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The ISHR Richard J. Bing Award for Young Investigators

The International Society for Heart Research (ISHR) is seeking applications for a distinguished award of international importance for recognizing outstanding young scientists: The Richard J Bing Young Investigator Award. The monetary prize is $1,500 for the winner of the Richard J Bing Award and $1,000 for 3 runner-up Finalists. This high-profile recognition will be presented at the XXIIIth ISHR World Congress in Beijing, China, June 3-6, 2019. The Winner and Finalists will be announced in the Journal of Molecular and Cellular Cardiology (the official publication of the ISHR), on the ISHR website, and in Heart News and Views (the newsletter of the ISHR).

Full details of this award, including a list of previous recipients and relevant guidelines can be found here.

The guidelines should be consulted before preparing any application.

  • The purpose of this Award is to recognize outstanding research endeavors by new investigators and to encourage continued cardiovascular research careers
  • Candidates must be active members (or have applied for membership) of the ISHR at the time of application
  • Candidates must have received their PhD or equivalent less than 8 years prior to the opening day of the World Congress. Allowance will be made for career breaks. It is the responsibility of the candidate and supervisor to justify the degree of disruption to the career
  • Four finalists will present their work at the XXIIIth ISHR World Congress
  • The deadline for receipt of applications is February 1, 2019

As detailed in the relevant guidelines on the ISHR website, all nomination materials should be provided in electronic format, as a SINGLE PDF file either via email or on a flash drive. If you do not get a confirming e-mail within one week, please send a follow-up inquiry without the attached files.

Applications/Nominations should be submitted (by email, mail/airmail or courier) to BOTH:

Dr Åsa Gustafsson
Chair – Bing Award Selection Committee
Skaggs School of Pharmacy and Pharmaceutical Sciences
University of California San Diego
9500 Gilman Drive #0758
La Jolla, CA 92093-0758
Tel: (858)822-5569
Email: [email protected]

And

Dr Leslie Anderson Lobaugh
ISHR Executive Secretary
PO Box 52643
Durham, NC 27717-2643
Tel: (919)493-4418
Email: [email protected]

Travel Report – ISSCR Annual Meeting 2018

Melbourne Convention & Exhibition Centre Melbourne, Australia

A report by Worrapong Kit-Anan

The Stevens, Terracciano and Harding laboratory

Department of Materials, Bioengineering, Myocardial Function

Imperial College London, UK

A great excitement in regenerative medicine drew a gigantic attention from both researchers and the public when scientists can reprogram somatic cells into pluripotent stem cells. This novel technology holds a great promise in a range of applications including cardiac repairs, disease modelling and drug discovery.

 

ISSCR 2018 Entrance

The ISSCR Annual Meeting 2018 is the biggest and most prestigious international conference in stem cell society and brings together global leading researchers and innovators on all aspect of stem cell for the future of medicine and research. Topics of discussion ranged from biomaterials for tissue regeneration and disease modelling, epigenetics and genetic regulatory networks, and clinical translation session. This allows participants to engage in cross-disciplinary dialogue and exchange of ideas. This episode of the annual meeting was held in Melbourne Convention & Exhibition Centre Melbourne, Australia.

 

My research project focuses on cardiac biology for a better understanding of physical cues that essentially play roles during cardiac development. My research addresses the significant challenges present due to the complex and dynamic interplay of electrical and biomechanical signals involved in the development and physiology of the myocardium. The study involves interdisciplinary techniques from synthetic biology, polymer synthesis and cardiac electrophysiology. This requires cross-disciplinary expertise and state of art techniques. Thus, the field is very dynamic as new techniques are continuously being innovated for an application.

