Imperial College London

ProfessorMichaelSchneider

Faculty of MedicineNational Heart & Lung Institute

Chair in Cardiology
 
 
 
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Contact

 

+44 (0)20 7594 3027m.d.schneider Website

 
 
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Assistant

 

Miss Cassie Tarquini +44 (0)20 7594 3020

 
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Location

 

336ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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167 results found

Schneider M, Fiedler L, Chapman K, Xie M, Maifosie E, Jenkins M, Golforoush P, Bellahcene M, Noseda M, Faust D, Jarvis A, Newton G, Paiva MA, Harada M, Stuckey DJ, Song W, Habib J, Narasimham P, Aqil R, Sanmugalingam D, Yan R, Pavanello L, Sano M, Wang SC, Sampson RD, Kanayaganam S, Taffet GE, Michael LH, Entman ML, Tan T, Harding S, Low CMR, Tralau-Stewart C, Perrior T, Schneider MDet al., 2019, MAP4K4 inhibition promotes survival of human stem cell derived cardiomyocyte and reduces infarct size in vivo, Cell Stem Cell, Vol: 24, Pages: 579-591.e12, ISSN: 1875-9777

Heart disease is a paramount cause of global death and disability. Although cardiomyocyte death plays a causal role and its suppression would be logical, no clinical counter-measures target the responsible intracellular pathways. Therapeutic progress has been hampered by lack of preclinical human validation. Mitogen-activated protein kinase kinase kinase kinase-4 (MAP4K4) is activated in failing human hearts and relevant rodent models. Using human induced-pluripotent-stem-cell-derived cardiomyocytes (hiPSC-CMs) and MAP4K4 gene silencing, we demonstrate that death induced by oxidative stress requires MAP4K4. Consequently, we devised a small-molecule inhibitor, DMX-5804, that rescues cell survival, mitochondrial function, and calcium cycling in hiPSC-CMs. As proof of principle that drug discovery in hiPSC-CMs may predict efficacy in vivo, DMX-5804 reduces ischemia-reperfusion injury in mice by more than 50%. We implicate MAP4K4 as a well-posed target toward suppressing human cardiac cell death and highlight the utility of hiPSC-CMs in drug discovery to enhance cardiomyocyte survival.

Journal article

Bowling S, Di Gregorio A, Sancho M, Pozzi S, Aarts M, Signore M, Schneider MD, Martinez-Barbera JP, Gil J, Rodriguez TAet al., 2018, Author correction: P53 and mTOR signalling determine fitness selection through cell competition during early mouse embryonic development, Nature Communications, Vol: 9, ISSN: 2041-1723

The original version of this Article contained an error in the spelling of Juan Pedro Martinez-Barbera, which was incorrectly given as Juan Pedro Martinez Barbera. This error has now been corrected in both the PDF and HTML versions of the Article.

Journal article

Biswas S, Li P, Wu H, Shaffiquzzaman M, Murakami S, Schneider M, Mishina Y, Li B, Li Jet al., 2018, BMPRIA is required for osteogenic differentiation and RANKL expression in adult bone marrow mesenchymal stromal cells, Scientific Reports, Vol: 8, ISSN: 2045-2322

Bone morphogenetic proteins (BMPs) activate the canonical Smad1/5/8 and non-canonical Tak1-MAPK pathways via BMP receptors I and II to regulate skeletal development and bone remodeling. Specific ablation of Bmpr1a in immature osteoblasts, osteoblasts, or osteocytes results in an increase incancellousbone mass, yet opposite results have been reported regarding the underlying mechanisms. Moreover, the role for BMPRIA-mediated signaling in bone marrow mesenchymal stromal cells (BM-MSCs) has not been explored. Here, we specifically ablated Bmpr1a in BM-MSCs in adult mice to study the function of BMPR1A in bone remodeling and found that the mutant mice showed an increase in cancellousand cortical bone mass, which was accompanied by a decrease in bone formation rate and a greater decrease in bone resorption. Decreased bone formation was associated with a defect in BM-MSC osteogenic differentiation whereas decreased bone resorption was associated with a decrease in RANKL production and osteoclastogenesis. However, ablation of Ta k 1, a critical non-canonical signaling molecule downstream of BMP receptors, in BM-MSCs at adult stage did not affect bone remodeling. These results suggest that BMP signaling through BMPRIA controls BM-MSC osteogenic differentiation/bone formation and RANKL expression/osteoclastogenesis in adult mice independent of Tak1 signaling.

