Leducq Networks meet to discuss cardiac regeneration
Foundation Leducq inspired networking
By promoting global networks of excellence and innovation, the mission of the Fondation Leducq is to engender international collaboration in cardiovascular research. In this very spirit, and complementing the traditional intra-network collaborative focus, meeting of several networks was convened to assess and to consolidate the state of knowledge in the field of cardiac regeneration.
On October 5-6, 2018, researchers–including many young investigators–from Europe and North America participating in four Fondation Leducq supported networksstudying cardiac regeneration over the last decade, met together in Cabriès in Provence (France). These networks included the program: “Programming the Failing Heart to a Regenerative State,” “Eliciting Heart Regeneration through Cardiomyocyte Division,” “Cellular and Molecular Targets to Promote Therapeutic Cardiac Regeneration,” and “Translating human pluripotent stem cells from heart disease models to cardiac repair.”* The gathering had multiple interrelated sessions covering the span from fundamental science to translational ramifications with future trends presented in the context of a social impact. Dr. David Tancredi, Executive Director Fondation Leducq, provided a global perspective.
The meeting started with a session dedicated to the biology of cardiac reprograming. Although direct reprogramming of cardiac fibroblasts had emerged as an elegant means to endogenously regenerate heart muscle, this powerful approach remains challenging. Furthermore, the risk of chromosomal instability of reprogrammed progeny raises questions about the translational and ultimately clinical readiness of such a strategy. As an alternative, laboratories have increasingly focused on ways to facilitate the re-entry of cardiomyocyte into cell cycle. To this end, different strategies have been deployed. These include single cell-RNA sequencing to map genes encoding cell cycle proteins that may remain functional in a subset of cardiomyocytes, or that can be used in “gene therapy” to force cell-cycle execution. In particular, there was discussion of the use of microRNAs that leverages their pleiotropic biological impact to target genes that decrease fibroblast proliferation and/or activate fibrosis by triggering fibroblast senescence, while facilitating and/or inducing cardiomyocyte proliferation.
Cardiac cell proliferation has been a topic of controversy over the years. Indeed, the follow-up session centered on the rich literature revealing ki67+ cells or BrdU cell nuclei incorporation often observed in cardiomyocytes. Yet, no definite proof of cytokinesis has ever been provided. Significant further discussion included comparison between regeneration paradigms. Skeletal muscle versus heart muscle are tissues that may originate very early in the embryo from a common mesodermal ancestor, but display distinct aptitudes of regeneration. This offers the opportunity to recognize tissue-specific regenerative pathways. A cell therapy approach was also presented as a therapeutic option for patients affected by congenital heart disease.
The meeting concluded with a new dimension focused on the sociology of regenerative science and medicine. Led by a social scientist,¤ this session provided the opportunity to discuss the impact of society on biological science and to debate on the role of biologists in the society. Broadly, cardiac or organ regeneration are expressions that are of interest for patients, families, and society-at-large. Social justice with emphasis on access to affordable new treatments has emerged as a central question. How biologists communicate not only their data but also their way of thinking about society, and how biologist listen to the society, are becoming important issues to take into consideration
The ‘inter-networks’ meeting was intense, and provocative, with constructive debates, point-and-counterpoint, and ongoing exchanges involving enthusiastic young investigators. It was a forum for new ideas, and collaborative planning. It further underscored the need for rigorous science, independent validation, and multidisciplinary engagement to ultimately ensure the development of proven therapies for cardiovascular conditions that address the needs of patients.
Michel Pucéat,Faculté de Médecine La Timone, Marseille
André Terzic, Mayo Clinic, Rochester, Minnesota
*Participating Networks and respective Lead Coordinators:
Eliciting Heart Regeneration through Cardiomyocyte Division (2015)
Elly Tanaka and Ken Poss
Programming the Failing Heart to a Regenerative State (2014)
Mauro Giacca and Richard Lee
Cellular and Molecular Targets to Promote Therapeutic Cardiac Regeneration (2013)
David Sassoon and Toren Finkel
Translating human pluripotent stem cells from heart disease models to cardiac repair SHAPEHEART (2011)
André Terzic and Michel Pucéat