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.
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 cardiac 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 (Gomez I et al, Int J Mol Sci, 2022; Zlatanova I et al, Circulation, 2019; Loyer X et al, Circ Res, 2018). Notably, following our seminal work demonstrating for the first time that B lymphocytes played a deleterious role in post-myocardial infarction cardiac repair (Zouggari Y et al, Nat Med, 2013), we have recently revealed a specific function of splenic marginal zone B cells with potential major implications for the modulation of cardiac function after acute myocardial infarction (Sun Y et al, J Am Coll Cardiol, 2022).
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 (of the same pluripotent stem cell cardiac derivatives) to further streamlining the clinical translatability of this myocardial repair strategy (Lima Correa B et al, Cardiovasc Res, 2021 & Theranostics 2021; El Harane N et al, Eur Heart J, 2018). Through a tight interaction with the Advanced Therapy Medicinal Products platform of AP-HP (hôpital Saint-Louis, Paris), we have implemented 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. The protocol of a phase 1 trial testing this secretome has been submitted to the French regulatory agency and has already received approval from the Ethics Committee, making reasonable to expect its launch in 2023. In parallel, we explore different delivery strategies along with their biodistribution patterns in an attempt to conciliate optimization of targeting with user-friendly approaches (Pezzana C et al, Biomaterials, 2022).
The understanding of the molecular and cellular mechanisms involved in the inter and intra-organ pathogenic dialogue in cardiac diseases. We speculate that cardiac resident macrophages (CRM) establishing time-dependent residence in the perivascular niche acquire unchallenged reparative function in the cardiac tissue. We will characterize the perivascular identity of CRM in the cardiac tissue and unravel the environmental cues involved in this niche-dependent functional programming. We also hypothesize that efferocytosis favors the activation of the regulated secretion pathways allowing CRM to immediately adjust their phenotype and cytokine secretion to promote inflammation resolution and initiate reparative processes (Project funded by ANR-22-CE14-0008; ANR-21-CE14-0073-01). Furthermore, we speculate that extracellular vesicles (EVs) are decisive components of the common body language as EVs may employ an apoptotic mimicry strategy to subjugate CRM efferocytic function, playing a fundamental role in CRM-based organ quorum sensing.
The development of innovative therapeutic modalities for cardiac diseases. Since 2019 a new line of research has emerged in the JS Silvestre and P Menasché’s groups around the understanding of the molecular and cellular mechanisms underlying the cardiac regeneration process. The underlying rationale is that although cell and non cell-based therapies improve heart function in experimental models, they still fail to address the root cause of systolic heart failure which is the loss of millions of contractile cardiomyocytes. Consequently, replenishment of this pool still remains an unmet, yet critical, challenge. In order to address this issue and integrate it in the cardiac repair process, we have developed models of cardiac regeneration in mice (Zlatanova I et al, Circulation, 2019; Lima-Correa B et al, Theranostics, 2021) and obtained a grant from the European Union on this theme, whose European coordinator is P. Menasché (REGeRNA, Horizon-RIA 101057318, 2022). We have therefore framed a project aimed at developing a synthetic mRNA able to trigger a time-controlled induction of endogenous (quiescent) cardiomyocyte proliferation in the context of heart failure with loss of contractile function. We thus intend to develop specific cardiomyocyte-targeted lipid nanoparticles that can efficiently transfect cardiomyocytes with mRNA encoding factors which unlock cardiomyocyte proliferation checkpoints. This approach should result in the generation of new cells, allow them to couple with their neighbours without causing arrhythmias and ultimately improve left ventricular function (REGeRNA, Horizon-RIA 101057318, 2022).