Journal article

Bowling S, Di Gregorio A, Sancho M, Pozzi S, Aarts M, Signore M, Schneider M, Martinez Barbera JP, Gil J, Rodriguez TAet al., 2018, P53 and mTOR signalling determine fitness selection through cell competition during early mouse embryonic development, Nature Communications, Vol: 9, ISSN: 2041-1723

Ensuring the fitness of the pluripotent cells that will contribute to future development is important both for the integrity of the germline and for proper embryogenesis. Consequently, it is becoming increasingly apparent that pluripotent cells can compare their fitness levels and signal the elimination of those cells that are less fit than their neighbours. In mammals the nature of the pathways that communicate fitness remain largely unknown. Here we identify that in the early mouse embryo and upon exit from naive pluripotency, the confrontation of cells with different fitness levels leads to an inhibition of mTOR signalling in the less fit cell type, causing its elimination. We show that during this process, p53 acts upstream of mTOR and is required to repress its activity. Finally, we demonstrate that during normal development around 35% of cells are eliminated by this pathway, highlighting the importance of this mechanism for embryonic development.

Journal article

Adamowicz M, Morgan CC, Haubner BJ, Noseda M, Collins MJ, Paiva MA, Srivastava PK, Gellert P, Razzaghi B, O'Gara P, Raina P, Game L, Bottolo L, Schneider MD, Harding SE, Penninger J, Aitman TJet al., 2018, Functionally conserved noncoding regulators of cardiomyocyte proliferation and regeneration in mouse and human, Circulation: Cardiovascular Genetics, Vol: 11, ISSN: 1942-325X

Background: The adult mammalian heart has little regenerative capacity after myocardial infarction (MI), whereas neonatal mouse heart regenerates without scarring or dysfunction. However, the underlying pathways are poorly defined. We sought to derive insights into the pathways regulating neonatal development of the mouse heart and cardiac regeneration post-MI.Methods and Results: Total RNA-seq of mouse heart through the first 10 days of postnatal life (referred to as P3, P5, P10) revealed a previously unobserved transition in microRNA (miRNA) expression between P3 and P5 associated specifically with altered expression of protein-coding genes on the focal adhesion pathway and cessation of cardiomyocyte cell division. We found profound changes in the coding and noncoding transcriptome after neonatal MI, with evidence of essentially complete healing by P10. Over two-thirds of each of the messenger RNAs, long noncoding RNAs, and miRNAs that were differentially expressed in the post-MI heart were differentially expressed during normal postnatal development, suggesting a common regulatory pathway for normal cardiac development and post-MI cardiac regeneration. We selected exemplars of miRNAs implicated in our data set as regulators of cardiomyocyte proliferation. Several of these showed evidence of a functional influence on mouse cardiomyocyte cell division. In addition, a subset of these miRNAs, miR-144-3p, miR-195a-5p, miR-451a, and miR-6240 showed evidence of functional conservation in human cardiomyocytes.Conclusions: The sets of messenger RNAs, miRNAs, and long noncoding RNAs that we report here merit further investigation as gatekeepers of cell division in the postnatal heart and as targets for extension of the period of cardiac regeneration beyond the neonatal period.

Journal article

Fujita J, Freire P, Coarfa C, Benham AL, Gunaratne P, Schneider MD, Dejosez M, Zwaka TPet al., 2017, Ronin Governs Early Heart Development by Controlling Core Gene Expression Programs., Cell Reports, Vol: 21, Pages: 1562-1573, ISSN: 2211-1247

Ronin (THAP11), a DNA-binding protein that evolved from a primordial DNA transposon by molecular domestication, recognizes a hyperconserved promoter sequence to control developmentally and metabolically essential genes in pluripotent stem cells. However, it remains unclear whether Ronin or related THAP proteins perform similar functions in development. Here, we present evidence that Ronin functions within the nascent heart as it arises from the mesoderm and forms a four-chambered organ. We show that Ronin is vital for cardiogenesis during midgestation by controlling a set of critical genes. The activity of Ronin coincided with the recruitment of its cofactor, Hcf-1, and the elevation of H3K4me3 levels at specific target genes, suggesting the involvement of an epigenetic mechanism. On the strength of these findings, we propose that Ronin activity during cardiogenesis offers a template to understand how important gene programs are sustained across different cell types within a developing organ such as the heart.