My personal highlights were the tissue engineering session and cardiac development and disease, chaired by Professor Matthias Lutolf and Professor Charles Murry, respectively. Memorable talks in tissue engineering were given by Dr Kiryu Yap and Professor Gordana Vunjak-Novakovic. Dr Yap’s talk was related to a novel vascularisation technique that he recently published, which utilises our body’s repair mechanism to form an extensive vascular network in a scaffold. He then explanted the scaffold that had been vascularised for further application. This technique potentially allows scientists to create more relevant regenerative scaffold allowing healthy integration with the human body. This talk was followed by Professor Vunjak-Novakovic. She presented her recent works in cardiac tissue engineering and extracellular vesicles (EVs). The study used dynamic mechanical stimulation synchronously with electrical stimulation to create cardiac sheet made of human induce pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The microtissue showed promisingly many adult-like features such as microstructure and force generation. EVs is an emerging area of great excitement in cell biology and signalling involves the release and subsequent uptake of membrane enclosed packages of information. She presented EVs that has been isolated from hiPSC-CMs in comparison to hiPSC can rescue cardiac function after myocardial infarction, having a cardiac protective effect.

Worrapong Kit-Anan at his poster

 

Another concurrent session, cardiac development and disease, featured many renown leading scientists includes Professor Christine L. Mummery and Professor Deepak Srivastava. Professor Mummery presented her current work on organ-on-a-chip and microtissue solutions in which co-culture technique was used with a mixture of cardiomyocytes, cardiac vascular and stromal cells were presented. She introduced novel differentiation technique in which those earlier mentioned cell types were derived spontaneously single in vitro, showing improvement in structural and functional maturity. The group combined with new methods for functional phenotyping to quantify the outcomes of drug and disease mutation responses in situ. Next session was featured by professor Srivastava, introducing his novel direct reprogramming of resident fibroblasts for cardiac regeneration. By using his novel technique, cardiomyocytes can re-enter cell cycle allowing them to undergo cell division.

Finally, I am very grateful for the opportunity that BSCR gave me to go to this conference and expand my network, as well as meet a number of dedicated scientists. I also had many insightful, thought-provoking discussions with other attendees. I believe we will be able to continue our discussions in future formal or informal collaborations. It was a great experience and I hope to attend more conferences in the future to present scientific findings.

The Bernard and Joan Marshall Young Investigator Prize

The role of the epicardium in cardiac repair

Johannes Bargehr

The Anne McLaren Laboratory, Wellcome Trust –MRC Cambridge Stem Cell Institute, Forvie Site, University of Cambridge, Robinson Way, Cambridge CB2 0SZ, UK

Division of Cardiovascular Medicine, University of Cambridge, ACCI Level 6, Box 110, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK

 

  1. Introduction

At present, around 25 Million people worldwide suffer from chronic heart failure. Following the exhaustion of medical and device therapy, these patients have no other therapeutic option to make up for the loss of contractile working myocardium other than heart transplantation. Approaches in regenerative medicine making use of human pluripotent stem cell (hPSC)-derived cardiomyocytes in order to remuscularise the infarcted heart and restore function have provided promising preclinical data in large animal models but limitations such as cardiomyocyte immaturity and poor vascularisation remain. Concomitantly, over the past decade the epicardium has sparked much interest in regenerative cardiovascular medicine due to its pivotal role in embryonic heart development, serving as a cellular source for coronary smooth muscle cells and interstitial fibroblasts. Here the role of hPSC-derived epicardial cells is discussed in the context of regenerative cardiovascular medicine.

  1. The epicardium in embryonic heart development

It is in early embryonic heart development, that the epicardium displays unique functionality that makes it an interesting candidate for cardiac repair. At around 3.5 weeks of human heart development epicardial cells arise from the proepicardial organ and cover the surface of the embryonic heart tube. The epicardium then starts to undergo epithelial to mesenchymal transition (EMT) and invades the subepicardial space and subjacent compact myocardium [1]. During this process epicardial cells give rise to smooth muscle cells (SMC), required for the formation of the coronary vasculature as well as to interstitial cardiac fibroblasts (CF), which result in cardiac compaction and maturation [2-4] (Figure 1, Panel A). Epicardial outgrowth inhibition in chicken embryos has resulted in malformation of the coronary vasculature and myocardial non-compaction, resulting in early embryonic death [5]. The developmental cues driving the chemically defined differentiation of epicardial cells as well as epicardium-derived smooth muscle cells and fibroblasts from human pluripotent stem cells are shown in Figure 2. In this context, some of our own data have shown that the fate of epicardial cells is system and developmental stage dependent (Figure 1, Panel B). Using an athymic rat model of myocardial infarction, we observed that intramyocardial injection of hPSC-derived epicardial cells into the infarct zone resulted in robust fibroblast graft formation. In contrast, using a developmental chicken embryo transplantation of hPSC-epicardial cells into the extraembryonic vasculature resulted in formation of epicardium-derived smooth muscle cells and integration thereof into pre-existing chicken vasculature. Additionally, pioneering work by Nicola Smart and Paul Riley has shown that if primed with Thymosin beta 4, epicardial cells are even capable of giving rise to cardiomyocytes [6]. Increasing the efficiency of this process could open up another avenue in epicardium-mediated cardiac repair.

