• c-Myc inhibition decreases CIP2A and reduces BCR-ABL1 tyrosine kinase activity in chronic myeloid leukemia.

      Lucas, Claire; Harris, Robert; Giannoudis, Athina; Clark, Richard; University of Liverpool, Royal Liverpool University hospital (Ferrata Storti Foundation, 2015-05-01)
      NA
    • Ca

      Wong, Vincent K-W.; Qiu, Congling; Xu, Su-Wei; Law, Betty Yuen Kwan; Zeng, Wu; Wang, Hui; Michelangeli, Francesco; Dias, Ivo Ricardo De Seabra Rodrigues; Qu, Yuan Qing; Chan, Tsz Wai; et al. (2019-05-23)
      Celastrol exhibits anti-arthritic effect in rheumatoid arthritis (RA), but the role of celastrol-mediated Ca mobilization in treatment of RA remains unelucidated. Here, we illustrate the regulatory role of celastrol-induced Ca signalling in synovial fibroblasts of RA patients and adjuvant-induced arthritis (AIA) in rats. Molecular target of celastrol was determined by computational docking, Ca dynamic and functional assays on SERCA. Ca -mediated autophagy in RASFs/RAFLS and the underlying mechanism were verified by quantification of endogenous LC3-II puncta, immunoblotting, and flow cytometry with the Ca chelator (BAPTA/AM) or suitable inhibitors. The anti-arthritic effect of celastrol, autophagy induction and growth rate of synovial fibroblasts in AIA rats were monitored by microCT and immunofluorescence staining. mRNA from joint tissues of AIA rats was isolated for transcriptional analysis of inflammatory genes. The role of Ca in regulating the identified genes was investigated by knockdown of calmodulin, calpains, and calcineurin. Celastrol inhibited SERCA to induce autophagy-dependent cytotoxicity in RASFs/RAFLS via CaMKKβ-AMPK-mTOR pathway and repressed arthritis symptoms in AIA rats. BAPTA/AM hampered the in vitro and in vivo effectiveness of celastrol. Inflammatory- and autoimmunity-associated genes downregulated by celastrol in joint tissues of AIA rat were restored by BAPTA/AM. Knockdown of calmodulin, calpains, and calcineurin in RAFLS confirmed the role of Ca in celastrol-regulated gene expression. Celastrol triggered Ca signalling to induce autophagic cell death in RASFs/RAFLS and ameliorated arthritis in AIA rats mediated by calcium-dependent/-binding proteins facilitating the exploitation of anti-arthritic drugs based on manipulation of Ca signalling. [Abstract copyright: This article is protected by copyright. All rights reserved.]
    • Cancerous inhibitor of protein phosphatase 2A (CIP2A) modifies energy metabolism via 5′ AMP-activated protein kinase signalling in malignant cells

      Austin, James A.; orcid: 0000-0002-5384-5221; Jenkins, Rosalind E.; Austin, Gemma M.; Glenn, Mark A.; Dunn, Karen; Scott, Laura; Lucas, Claire M.; Clark, Richard E. (Portland Press Ltd., 2019-08-15)
      Abstract Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an adverse biomarker across many malignancies. Using K562 cells engineered to have high or low CIP2A expression, we show that high CIP2A levels significantly bias cellular energy production towards oxidative phosphorylation (OXPHOS) rather than glycolysis. Mass spectrometric analysis of CIP2A interactors and isobaric tagging for relative and absolute protein quantitation (ITRAQ) experiments identified many associated proteins, several of which co-vary with CIP2A level. Many of these CIP2A associating and co-varying proteins are involved in energy metabolism including OXPHOS, or in 5′ AMP-activated protein kinase (AMPK) signalling, and manipulating AMPK activity mimics the effects of low/high CIP2A on OXPHOS. These effects are dependent on the availability of nutrients, driven by metabolic changes caused by CIP2A. CIP2A level did not affect starvation-induced AMPK phosphorylation of Unc-51 autophagy activating kinase 1 (ULK-1) at Ser555, but autophagy activity correlated with an increase in AMPK activity, to suggest that some AMPK processes are uncoupled by CIP2A, likely via its inhibition of protein phosphatase 2A (PP2A). The data demonstrate that AMPK mediates this novel CIP2A effect on energy generation in malignant cells.
    • Canine mesenchymal stem cells are neurotrophic and angiogenic: An in vitro assessment of their paracrine activity.