Journal article

Schneider MD, 2017, Upstairs, Downstairs: Atrial and Ventricular Cardiac Myocytes from Human Pluripotent Stem Cells, CELL STEM CELL, Vol: 21, Pages: 151-152, ISSN: 1934-5909

Journal article

Speidel AT, Stuckey DJ, Chow LW, Jackson LH, Noseda M, Abreu Pavia M, Schneider MD, Stevens MMet al., 2017, Multi-modal hydrogel-based platform to deliver and monitor cardiac progenitor/stem cell engraftment, ACS Central Science, Vol: 3, Pages: 338-348, ISSN: 2374-7951

Retention and survival of transplanted cells are major limitations to the efficacy of regenerative medicine, with short-term paracrine signals being the principal mechanism underlying current cell therapies for heart repair. Consequently, even improvements in short-term durability may have a potential impact on cardiac cell grafting. We have developed a multimodal hydrogel-based platform comprised of a poly(ethylene glycol) network cross-linked with bioactive peptides functionalized with Gd(III) in order to monitor the localization and retention of the hydrogel in vivo by magnetic resonance imaging. In this study, we have tailored the material for cardiac applications through the inclusion of a heparin-binding peptide (HBP) sequence in the cross-linker design and formulated the gel to display mechanical properties resembling those of cardiac tissue. Luciferase-expressing cardiac stem cells (CSC-Luc2) encapsulated within these gels maintained their metabolic activity for up to 14 days in vitro. Encapsulation in the HBP hydrogels improved CSC-Luc2 retention in the mouse myocardium and hind limbs at 3 days by 6.5- and 12- fold, respectively. Thus, this novel heparin-binding based, Gd(III)-tagged hydrogel and CSC-Luc2 platform system demonstrates a tailored, in vivo detectable theranostic cell delivery system that can be implemented to monitor and assess the transplanted material and cell retention.

Journal article

Hasham MG, Baxan N, Stuckey D, Dent O, Branca J, Perkins BRA, Duffy T, Hameed TS, Stella SE, Bellahcene M, Schneider MD, Harding SE, Rosenthal N, Sattler Set al., 2017, Systemic autoimmunity induced by Toll-like receptor 7/8 agonist Resiquimod causes myocarditis and dilated cardiomyopathy: a new model of autoimmune heart disease, Disease Models & Mechanisms, Vol: 10, Pages: 259-270, ISSN: 1754-8411

Systemic autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA) show significant heart involvement and cardiovascular morbidity, which can be due to systemically increased levels of inflammation or direct autoreactivity targeting cardiac tissue. Despite high clinical relevance, cardiac damage secondary to systemic autoimmunity lacks inducible rodent models. Here we characterize immune-mediated cardiac tissue damage in a new model of SLE induced by topical application of the TLR-7/8 agonist Resiquimod. We observe a cardiac phenotype reminiscent of autoimmune-mediated dilated cardiomyopathy, and identify auto-antibodies as major contributors to cardiac tissue damage. Resiquimod-induced heart disease is a highly relevant mouse model for mechanistic and therapeutic studies aiming to protect the heart during autoimmunity.

Journal article

Schneider MD, Baker AH, Riley P, 2016, Hopx and the Cardiomyocyte Parentage, Molecular Therapy, Vol: 23, Pages: 1420-1422, ISSN: 1525-0016

Journal article

Gallego Colon EJ, Villalba M, Tonkin J, Cruz F, Bernal JA, Jimenez-Borreguero L, Schneider M, Lara E, Rosenthal Net al., 2016, Intravenous delivery of adeno-associated virus 9-encoded IGF-1Ea propeptide improves post-infarct cardiac remodelling, npj Regenerative Medicine, Vol: 1, ISSN: 2057-3995

The insulin-like growth factor Ea propeptide (IGF-1Ea) is a powerful enhancer of cardiac muscle growth and regeneration, also blocking age-related atrophy and beneficial in multiple skeletal muscle diseases. The therapeutic potential of IGF-1Ea compared with mature IGF-1 derives from its local action in the area of synthesis. We have developed an adeno-associated virus (AAV) vector for IGF-1Ea delivery to the heart to treat mice after myocardial infarction and examine the reparative effects of local IGF-1Ea production on left ventricular remodelling. A cardiotropic AAV9 vector carrying a cardiomyocyte-specific IGF-1Ea-luciferase bi-cistronic gene expression cassette (AAV9.IGF-1Ea) was administered intravenously to infarcted mice, 5 h after ischemia followed by reperfusion (I/R), as a model of myocardial infarction. Virally encoded IGF-1Ea in the heart improved global left ventricular function and remodelling, as measured by wall motion and thickness, 28 days after delivery, with higher viral titers yielding better improvement. The present study demonstrates that single intravenous AAV9-mediated IGF-1Ea Gene Therapy represents a tissue-targeted therapeutic approach to prevent the adverse remodelling after myocardial infarct.