  1. Remuscularising the failing heart with human pluripotent stem cell-derived-cardiomyocytes

The only therapeutic option for patients with heart failure that directly addresses the underlying loss of cardiomyocytes is heart transplantation. Despite a huge potentially eligible patient population only as many as 200 heart transplantations are performed in the entire UK every year. Regenerative medicine, using human pluripotent stem cells, including induced pluripotent stem cells (iPSC) or human embryonic stem cells (hESCs), is a promising novel therapeutic domain that has fostered the rise of 3D-engineered heart tissue (3D-EHT)-based approaches as well as those making use of direct intramyocardial cell injection of human pluripotent stem cell (hPSC)-derived cardiomyocytes. The latter of the two approaches has been very successful in rodent models of myocardial infarction where transplantation of hESC-derived cardiomyocytes has led to robust cardiovascular graft formation and rescue of global host heart function [7, 8]. Endeavours to translate this approach to a model that more closely resembles human disease demonstrated that transplantation of 1 Billion hESC-derived cardiomyocytes results in robust graft formation in infarcted non-human primates and more recently this was also shown for hiPSC-derived cardiomyocytes using the same model [9, 10]. While these studies have provided compelling pre-clinical data in a close-to-clinical-environment setting, elegantly using clinical grade heart catheters for percutaneous vascular access and delivery into the left ventricular wall, the field is eagerly awaiting functional data corroborating the concept that robust cardiac grafting also results in improvement of host heart function. While this technology has provided promising evidence for clinical applicability and translational potential a number of shortcomings remain.

  1. Key challenges remaining

Mechanistic insights into embryonic organ development have rendered possible the in vitro generation of a large number of different body tissues from hPSCs. While derived and terminally differentiated cells express all markers of their adult human counterparts and exhibit functionality, given the process and the time required for their derivation, they fall short of reaching sound levels of maturity. For cardiomyocytes, this means that hPSC-derived, beating monolayer cultures at best resemble the phenotype of those found in a third trimester embryo [11, 12]. Transplantation of cardiomyocytes with a relatively immature phenotype means suboptimal structural integrity of cardiac grafts and related function post engraftment. Additionally, cell death following transplantation into ischaemic myocardium is high resulting in optimizable cardiac graft size and vascular supply to grafts is poor compared to physiologic myocardial tissue [13]. Meeting these shortcomings could potentially catalyse critical progress in regenerative cardiovascular repair. While the embryonic identity of hPSC-derived tissues is often seen as a drawback in regenerative medicine, the functionality displayed by the epicardium in early embryonic heart development and reflected by hPSC-derived epicardium could critically aid meeting some of the key limitations currently present in cardiac repair, including vascularisation and maturation.

  1. Potential applications of the epicardium in regenerative medicine

Regenerative medicine has fostered the paradigm that a better understanding of developmental processes can aid organ regeneration. While only deeper molecular insights have allowed for the derivation of specific body tissues in vitro, the generation of more complex tissue-systems could help advance cardiac repair beyond current limitations. The use of the epicardium as an adjuvant cardiovascular therapeutic for tissue engineering application is hence a tantalising approach. HPSC-derived epicardial cells, if added to cardiomyocytes in 3D-EHTs could help to better vascularise transplantable heart patches and provide for structural integrity and maturation [14]. On a different note the capability to generate epicardial cells will also allow for mimicking of developmental processes like embryonic heart tube formation. Such a multi-cellular construct, incorporating epicardium, myocardium and endocardium, if devised, would allow for unprecedented opportunities to move forward our understanding of cardiac developmental and regenerative processes. Furthermore, the field of drug toxicity testing could substantially benefit from more mature hiPSC-derived cardiomyocytes to gain a more high-fidelity readout of calcium traces that more closely resemble the toxic effects seen in patients following drug administration. The functionality of hPSC-derived epicardial cells seen in preclinical studies makes them a potentially interesting adjuvant therapeutic for cardiac repair that promises to address some of the key limitations that the field currently faces. This could usher in a new, more complex era of cardiac regeneration that will move closer to generating bona fide cardiac tissue and more efficient repair.