      Johnson, William Eustace Basil; Al Delfi, Ibtesam; Aston University, University of Chester, Veterinary Tissue Bank Ltd (Elsevier, 2016-09-19)
      Mesenchymal stem cells (MSCs) have been used in cell replacement therapies for connective tissue damage, but also can stimulate wound healing through paracrine activity. In order to further understand the potential use of MSCs to treat dogs with neurological disorders, this study examined the paracrine action of adipose-derived canine MSCs on neuronal and endothelial cell models. The culture-expanded MSCs exhibited a MSC phenotype according to plastic adherence, cell morphology, CD profiling and differentiation potential along mesenchymal lineages. Treating the SH-SY5Y neuronal cell line with serum-free MSC culture-conditioned medium (MSC CM) significantly increased SH-SY5Y cell proliferation (P <0.01), neurite outgrowth (P = 0.0055) and immunopositivity for the neuronal marker βIII-tubulin (P = 0.0002). Treatment of the EA.hy926 endothelial cell line with MSC CM significantly increased the rate of wound closure in endothelial cell scratch wound assays (P = 0.0409), which was associated with significantly increased endothelial cell proliferation (P <0.05) and migration (P = 0.0001). Furthermore, canine MSC CM induced endothelial tubule formation in EA.hy926 cells in a soluble basement membrane matrix. Hence, this study has demonstrated that adipose-derived canine MSC CM stimulated neuronal and endothelial cells probably through the paracrine activity of MSC-secreted factors. This supports the use of canine MSC transplants or their secreted products in the clinical treatment of dogs with neurological disorders and provides some insight into possible mechanisms of action.
    • Cardiac Rehabilitation Delivery Model for Low-Resource Settings: An International Council of Cardiovascular Prevention and Rehabilitation Consensus Statement

      Grace, Sherry L.; Turk-Adawi, Karam I.; Contractor, Aashish; Atrey, Alison; Campbell, Norman R. C.; Derman, Wayne; Ghisi, Gabriela L. M.; Sarkar, Bidyut K.; Yeo, Tee J.; Lopez-Jimenenez, Francisco; et al. (Elsevier, 2016-08-17)
      Cardiovascular disease (CVD) is a global epidemic, which is largely preventable. Cardiac rehabilitation (CR) is demonstrated to be efficacious and cost-effective for secondary prevention in high-income countries. Given its affordability, CR should be more broadly implemented in middle-income countries as well. Hence, the International Council of Cardiovascular Prevention and Rehabilitation (ICCPR) convened a writing panel to recommend strategies to deliver all core CR components in low-resource settings, namely: (1) initial assessment, (2) lifestyle risk factor management (i.e., diet, tobacco, mental health), (3) medical risk factor management (lipids, blood pressure), (4) education for self-management; (5) return to work; and (6) outcome evaluation. Approaches to delivering these components in alternative, arguably lower-cost settings, such as the home, community and primary care, are provided. Recommendations on delivering each of these components where the most-responsible CR provider is a non-physician, such as an allied healthcare professional or community health care worker, are also provided.
    • CD271-selected mesenchymal stem cells from adipose tissue enhance cartilage repair and are less angiogenic than plastic adherent mesenchymal stem cells

      Kohli, Nupur; Johnson, William Eustace Basil; Uchida, Kenzo; Aston University, University of Chester, University of Fukui (Nature, 2019-02-28)
      CD271 is a marker of bone marrow MSCs with enhanced differentiation capacity for bone or cartilage repair. However, the nature of CD271+ MSCs from adipose tissue (AT) is less well understood. Here, we investigated the differentiation, wound healing and angiogenic capacity of plastic adherent MSCs (PA MSCs) versus CD271+ MSCs from AT. There was no difference in the extent to which PA MSCs and CD271+ MSCs formed osteoblasts, adipocytes or chondrocytes in vitro. In contrast, CD271+ MSCs transplanted into athymic rats significantly enhanced osteochondral wound healing with reduced vascularisation in the repair tissue compared to PA MSCs and control animals; there was little histological evidence of mature articular cartilage formation in all animals. Conditioned medium from CD271+ MSC cultures was less angiogenic than PA MSC conditioned medium, and had little effect on endothelial cell migration or endothelial tubule formation in vitro. The low angiogenic activity of CD271+ MSCs and improved early stage tissue repair of osteochondral lesions when transplanted, along with a comparable differentiation capacity along mesenchymal lineages when induced, suggests that these selected cells are a better candidate than PA MSCs for the repair of cartilaginous tissue.
    • CIP2A- and SETBP1-mediated PP2A inhibition reveals AKT S473 phosphorylation to be a new biomarker in AML

