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REGENERATIVE THERAPIES FOR CARDIAC AND VASCULAR DISEASES

TEAM LEADERS : Jean-Sébastien Silvestre and Philippe Menasché

Mail : jean-sebastien.silvestre@inserm.fr

PHONE :+33 1 53 98 80 60

Localisation :

DOCTORAL SCHOOL : Ecole Doctorale Bio-Sorbonne Paris Cité, Department of Cellular and Molecular Biology, Physiology and Pathology

Objectives

The team is based on the complementary expertise contributed by a group (Jean-Sébastien Silvestre) experienced in deciphering the signaling pathways involved in post-ischemic tissue remodeling and a group (Philippe Menasché) with a long–standing experience in the preclinical, translational and clinical aspects of stem cell research.

The team forms an ideal platform of expertise and technical know-how, ranging from the basic features of cell injury, regeneration and remodeling to the clinical applications of cell-based therapies complying with the increasingly stringent regulatory requirements. The background of the group members (both basic scientists and practising clinicians) as well as their respective expertises should allow the team to cover a spectrum of activities ranging from the mechanisms of postischemic tissue remodelling and regeneration at the molecular level to the development of therapeutic strategies to mimick and boost these processes.

Through the use of tools ranging from molecular biology methods to small and large animal models, the team spans a fully integrated spectrum encompassing basic, preclinical and translational research. The objective is thus to contribute to the burgeoning field of regenerative medicine where involved disciplines (cell biology, tissue engineering, immunology, regulation) are often partitioned by a cross-fertilization of the expertises located on the same site and allowing to both improve basic knowledge and clinical applications.

As such, this research is targeted to scientists, clinicians, students but ultimately to patients who are in need for these novel biologics-based therapeutic approaches, with the premise that implementation of these therapies cannot be truly relevant if it is not built on a robust understanding of the underlying mechanistic events.

Research TOPICS

1- RECENT RESULTS

Our main objectives are to decode the molecular and cellular mechanisms involved in cardiac repair after injury and to develop efficient therapeutic approaches to circumvent cardiac dysfunction occurring in patients with cardiovascular diseases. In particular, we have:

Decrypted the importance of the interaction between different cellular components of innate and adaptive immunity and cardiac homeostasis including cardiac regeneration and remodeling (Santos-Zia I et al, Nat Commun, 2021; Melham NJ et al, Circulation, 2021; Loyer X et al, Circ Res, 2018; Ngkelo A et al, J Exp Med, 2016; Howangyin K et al, Circulation, 2016). Notably, we showed that hepcidin, a master iron sensor, refrains macrophage-induced cardiac repair and regeneration through modulation of IL-4/IL-13 pathways (Zlatanova I et al, Circulation, 2019).
Developed cellular and acellular-based therapeutic approaches for patients with cardiac diseases. After the successful completion of our phase I trial testing cardiac progenitors derived from human embryonic stem cells embedded in a patch (Menasché P et al, Eur Heart J, 2015 & J Am Coll Cardiol, 2018). The recognition of the predominant role of paracrine signaling has led to shift towards an a-cellular therapy based on the exclusive use of the secretome to further streamlining the clinical translatability of this myocardial repair strategy (Lima Correa B et al, Cardiovasc Res, 2021; El Harane N et al, Eur Heart J, 2018; Kervadec A et al & Bellamy V et al, J Heart Lung Transplant, 2015 & 2016).

2- PROJECT

Our future research work is based on our previous studies and our technical and theoretical expertise. The overall strategy of team 06 will be to:

Analyze the molecular and cellular mechanisms involved in cardiac repair and regeneration. We will also characterize the perivascular identity of resident tissue macrophages in the heart and identify the environmental cues involved in this niche-dependent functional programming.
Develop a preclinical and translational program targeted at a phase I trial of cardiac progenitor-derived extracellular membrane vesicles in patients with severe heart failure who have exhausted conventional therapeutic options. Through a tight interaction with the Advanced Therapy Medicinal Products platform of AP-HP (hôpital Saint-Louis, Paris), we are implementing a stepwise program ranging from the use of preclinical models of cardiomyopathies and the assessment of their relevant mechanistic features to the purification of clinical-scale volumes of the secretome of cardiovascular progenitor cells (differentiated from induced pluripotent stem cells) under Good Manufacturing Practice conditions. In parallel, we explore different delivery strategies along with their biodistribution patterns in an attempt to conciliate optimization of targeting with user-friendly approaches.