Figure 1. Fate and function of the epicardium in development and disease. (A) The epicardium during embryonic heart development. At 3.5 weeks of human heart development the epicardium starts to cover the heart surface. It subsequently starts to invade the subepicardial space and undergoes epithelial to mesenchymal transition, giving rise to cardiac fibroblasts (CF) (1) and coronary smooth muscle cells (SMC) (2). It remains controversial whether epicardial cells can also give rise to endothelial cells (EC) (3) and cardiomyocytes (CM) (4). (B) The epicardium during cardiac injury. Top schematic demonstrates that in the adult organism CFs and SMCs are epicardium-derived. The bottom schematic demonstrates reactivation of the embryonic program in the epicardium following cardiac injury. Epicardial cells start to invade the myocardium and the infarct zone (1) mainly giving rise to CFs (3) within the infarct with a small fraction giving rise to the more mature myofibroblasts (MF) (4). In contrast, outside of the infarct zone the epicardium is capable of giving rise to smooth muscle cells (2).

Figure 2. Molecular cues driving germ layer and cardiovascular lineage specification. Activin and FGF pathways maintain pluripotency of hESCs [15]. Activation of FGF and inhibition of Activin/ Nodal signalling direct ectoderm formation, while Wnt-inhibition and activation of Activin and BMP signalling triggers endoderm formation[16]. The main cardiovascular lineages derive from the mesoderm, which forms through activation of Wnt, Activin and BMP signalling [17]. VEGF-A directs the differentiation to endothelial cells [18, 19], PDGF-BB and TGF-β1 to smooth muscle cells [20, 21], Wnt, BMP and RA to epicardium [22], and BMP activation and Wnt inhibition to cardiomyocytes [7, 23]. The epicardium, being a cardiovascular progenitor population, is capable of giving rise to cardiac fibroblasts and smooth muscle cells [22].

 

References:

  1. Compton, L.A., et al., Coronary vessel development is dependent on the type III transforming growth factor beta receptor. Circ Res, 2007. 101(8): p. 784-91.
  2. Ieda, M., et al., Cardiac fibroblasts regulate myocardial proliferation through beta1 integrin signaling. Dev Cell, 2009. 16(2): p. 233-44.
  3. Gittenberger-de Groot, A.C., et al., Epicardium-derived cells contribute a novel population to the myocardial wall and the atrioventricular cushions. Circ Res, 1998. 82(10): p. 1043-52.
  4. Guadix, J.A., et al., In vivo and in vitro analysis of the vasculogenic potential of avian proepicardial and epicardial cells. Dev Dyn, 2006. 235(4): p. 1014-26.
  5. Gittenberger-de Groot, A.C., et al., Epicardial outgrowth inhibition leads to compensatory mesothelial outflow tract collar and abnormal cardiac septation and coronary formation. Circ Res, 2000. 87(11): p. 969-71.
  6. Smart, N., et al., De novo cardiomyocytes from within the activated adult heart after injury. Nature, 2011. 474(7353): p. 640-4.
  7. Laflamme, M.A., et al., Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol, 2007. 25(9): p. 1015-24.
  8. Shiba, Y., et al., Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts. Nature, 2012. 489(7415): p. 322-5.
  9. Chong, J.J., et al., Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature, 2014.
  10. Shiba, Y., et al., Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts. Nature, 2016. 538(7625): p. 388-391.
  11. van den Berg, C.W., et al., Transcriptome of human foetal heart compared with cardiomyocytes from pluripotent stem cells. Development, 2015. 142(18): p. 3231-8.
  12. Denning, C., et al., Cardiomyocytes from human pluripotent stem cells: From laboratory curiosity to industrial biomedical platform. Biochim Biophys Acta, 2016. 1863(7 Pt B): p. 1728-48.
  13. Madonna, R., et al., Position Paper of the European Society of Cardiology Working Group Cellular Biology of the Heart: cell-based therapies for myocardial repair and regeneration in ischemic heart disease and heart failure. Eur Heart J, 2016. 37(23): p. 1789-98.
  14. Ogle, B.M., et al., Distilling complexity to advance cardiac tissue engineering. Sci Transl Med, 2016. 8(342): p. 342ps13.
  15. Vallier, L., M. Alexander, and R.A. Pedersen, Activin/Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells. J Cell Sci, 2005. 118(Pt 19): p. 4495-509.
  16. Vallier, L., et al., Early cell fate decisions of human embryonic stem cells and mouse epiblast stem cells are controlled by the same signalling pathways. PLoS One, 2009. 4(6): p. e6082.
  17. Kimelman, D., Mesoderm induction: from caps to chips. Nat Rev Genet, 2006. 7(5): p. 360-72.
  18. Patsch, C., et al., Generation of vascular endothelial and smooth muscle cells from human pluripotent stem cells. Nat Cell Biol, 2015. 17(8): p. 994-1003.
  19. Orlova, V.V., et al., Generation, expansion and functional analysis of endothelial cells and pericytes derived from human pluripotent stem cells. Nat Protoc, 2014. 9(6): p. 1514-31.
  20. Cheung, C., et al., Generation of human vascular smooth muscle subtypes provides insight into embryological origin-dependent disease susceptibility. Nat Biotechnol, 2012. 30(2): p. 165-73.
  21. Cheung, C., et al., Directed differentiation of embryonic origin-specific vascular smooth muscle subtypes from human pluripotent stem cells. Nat Protoc, 2014. 9(4): p. 929-38.
  22. Iyer, D., et al., Robust derivation of epicardium and its differentiated smooth muscle cell progeny from human pluripotent stem cells. Development, 2015. 142(8): p. 1528-41.
  23. Burridge, P.W., et al., Chemically defined generation of human cardiomyocytes. Nat Methods, 2014. 11(8): p. 855-60.

 

Scottish Cardiovascular Forum 2018 Meeting Report

The 21st annual meeting of the Scottish Cardiovascular Forum (SCF) was held on the 3rd of February in Trinity Biomedical Sciences Institute, Trinity College Dublin. The SCF is a meeting focused on different aspects of cardiovascular research including vascular dysfunction, inflammation, oxidative stress, cardiac and vascular remodelling.

The beauty of the SCF is that it provides a platform for undergraduate students, PhD students and postdocs to present their research findings in a comfortable and encouraging environment alongside principal investigators and leaders in cardiovascular research. It enables open discussion among all participants and facilitates the exchange of new ideas, new connections and networking opportunities among basic science and translational cardiovascular researchers from Scotland, Ireland, Northern Ireland and England.

This year’s programme was delivered primarily by PhD students and postdocs of all stages and included plenary lectures presented by Dr. Mathew Campbell and Professor Mark Little (TCD). Dr Mathew Campbell (TCD), opened the meeting by discussing his work on the importance of the blood-brain barrier and the crucial role it plays especially in neurological conditions such as schizophrenia, traumatic brain injury and chronic traumatic encephalopathy. He highlighted the important role that the tight junction protein, claudin-5, plays in regulating the blood-brain barrier integrity. His research group found that targeted suppression of claudin 5 induced psychosis-like behaviour in an inducible claudin-5 knockdown mouse model with these mice displaying characteristic features of schizophrenia.