      Hills, Robert; Burnett, Alan; Lucas, Claire; Scott, Laura; Carmell, Natasha; Holcroft, Alison; Clark, Richard; University of Liverpool, Royal Liverpool University hospital, University of Cardiff (American Society for Hematology, 2018-04-27)
      Key Points PP2A inhibition occurs in AML by 2 different pathways: CIP2A in normal karyotype patients and SETBP1 in adverse karyotype patients. AKTS473 phosphorylation is a predictor of survival, and diagnostic levels of AKTS473 could be a novel biomarker in AML.
    • Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017)

      Huang, Hongyun; Young, Wise; Chen, Lin; Feng, Shiqing; Zoubi, Ziad M. Al.; Sharma, Hari Shanker; Saberi, Hooshang; Moviglia, Gustavo A.; He, Xijing; Muresanu, Dafin F.; et al. (SAGE Publications, 2018-04-11)
    • Cognitive function and disability in late Life: An ecological validation of the 10/66 battery of cognitive tests among community dwelling older adults in south India

      Krishna, Murali; Beulah, Eunice; Jones, Steven; Sundaracharj, Rajesh; Saroja, A.; Kumaran, Kalyanaraman; Karat, Samuel C.; Prince, Martin; Fall, Caroline H. D.; University of Chester (Wiley, 2015-12-17)
      Key Points • 10/66 cognitive tests are well suited for identification of older adults with cognitive and functional impairment at a population level in LMIC setting. • Lower scores on individual domains of the 10/66 battery of cognitive tests are associated with higher levels of disability and functional impairment. • It is feasible to administer 10/66 cognitive assessments in participant's own homes in India. • 10/66 cognitive tests are education and culture fair, suitable for use in population based research in India.
    • Comment on "PP2A inhibition sensitizes cancer stem cells to ABL tyrosine kinase inhibitors in BCR-ABL human leukemia".

      Perrotti, Danilo; Agarwal, Anupriya; Lucas, Claire; Narla, Goutham; Neviani, Paolo; Odero, Maria D.; Ruvolo, Peter P.; Verrills, Nicole M. (American Association for the Advancement of Science, 2019-07-17)
      LB100 does not sensitize CML stem cells to tyrosine kinase inhibitor–induced apoptosis.
    • Commentary: Endovascular Sealing of Abdominal Aortic Aneurysms: Do Current Data Justify Wider Use?

      Torella, Francesco; McWilliams, Richard G.; Fisher, Robert K. (SAGE Publications, 2018-04-12)
    • Comparison of Mesenchymal Stromal Cells Isolated From Murine Adipose Tissue and Bone Marrow in the Treatment of Spinal Cord Injury

      Takahashi, Ai; Johnson, William Eustace Basil; Uchida, Kenzo; Matsumine, Akihiko; University of Chester, University of Fukui (SAGE, 2018-05-10)
      The use of mesenchymal stromal cell (MSC) transplantation to repair the injured spinal cord has shown consistent benefits in preclinical models. However, the low survival rate of grafted MSC is one of the most important problems. In the injured spinal cord, transplanted cells are exposed to hypoxic conditions and exposed to nutritional deficiency caused by poor vascular supply. Also, the transplanted MSCs face cytotoxic stressors that cause cell death. The aim of this study was to compare adipose-derived MSCs (AD-MSCs) and bone marrow-derived MSCs (BM-MSCs) isolated from individual C57BL6/J mice in relation to: (i) cellular characteristics, (ii) tolerance to hypoxia, oxidative stress and serum-free conditions, and (iii) cellular survival rates after transplantation. AD-MSCs and BM-MSCs exhibited a similar cell surface marker profile, but expressed different levels of growth factors and cytokines. To research their relative stress tolerance, both types of stromal cells were incubated at 20.5% O2 or 1.0% O2 for 7 days. Results showed that AD-MSCs were more proliferative with greater culture viability under these hypoxic conditions than BM-MSCs. The MSCs were also incubated under H2O2-induced oxidative stress and in serum-free culture medium to induce stress. AD-MSCs were better able to tolerate these stress conditions than BMMSCs; similarly when transplanted into the spinal cord injury region in vivo, AD-MSCs demonstrated a higher survival rate post transplantation Furthermore, this increased AD-MSC survival post transplantation was associated with preservation of axons and enhanced vascularization, as delineated by increases in anti-gamma isotype of protein kinase C and CD31 immunoreactivity, compared with the BM-MSC transplanted group. Hence, our results indicate that AD-MSCs are an attractive alternative to BM-MSCs for the treatment of severe spinal cord injury. However, it should be noted that the motor function was equally improved following moderate spinal cord injury in both groups, but with no significant improvement seen unfortunately following severe spinal cord injury in either group
    • A comparison of self-reported and device measured sedentary behaviour in adults: a systematic review and meta-analysis.

