO Mol Med (2015) 7: 1090–1103
- Received March 22, 2015.
- Revision received June 7, 2015.
- Accepted June 15, 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.
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