Journal article

Schneider MD, 2016, Heartbreak hotel: a convergence in cardiac regeneration, Development, Vol: 143, Pages: 1435-1441, ISSN: 0165-2214

In February 2016, the Company of Biologists hosted an intimate gathering of leading international researchers at the forefront of experimental cardiovascular regeneration, with its emphasis on ‘Transdifferentiation and Tissue Plasticity in Cardiovascular Rejuvenation’. As I review here, participants at the workshop revealed how understanding cardiac growth and lineage decisions at their most fundamental level has transformed the strategies in hand that presently energize the prospects for human heart repair.

Journal article

Wei K, Serpooshan V, Hurtado C, Diez-Cunado M, Zhao M, Maruyama S, Zhu W, Fajardo G, Noseda M, Nakamura K, Tian X, Liu Q, Wang A, Matsuura Y, Bushway P, Cai W, Savchenko A, Mahmoudi M, Schneider MD, van den Hoff MJB, Butte MJ, Yang PC, Walsh K, Zhou B, Bernstein D, Mercola M, Ruiz-Lozano Pet al., 2015, Epicardial FSTL1 reconstitution regenerates the adult mammalian heart, Nature, Vol: 525, Pages: 479-485, ISSN: 0028-0836

The elucidation of factors that activate the regeneration of the adult mammalian heart is of major scientific and therapeutic importance. Here we found that epicardial cells contain a potent cardiogenic activity identified as follistatin-like 1 (Fstl1). Epicardial Fstl1 declines following myocardial infarction and is replaced by myocardial expression. Myocardial Fstl1 does not promote regeneration, either basally or upon transgenic overexpression. Application of the human Fstl1 protein (FSTL1) via an epicardial patch stimulates cell cycle entry and division of pre-existing cardiomyocytes, improving cardiac function and survival in mouse and swine models of myocardial infarction. The data suggest that the loss of epicardial FSTL1 is a maladaptive response to injury, and that its restoration would be an effective way to reverse myocardial death and remodelling following myocardial infarction in humans.

Journal article

Gallego Colon E, Sampson RD, Sattler S, Schneider MD, Rosenthal N, Tonkin Jet al., 2015, Cardiac-restricted IGF-1Ea overexpression reduces the early accumulation of inflammatory myeloid cells and mediates expression of extracellular matrix remodelling genes after myocardial infarction, Mediators of Inflammation, Vol: 2015, ISSN: 1466-1861

Strategies to limit damage and improve repair after myocardial infarct remain a major therapeutic goal in cardiology. Our previous studies have shown that constitutive expression of a locally acting insulin-like growth factor-1 Ea (IGF-1Ea) propeptide promotes functional restoration after cardiac injury associated with decreased scar formation. In the current study, we investigated the underlying molecular and cellular mechanisms behind the enhanced functional recovery. We observed improved cardiac function in mice overexpressing cardiac-specific IGF-1Ea as early as day 7 after myocardial infarction. Analysis of gene transcription revealed that supplemental IGF-1Ea regulated expression of key metalloproteinases (MMP-2 and MMP-9), their inhibitors (TIMP-1 and TIMP-2), and collagen types (Col 1α1 and Col 1α3) in the first week after injury. Infiltration of inflammatory cells, which direct the remodelling process, was also altered; in particular there was a notable reduction in inflammatory Ly6C+ monocytes at day 3 and an increase in anti-inflammatory CD206+ macrophages at day 7. Taken together, these results indicate that the IGF-1Ea transgene shifts the balance of innate immune cell populations early after infarction, favouring a reduction in inflammatory myeloid cells. This correlates with reduced extracellular matrix remodelling and changes in collagen composition that may confer enhanced scar elasticity and improved cardiac function.