      Cardilli, Luca; Reed, Jennifer L; Saunders, Travis J; Kite, Chris; Douilette, K; Fournier, K; Buckley, John P; University of Ottawa
      Abstract BACKGROUND: Sedentary behaviour (SB) is a risk factor for chronic disease and premature mortality. While many individual studies have examined the reliability and validity of various self-report measures for assessing SB, it is not clear, in general, how self-reported SB (e.g., questionnaires, logs, ecological momentary assessments (EMAs)) compares to device measures (e.g., accelerometers, inclinometers). OBJECTIVE: The primary objective of this systematic review was to compare self-report versus device measures of SB in adults. METHODS: Six bibliographic databases were searched to identify all studies which included a comparable self-report and device measure of SB in adults. Risk of bias within and across studies was assessed. Results were synthesized using meta-analyses. RESULTS: The review included 185 unique studies. A total of 123 studies comprising 173 comparisons and data from 55,199 participants were used to examine general criterion validity. The average mean difference was -105.19 minutes/day (95% CI: -127.21, -83.17); self-report underestimated sedentary time by ~1.74 hours/day compared to device measures. Self-reported time spent sedentary at work was ~40 minutes higher than when assessed by devices. Single item measures performed more poorly than multi-item questionnaires, EMAs and logs/diaries. On average, when compared to inclinometers, multi-item questionnaires, EMAs and logs/diaries were not significantly different, but had substantial amount of variability (up to 6 hours/day within individual studies) with approximately half over-reporting and half under-reporting. A total of 54 studies provided an assessment of reliability of a self-report measure, on average the reliability was good (ICC = 0.66). CONCLUSIONS: Evidence from this review suggests that single-item self-report measures generally underestimate sedentary time when compared to device measures. For accuracy, multi-item questionnaires, EMAs and logs/diaries with a shorter recall period should be encouraged above single item questions and longer recall periods if sedentary time is a primary outcome of study. Users should also be aware of the high degree of variability between and within tools. Studies should exert caution when comparing associations between different self-report and device measures with health outcomes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019118755. KEYWORDS: Self-report; device; sedentary behaviour; systematic review
    • Comparison of whole body SOD1 knockout with muscle specific SOD1 knockout mice reveals a role for nerve redox signaling in regulation of degenerative pathways in skeletal muscle.