The Roger Wadsworth competition swiftly followed the keynote lecture from Dr. Campbell. This competition is named in memory of Roger M. Wadsworth, a Professor of Cardiovascular Pharmacology at Strathclyde University, who made huge contributions both scientifically and academically in the field of cardiovascular research where he is held in the highest esteem as a supervisor for his commitment and mentoring of young cardiovascular scientists. Final year PhD students must present their research and the award is given to the student who delivers the most outstanding oral presentation at the meeting along with their achievements during their PhD. This year’s topics covered a diverse range of topics including epigenetic therapy for heart failure; optical imaging for the detection of microcalcification in atherosclerotic plaques; and the role of protein phosphatase 2A in modulating permeability of the blood-brain barrier. Personally, it was an honour to be given the opportunity to present work from my PhD in the Roger Wadsworth competition. My research has demonstrated that administration of the DNA methylation inhibitor, 5-azacytidine, can reduce aberrant cardiac remodelling in the setting of hypertension-induced cardiac injury and improve cardiac function in the naturally aged heart. It is the hope that pharmacological manipulation of epigenetic mechanisms may potentially lead to novel therapeutic strategies for cardiomyopathies where remodelling plays an important role in driving disease with limited effective treatment options. This work was carried out as part of a commercialisation grant funded by Enterprise Ireland.

After a very exciting morning session, it was time for lunch and the conference poster session. All presenters did a fantastic job of conveying a broad range of topics and methodologies to the audience. It was very motivating to see the vast quantity and quality of research that is being carried out by research groups in Scotland, Ireland, Northern Ireland and England. Following lunch, the afternoon session covered a collection of different areas of cardiovascular research from the role of the anti-angiogenic protein FKBPL in cardiac dysfunction and preeclampsia to the role and therapeutic delivery of the counter regulatory renin-angiotensin system in stroke and cardiac hypertrophy.

The afternoon was rounded off with an intriguing talk from Professor Mark Little (TCD), presenting his work on the rare autoimmune disease Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Prof Little elaborated through a clinical case study of how there is large variability in the clinical onset observed in ANCA vasculitis. Due to the clinical variability of rare diseases such as ANCA vasculitis, Prof. Little highlighted the critical importance for establishing universal networks to bring together concerted efforts to improve patient care. He drew on recent advancements in the field including the development of a mobile based app for patients with vasculitis known as patientMpower which offers personalised tips on staying well and help with medication adherence and provides a cloud based platform to store clinical data. This will ultimately enhance patient-physician interaction and reduce the clinical variability of ANCA vasculitis as it allows the linkage of relapse events to environmental factors.

The meeting was brought to a close with the prize-giving ceremony delivered by Dr. Susan Currie. The standard of presentations by all competing had been excellent. Difficulty in selecting the winners of each category was a point which Dr. Currie emphasized in her closing speech. To say that I was shocked when my name was announced as the winner of the Roger Wadsworth prize was an understatement. The Roger Wadsworth prize was presented by Professor Wadsworths’ wife, Dr Moira Wadsworth. It was a true honour to receive this prestigious award from Moira and an absolute pleasure to meet her. Her kind words of congratulations were heart-warming and made the achievement that little bit more special.

Adam Russell-Hallinan receiving the Roger Wadsworth Prize from Dr Moira Wadsworth

Karla O’Neil receiving the SCF Best Oral Presentation prize from Dr. Susan Currie

Eleanor Gill receiving the SCF Best Poster Presentation prize from Dr. Susan Currie

The SCF Best Oral Presentation prize was awarded to Ms. Karla O’Neil of Queens University Belfast for her captivating talk on the regulatory role of NOX4 in cord-blood derived endothelial colony forming cells to promote post-ischaemic revascularisation. The final prize of the afternoon was the SCF Best Poster Presentation which was awarded to Ms. Eleanor Gill of Queen’s University Belfast for her poster titled “NOX4 NADPH oxidase is a key regulator of endothelial cell function in experimental diabetes. All abstracts of the presentations and posters will be published in the journal Heart, following a recent agreement that will allow the research showcased from this year’s SCF meeting to be shared with the wider scientific community.

I would now like to take the opportunity to thank both the SCF and the Wadsworth family for their continued support of young and driven cardiovascular researchers. Furthermore, I think I speak for everyone in thanking Professor Paul Spiers, Dr. Margaret Lucitt, Dr. Martina Hennessy and Ms. Gillian Casey for arranging such a fantastic event. It was thoroughly entertaining, enlightening, and I very much look forward to next years meeting. SCF2019 meeting will take place in the Scottish Highlands in Inverness, so keep your eyes peeled on www.scf.strath.ac.uk for updates! - Until next year!