Journal article

Laury-Kleintop LD, Mulgrew JR, Heletz I, Nedelcoviciu RA, Chang MY, Harris DM, Koch WJ, Schneider MD, Muller AJ, Prendergast GCet al., 2015, Cardiac-Specific Disruption of Bin1 in Mice Enables a Model of Stress- and Age-Associated Dilated Cardiomyopathy, Journal of Cellular Biochemistry, Vol: 116, Pages: 2541-2551, ISSN: 1097-4644

Non-compensated dilated cardiomyopathy (DCM) leading to death from heart failure is rising rapidly in developed countries due to aging demographics, and there is a need for informative preclinical models to guide the development of effective therapeutic strategies to prevent or delay disease onset. In this study, we describe a novel model of heart failure based on cardiac-specific deletion of the prototypical mammalian BAR adapter-encoding gene Bin1, a modifier of age-associated disease. Bin1 deletion during embryonic development causes hypertrophic cardiomyopathy and neonatal lethality, but there is little information on how Bin1 affects cardiac function in adult animals. Here we report that cardiomyocyte-specific loss of Bin1 causes age-associated dilated cardiomyopathy (DCM) beginning by 8–10 months of age. Echocardiographic analysis showed that Bin1 loss caused a 45% reduction in ejection fraction during aging. Younger animals rapidly developed DCM if cardiac pressure overload was created by transverse aortic constriction. Heterozygotes exhibited an intermediate phenotype indicating Bin1 is haplo-insufficient to sustain normal heart function. Bin1 loss increased left ventricle (LV) volume and diameter during aging, but it did not alter LV volume or diameter in hearts from heterozygous mice nor did it affect LV mass. Bin1 loss increased interstitial fibrosis and mislocalization of the voltage-dependent calcium channel Cav1.2, and the lipid raft scaffold protein caveolin-3, which normally complexes with Bin1 and Cav1.2 in cardiomyocyte membranes. Our findings show how cardiac deficiency in Bin1 function causes age- and stress-associated heart failure, and they establish a new preclinical model of this terminal cardiac disease.

Journal article

Morez CY, Noseda M, Abreu Paiva M, Belian E, Schneider MD, Stevens MMet al., 2015, Enhanced efficiency of genetic programming toward cardiomyocyte creation through topographical cues, Biomaterials, Vol: 70, Pages: 94-104, ISSN: 1878-5905

Generation of de novo cardiomyocytes through viral over-expression of key transcription factors represents a highly promising strategy for cardiac muscle tissue regeneration. Although the feasibility of cell reprogramming has proven possible both in vitro and in vivo, the efficiency of the process remains extremely low. Here, we report a chemical-free technique in which topographical cues, more specifically parallel microgrooves, enhance the trans-differentiation of cardiac progenitors into cardiomyocyte-like cells. Using a lentivirus-mediated direct reprogramming strategy for expression of Myocardin, Tbx5, and Mef2c, we showed that the microgrooved substrate provokes an increase in histone H3 acetylation (AcH3), known to be a permissive environment for reprogramming by “stemness” factors, as well as stimulation of myocardin sumoylation, a post-translational modification essential to the transcriptional function of this key co-activator. These biochemical effects mimicked those of a pharmacological histone deacetylase inhibitor, valproic acid (VPA), and like VPA markedly augmented the expression of cardiomyocyte-specific proteins by the genetically engineered cells. No instructive effect was seen in cells unresponsive to VPA. In addition, the anisotropy resulting from parallel microgrooves induced cellular alignment, mimicking the native ventricular myocardium and augmenting sarcomere organization.

Journal article

Buyandelger B, Mansfield C, Kostin S, Choi O, Roberts AM, Ware JS, Mazzarotto F, Pesce F, Buchan R, Isaacson RL, Vouffo J, Gunkel S, Knöll G, McSweeney SJ, Wei H, Perrot A, Pfeiffer C, Toliat MR, Ilieva K, Krysztofinska E, López-Olañeta MM, Gómez-Salinero JM, Schmidt A, Ng KE, Teucher N, Chen J, Teichmann M, Eilers M, Haverkamp W, Regitz-Zagrosek V, Hasenfuss G, Braun T, Pennell DJ, Gould I, Barton PJ, Lara-Pezzi E, Schafer S, Hübner N, Felkin LE, O'Regan DP, Petretto E, Brand T, Milting H, Nürnberg P, Schneider MD, Prasad S, Knöll Ret al., 2015, ZBTB17 (MIZ1) Is Important for the Cardiac Stress Response and a Novel Candidate Gene for Cardiomyopathy and Heart Failure., Circulation. Cardiovascular Genetics, Vol: 8, Pages: 643-652, ISSN: 1942-3268

BACKGROUND: -Mutations in sarcomeric and cytoskeletal proteins are a major cause of hereditary cardiomyopathies, but our knowledge remains incomplete as to how the genetic defects execute their effects. METHODS AND RESULTS: -We used cysteine and glycine-rich protein 3 (CSRP3), a known cardiomyopathy gene, in a yeast two-hybrid screen and identified zinc finger and BTB domain containing protein 17 (ZBTB17) as a novel interacting partner. ZBTB17 is a transcription factor that contains the peak association signal (rs10927875) at the replicated 1p36 cardiomyopathy locus. ZBTB17 expression protected cardiac myocytes from apoptosis in vitro and in a mouse model with cardiac myocyte-specific deletion of Zbtb17, which develops cardiomyopathy and fibrosis after biomechanical stress. ZBTB17 also regulated cardiac myocyte hypertrophy in vitro and in vivo in a calcineurin-dependent manner. CONCLUSIONS: -We revealed new functions for ZBTB17 in the heart, a transcription factor which may play a role as a novel cardiomyopathy gene.