      Nye, Gareth; Sakellariou, Giorgos; McDonagh, Brian; Porter, Helen; Giakoumaki, Ifigeneia; Earl, Kate; Vasilaki, Aphrodite; Brooks, Susan; Richardson, Arlan; Van Remmen, Holly; et al. (Mary Ann Liebert, 2017-12-12)
      Aims: Lack of Cu,Zn-superoxide dismutase (CuZnSOD) in homozygous knockout mice (Sod1−/−) leads to accelerated age-related muscle loss and weakness, but specific deletion of CuZnSOD in skeletal muscle (mSod1KO mice) or neurons (nSod1KO mice) resulted in only mild muscle functional deficits and failed to recapitulate the loss of mass and function observed in Sod1−/− mice. To dissect any underlying cross-talk between motor neurons and skeletal muscle in the degeneration in Sod1−/− mice, we characterized neuromuscular changes in the Sod1−/− model compared with mSod1KO mice and examined degenerative molecular mechanisms and pathways in peripheral nerve and skeletal muscle. Results: In contrast to mSod1KO mice, myofiber atrophy in Sod1−/− mice was associated with increased muscle oxidative damage, neuromuscular junction degeneration, denervation, nerve demyelination, and upregulation of proteins involved in maintenance of myelin sheaths. Proteomic analyses confirmed increased proteasomal activity and adaptive stress responses in muscle of Sod1−/− mice that were absent in mSod1KO mice. Peripheral nerve from neither Sod1−/− nor mSod1KO mice showed increased oxidative damage or molecular responses to increased oxidation compared with wild type mice. Differential cysteine (Cys) labeling revealed a specific redox shift in the catalytic Cys residue of peroxiredoxin 6 (Cys47) in the peripheral nerve from Sod1−/− mice. Innovation and Conclusion: These findings demonstrate that neuromuscular integrity, redox mechanisms, and pathways are differentially altered in nerve and muscle of Sod1−/− and mSod1KO mice. Results support the concept that impaired redox signaling, rather than oxidative damage, in peripheral nerve plays a key role in muscle loss in Sod1−/− mice and potentially sarcopenia during aging. Antioxid. Redox Signal. 28, 275–295. Innovation This is the first study to compare the molecular mechanisms and pathways that occur in both skeletal muscle and peripheral nerve of Sod1−/− and mSod1KO mice in an effort to examine the relative cross-talk and role of pre- and postsynaptic changes in redox homeostasis in loss of neuromuscular integrity and function that occurs with aging. This study highlights that impaired redox signaling in peripheral nerve rather than oxidative damage appears to play a key role in altering the integrity of peripheral nerves and motor neurons and potentially age-associated muscle atrophy and functional deficits. These results are potentially clinically significant and have widespread implications for the understanding of sarcopenia during aging.
    • Comparisons of attempted suicide between India and UK

      Jones, Steven; Keenan, Paul; Krishna, Murali; University of Chester (Mental Health Nursing Association, 2014)
      This paper aims to raise the issues and dilemmas within India by suicide and attempted suicide. In the UK evidence-based interventions have progressed over the past 20 years and changes are having positive benefits on standards of interventions and reducing deaths in some areas by suicide. However, when comparing one culture’s custom and practice with another, deficits of some areas of practice present and this facilitates some interesting insights for investigation. Fundamentally, the aim is not to place one above another but to aid identification for cross-cultural comparisons leading to practice advancements.
    • Conscientious objection and physician-assisted suicide: a viable option in the UK?

      Willis, Derek; George, Rob (2018-11-15)
      Conscience objection is a proposed way of ensuring that medical practitioners who object to physician-assisted suicide may avoid having to be involved in such a procedure if this is legalised. This right on the part of healthcare professionals already exists in certain circumstances. This paper examines the ethical and legal grounds for conscientious objection for medical professionals and shows how it is heavily criticised in circumstances where it is already used. The paper comes to the conclusion that as the grounds and application of conscience objection are no longer as widely accepted, its future application in any legislation can be called into question. [Abstract copyright: © Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.]
    • Conserved sequence-specific lincRNA-steroid receptor interactions drive transcriptional repression and direct cell fate

      Hudson, William H.; Pickard, Mark R.; de Vera, Ian M.; Kuiper, Emily G.; Mourtada-Maarabouni, Mirna; Conn, Graeme L.; Kojetin, Douglas J.; Williams, Gwyn T.; Ortlund, Eric A.; Emory University School of Medicine; Keele University; Scripps Research Institute (Nature Publishing Group, 2014-11-07)
      The majority of the eukaryotic genome is transcribed, generating a significant number of long intergenic noncoding RNAs (lincRNAs). Although lincRNAs represent the most poorly understood product of transcription, recent work has shown lincRNAs fulfill important cellular functions. In addition to low sequence conservation, poor understanding of structural mechanisms driving lincRNA biology hinders systematic prediction of their function. Here we report the molecular requirements for the recognition of steroid receptors (SRs) by the lincRNA growth arrest-specific 5 (Gas5), which regulates steroid-mediated transcriptional regulation, growth arrest and apoptosis. We identify the functional Gas5-SR interface and generate point mutations that ablate the SR-Gas5 lincRNA interaction, altering Gas5-driven apoptosis in cancer cell lines. Further, we find that the Gas5 SR-recognition sequence is conserved among haplorhines, with its evolutionary origin as a splice acceptor site. This study demonstrates that lincRNAs can recognize protein targets in a conserved, sequence-specific manner in order to affect critical cell functions.
    • Decision making for refusals of treatment—a framework to consider