Journal article

Tonkin J, Temmerman L, Sampson RD, Gallego-Colon E, Barberi L, Bilbao D, Schneider MD, Musaro A, Rosenthal Net al., 2015, Monocyte/Macrophage-derived IGF-1 Orchestrates Murine Skeletal Muscle Regeneration and Modulates Autocrine Polarization, MOLECULAR THERAPY, Vol: 23, Pages: 1189-1200, ISSN: 1525-0016

Journal article

Noseda M, Abreu-Paiva M, Schneider MD, 2015, The Quest for the Adult Cardiac Stem Cell, Circulation Journal, Vol: 79, Pages: 1422-1430, ISSN: 1347-4820

Over the past 2 decades, cardiac regeneration has evolved from an exotic fringe of cardiovascular biology to theforefront of molecular, genetic, epigenetic, translational, and clinical investigations. The unmet patient need is thepaucity of self-repair following infarction. Robust regeneration seen in models such as zebrafish and newborn micehas inspired the field, along with encouragement from modern methods that make even low levels of restorativegrowth discernible, changing the scientific and technical landscape for effective counter-measures. Approachesunder study to augment cardiac repair complement each other, and encompass grafting cells of diverse kinds,restarting the cell cycle in post-mitotic ventricular myocytes, reprogramming non-myocytes, and exploiting the dormantprogenitor/stem cells that lurk within the adult heart. The latter are the emphasis of the present review. Cardiacresidentstem cells (CSC) can be harvested from heart tissue, expanded, and delivered to the myocardium as atherapeutic product, whose benefits may be hoped to surpass those achieved in human trials of bone marrow.However, important questions are prompted by such cells’ discovery. How do they benefit recipient hearts? Do theycontribute, measurably, as an endogenous population, to self-repair? Even if “no,” might CSCs be targets for activationin situ by growth factors and other developmental catalysts? And, what combination of distinguishing markersbest demarcates the cells with robust clonal growth and cardiogenic potential?

Journal article

Belian E, Noseda M, Abreu Paiva MS, Leja T, Sampson R, Schneider MDet al., 2015, Forward Programming of Cardiac Stem Cells by Homogeneous Transduction with MYOCD plus TBX5., PLOS One, Vol: 10, ISSN: 1932-6203

UNLABELLED: Adult cardiac stem cells (CSCs) express many endogenous cardiogenic transcription factors including members of the Gata, Hand, Mef2, and T-box family. Unlike its DNA-binding targets, Myocardin (Myocd)-a co-activator not only for serum response factor, but also for Gata4 and Tbx5-is not expressed in CSCs. We hypothesised that its absence was a limiting factor for reprogramming. Here, we sought to investigate the susceptibility of adult mouse Sca1+ side population CSCs to reprogramming by supplementing the triad of GATA4, MEF2C, and TBX5 (GMT), and more specifically by testing the effect of the missing co-activator, Myocd. Exogenous factors were expressed via doxycycline-inducible lentiviral vectors in various combinations. High throughput quantitative RT-PCR was used to test expression of 29 cardiac lineage markers two weeks post-induction. GMT induced more than half the analysed cardiac transcripts. However, no protein was detected for the induced sarcomeric genes Actc1, Myh6, and Myl2. Adding MYOCD to GMT affected only slightly the breadth and level of gene induction, but, importantly, triggered expression of all three proteins examined (α-cardiac actin, atrial natriuretic peptide, sarcomeric myosin heavy chains). MYOCD + TBX was the most effective pairwise combination in this system. In clonal derivatives homogenously expressing MYOCD + TBX at high levels, 93% of cardiac transcripts were up-regulated and all five proteins tested were visualized. IN SUMMARY: (1) GMT induced cardiac genes in CSCs, but not cardiac proteins under the conditions used. (2) Complementing GMT with MYOCD induced cardiac protein expression, indicating a more complete cardiac differentiation program. (3) Homogeneous transduction with MYOCD + TBX5 facilitated the identification of differentiating cells and the validation of this combinatorial reprogramming strategy. Together, these results highlight the pivotal importance of MYOCD in driving CSCs toward a cardiac muscle fate

Journal article

Noseda M, Harada M, McSweeney S, Leja T, Belian E, Stuckey DJ, Abreu Paiva MS, Habib J, Macaulay I, de Smith AJ, Al-Beidh F, Sampson R, Lumbers RT, Rao P, Harding SE, Blakemore AI, Eirik Jacobsen S, Barahona M, Schneider MDet al., 2015, PDGFRα demarcates the cardiogenic clonogenic Sca1(+) stem/progenitor cell in adult murine myocardium., Nature Communications, Vol: 6, Pages: 6930-6930, ISSN: 2041-1723

Cardiac progenitor/stem cells in adult hearts represent an attractive therapeutic target for heart regeneration, though (inter)-relationships among reported cells remain obscure. Using single-cell qRT-PCR and clonal analyses, here we define four subpopulations of cardiac progenitor/stem cells in adult mouse myocardium all sharing stem cell antigen-1 (Sca1), based on side population (SP) phenotype, PECAM-1 (CD31) and platelet-derived growth factor receptor-α (PDGFRα) expression. SP status predicts clonogenicity and cardiogenic gene expression (Gata4/6, Hand2 and Tbx5/20), properties segregating more specifically to PDGFRα(+) cells. Clonal progeny of single Sca1(+) SP cells show cardiomyocyte, endothelial and smooth muscle lineage potential after cardiac grafting, augmenting cardiac function although durable engraftment is rare. PDGFRα(-) cells are characterized by Kdr/Flk1, Cdh5, CD31 and lack of clonogenicity. PDGFRα(+)/CD31(-) cells derive from cells formerly expressing Mesp1, Nkx2-5, Isl1, Gata5 and Wt1, distinct from PDGFRα(-)/CD31(+) cells (Gata5 low; Flk1 and Tie2 high). Thus, PDGFRα demarcates the clonogenic cardiogenic Sca1(+) stem/progenitor cell.

Journal article

Yue J, Xie M, Gou X, Lee P, Schneider MD, Wu Xet al., 2014, Microtubules Regulate Focal Adhesion Dynamics through MAP4K4, DEVELOPMENTAL CELL, Vol: 31, Pages: 572-585, ISSN: 1534-5807

Journal article

Fiedler LR, Jenkins M, Maifoshie E, Harada M, Stuckey DJ, Song W, Sampson R, Harding SE, Schneider MDet al., 2014, MAP4K4 MEDIATES CARDIOMYOCYTE CELL DEATH AND POTENTIATES A HEART FAILURE PHENOTYPE, Autumn Meeting of the British-Society-for-Cardiovascular-Research (BSCR) on Cardiovascular Signalling in Health and Disease, Publisher: BMJ PUBLISHING GROUP, ISSN: 1355-6037

Conference paper

Qi B, Cong Q, Li P, Ma G, Guo X, Yeh J, Xie M, Schneider MD, Liu H, Li Bet al., 2014, Ablation of Tak l in osteoclast progenitor leads to defects in skeletal growth and bone remodeling in mice, Scientific Reports, Vol: 4, ISSN: 2045-2322

Tak1 is a MAPKKK that can be activated by growth factors and cytokines such as RANKL and BMPs and its downstream pathways include NF-κB and JNK/p38 MAPKs. Tak1 is essential for mouse embryonic development and plays critical roles in tissue homeostasis. Previous studies have shown that Tak1 is a positive regulator of osteoclast maturation, yet its roles in bone growth and remodeling have not been assessed, as mature osteoclast-specific Tak1 deletion with Cstk-Cre resulted in runtedness and postnatal lethality. Here we generated osteoclast progenitor (monocyte)-specific Tak1 knockout mice and found that these mice show normal body weight, limb size and fertility, and osteopetrosis with severity similar to that of RANK or RANKL deficient mice. Mechanistically, Tak1 deficiency altered the signaling of NF-κB, p38MAPK, and Smad1/5/8 and the expression of PU.1, MITF, c-Fos, and NFATc1, suggesting that Tak1 regulates osteoclast differentiation at multiple stages via multiple signaling pathways. Moreover, the Tak1 mutant mice showed defects in skull, articular cartilage, and mesenchymal stromal cells. Ex vivo Tak1−/− monocytes also showed enhanced ability in promoting osteogenic differentiation of mesenchymal stromal cells. These findings indicate that Tak1 functions in osteoclastogenesis in a cell-autonomous manner and in osteoblastogenesis and chondrogenesis in non-cell-autonomous manners.