      Jones, Steven; Monteith, Paul; Williams, Barry (Journal of Paramedic Practice, 2014-05-02)
      Challenges to practice are encountered on a daily basis by paramedics that often share many common recurring themes around consent or refusal to treatment. The benefits of training and open debate acknowledge the often complex decisions relating to consent and mental capacity and reduce opportunities for future legal challenge. How the law should be integrated into everyday decision making will be examined and a framework proposed to assist practice for defendable decision making. This article was inspired following joint training undertaken with paramedics and local critical incident managers from the police, which highlighted a need for a practical decision-making framework to be available for application during incidents and for use as an analytical tool to aid post-decision reflection and learning at debrief.
    • The developing landscape of diagnostic and prognostic biomarkers for spinal cord injury in cerebrospinal fluid and blood

      Hulme CH; Brown SJ; Fuller HR; Riddell J; Osman A; Chowdhury J; Kumar N; Johnson WE; Wright KT; Keele University, RJAH Orthopaedic Hospital, University of Glasgow, University of Chester (Nature Publishing Group, 2016-12-20)
      STUDY DESIGN: Review study. OBJECTIVES: The identification of prognostic biomarkers of spinal cord injury (SCI) will help to assign SCI patients to the correct treatment and rehabilitation regimes. Further, the detection of biomarkers that predict permanent neurological outcome would aid in appropriate recruitment of patients into clinical trials. The objective of this review is to evaluate the current state-of-play in this developing field. SETTING: Studies from multiple countries were included. METHODS: We have completed a comprehensive review of studies that have investigated prognostic biomarkers in either the blood or cerebrospinal fluid (CSF) of animals and humans following SCI. RESULTS: Targeted and unbiased approaches have identified several prognostic biomarkers in CSF and blood. These proteins associate with cellular damage following SCI and include components from neurons, oligodendrocytes and reactive astrocytes, that is, neurofilament proteins, glial fibrillary acidic protein, Tau and S100 calcium-binding protein β. Unbiased approaches have also identified microRNAs that are specific to SCI, as well as other cell damage-associated proteins. CONCLUSIONS: The discovery and validation of stable, specific, sensitive and reproducible biomarkers of SCI is a rapidly expanding field of research. So far, few studies have utilised unbiased approaches aimed at the discovery of biomarkers within the CSF or blood in this field; however, some targeted approaches have been successfully used. Several studies using various animal models and some with small human patient cohorts have begun to pinpoint biomarkers in the CSF and blood with putative prognostic value. An increased sample size will be required to validate these biomarkers in the heterogeneous clinical setting.
    • The Development and Growth of Tissues Derived From Cranial Neural Crest and Primitive Mesoderm Is Dependent on the Ligation Status of Retinoic Acid Receptor γ: Evidence That Retinoic Acid Receptor γ Functions to Maintain stem/progenitor Cells in the Absence of Retinoic Acid

      Johnson, William Eustace Basil; Wai, Htoo Aung; Aston University (Mary Ann Liebert, Inc, 2015-02-15)
      Retinoic acid (RA) signaling is important to normal development. However, the function of the different RA receptors (RARs)--RARα, RARβ, and RARγ--is as yet unclear. We have used wild-type and transgenic zebrafish to examine the role of RARγ. Treatment of zebrafish embryos with an RARγ-specific agonist reduced somite formation and axial length, which was associated with a loss of hoxb13a expression and less-clear alterations in hoxc11a or myoD expression. Treatment with the RARγ agonist also disrupted formation of tissues arising from cranial neural crest, including cranial bones and anterior neural ganglia. There was a loss of Sox 9-immunopositive neural crest stem/progenitor cells in the same anterior regions. Pectoral fin outgrowth was blocked by RARγ agonist treatment. However, there was no loss of Tbx-5-immunopositive lateral plate mesodermal stem/progenitor cells and the block was reversed by agonist washout or by cotreatment with an RARγ antagonist. Regeneration of the caudal fin was also blocked by RARγ agonist treatment, which was associated with a loss of canonical Wnt signaling. This regenerative response was restored by agonist washout or cotreatment with the RARγ antagonist. These findings suggest that RARγ plays an essential role in maintaining stem/progenitor cells during embryonic development and tissue regeneration when the receptor is in its nonligated state.