Journal article

Hasumi Y, Baba M, Hasumi H, Huang Y, Lang M, Reindorf R, Oh H-B, Sciarretta S, Nagashima K, Haines DC, Schneider MD, Adelstein RS, Schmidt LS, Sadoshima J, Linehan WMet al., 2014, Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation, HUMAN MOLECULAR GENETICS, Vol: 23, Pages: 5706-5719, ISSN: 0964-6906

Journal article

Foldes G, Matsa E, Kriston-Vizi J, Leja T, Amisten S, Kolker L, Kodagoda T, Dolatshad NF, Mioulane M, Vauchez K, Aranyi T, Ketteler R, Schneider MD, Denning C, Harding SEet al., 2014, Aberrant alpha-Adrenergic Hypertrophic Response in Cardiomyocytes from Human Induced Pluripotent Cells, Stem Cell Reports, Vol: 3, Pages: 905-914, ISSN: 2213-6711

Journal article

Weinreuter M, Kreusser MM, Beckendorf J, Schreiter FC, Leuschner F, Lehmann LH, Hofmann KP, Rostosky JS, Diemert N, Xu C, Volz HC, Jungmann A, Nickel A, Sticht C, Gretz N, Maack C, Schneider MD, Groene H-J, Mueller OJ, Katus HA, Backs Jet al., 2014, CaM Kinase II mediates maladaptive post-infarct remodeling and pro-inflammatory chemoattractant signaling but not acute myocardial ischemia/reperfusion injury, EMBO Molecular Medicine, Vol: 6, Pages: 1231-1245, ISSN: 1757-4676

Journal article

Lehmann LH, Rostosky JS, Buss SJ, Kreusser MM, Krebs J, Mier W, Enseleit F, Spiger K, Hardt SE, Wieland T, Haass M, Luescher TF, Schneider MD, Parlato R, Groene H-J, Haberkorn U, Yanagisawa M, Katus HA, Backs Jet al., 2014, Essential role of sympathetic endothelin A receptors for adverse cardiac remodeling, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 111, Pages: 13499-13504, ISSN: 0027-8424

Journal article

Kreusser MM, Lehmann LH, Keranov S, Hoting M-O, Oehl U, Kohlhaas M, Reil J-C, Neumann K, Schneider MD, Hill JA, Dobrev D, Maack C, Maier LS, Groene H-J, Katus HA, Olson EN, Backs Jet al., 2014, Cardiac CaM Kinase II Genes delta and gamma Contribute to Adverse Remodeling but Redundantly Inhibit Calcineurin-Induced Myocardial Hypertrophy, Circulation, Vol: 130, Pages: 1262-1273, ISSN: 0009-7322

Journal article

Chuang H-C, Sheu WH-H, Lin Y-T, Tsai C-Y, Yang C-Y, Cheng Y-J, Huang P-Y, Li J-P, Chiu L-L, Wang X, Xie M, Schneider MD, Tan T-Het al., 2014, HGK/MAP4K4 deficiency induces TRAF2 stabilization and Th17 differentiation leading to insulin resistance, Nature Communications, Vol: 5, ISSN: 2041-1723

Proinflammatory cytokines play important roles in insulin resistance. Here we report thatmice with a T-cell-specific conditional knockout of HGK (T-HGK cKO) develop systemicinflammation and insulin resistance. This condition is ameliorated by either IL-6 or IL-17neutralization. HGK directly phosphorylates TRAF2, leading to its lysosomal degradationand subsequent inhibition of IL-6 production. IL-6-overproducing HGK-deficient T cellsaccumulate in adipose tissue and further differentiate into IL-6/IL-17 double-positive cells.Moreover, CCL20 neutralization or CCR6 deficiency reduces the Th17 population or insulinresistance in T-HGK cKO mice. In addition, leptin receptor deficiency in T cells inhibits Th17differentiation and improves the insulin sensitivity in T-HGK cKO mice, which suggests thatleptin cooperates with IL-6 to promote Th17 differentiation. Thus, HGK deficiency inducesTRAF2/IL-6 upregulation, leading to IL-6/leptin-induced Th17 differentiation in adiposetissue and subsequent insulin resistance. These findings provide insight into the reciprocalregulation between the immune system and the metabolism.

Journal article

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