The lymphatic system is comprised of a network of blind-ended capillaries and collecting vessels, which drain interstitial fluids, fat, and immune cells through the lymph nodes to return them back to the blood circulation in the jugular area. It maintains fluid homeostasis, performs the immune surveillance and transports intestinal lipids. In the adulthood, lymphangiogenesis, the growth of new lymphatic vessels, occurs in pathological conditions including tumor metastasis, inflammatory and cardiovascular diseases, and a dysfunction of the lymphatic system leads to lymphedema, an accumulation of fluids and adipose tissue in the limb.
Our working hypothesis is that restoring lymphatic drainage in injured tissues will substantially accelerate healing by improving tissue homeostasis, regulating inflammatory cells trafficking and promoting edema drainage. In that context, our group focuses on pathologies characterized by a massive lymphatic dysfunction: secondary lymphedema and cardiac ischemia.
Our objective is to connect fundamental and translational research approaches in the field of lymphatic biology. We develop research axes including gene expression control in response to stress, pathophysiology of the lymphatic system, and therapeutic axes of gene therapy of ischemic heart disease and lymphedema.
Barbara Garmy-Susini’s project aims at characterizing the pathophysiology of lymphedema. She is investigating both risk factors (hormone- and chemotherapy) and aggravating factors of the pathology. Using OMICS approaches (lipidomic, RNAseq), she identified potential therapeutic targets to restore the lymphatic flow. In particular, her group pointed out the crucial role of the resolution of inflammation in the development of lymphedema. Her main goal is to provide treatment for an unmet medical need with no approved therapy. Her project named “Theralymph” has been granted by the call H2020 “regenerative medicine new insight to new application » to perform a Phase I/II clinical trial for lymphedema. Her group is developing a gene therapy for lymphedema based on VEGFC delivery (to target capillaries) coupled to a molecule able to restore the lymphatic collecting pumping. The consortium is including laboratories located in Finland (K. Alitalo), Sweden (T. Makinen), Switzerland (T. Petrova), Czech republic (L. Rossmeislova), Belgium (M. Vikkula, A. Noel) and France (G. Pagès).
Anne-Catherine Prats’ project focuses onto mRNA translational control in stressed cells. The current project, RIBOCARD (funded by ANR) aims to identify ribosome modifications in ischemic heart disease and measure their impact on IRES activity. IRESs are mRNA structures able to activate translation during stress. The cryoEM structure of a human ribosome bound to an IRES will also be determined, in order to shed light onto the mechanism of IRES-dependent translation. A similar study is being performed in lymphatic endothelial cells. This project will improve understanding gene expression control in cardiovascular diseases as well as in other pathologies related to stress. Partners : J.J. Diaz et F. Catez, CRCL Lyon ; B. Klaholz, IGBMC Strasbourg
Eric Lacazette is investigating the characterization of a new family of RNAs, circular RNAs, in lymphatic endothelial cells. It is known that these cells fine-tune their gene expression program according to the microenvironment. These circular RNAs are identified by RNA-seq followed by a dedicated bioinformatics analysis and then functionally characterized in in-vitro and in-vivo models. Our work shows that some of the characterized circular RNAs are translated using an alternative translation initiation mechanism leading to the production of proteins with currently unknown functions. This project will provide a better understanding of the fine regulation that takes place during the establishment of the lymphatic system in a physiological or pathophysiological context. Collaboration : Christine Gaspin et Jérôme Mariette (Unité de Mathématiques et Informatique Appliquées de Toulouse, INRA Auzeville).
Florence Tatin aims to characterize collecting lymphatic vessels in adipose territories and to determine the consequence of an alteration of collecting lymphatic vessels on adipose microenvironment. Towards this aim, she has an unique mouse model where collecting vessels have dysfunctional valves. This model will allow us to determine for the first time the consequence of valves incompetency in lymphatic function and their implication in lymphedema. In addition, she will use genetic tools in mice and 3D imaging to visualize and determine the molecular pattern of the collecting vessels in their microenvironment in physiopathological context. Thanks to our collaboration with IMACTIV-3D, we will be able to visualize the lymphatic network in deeper adipose tissue territories. Their expertise will allow us to image lymphatic dysfunction and determine the consequence on the cellular microenvironment in the preclinical model of secondary lymphedema. In this project APELYM-3D, we postulate that the growth of new mature and functional lymphatic vessels is crucial to preserve the mechanisms of regeneration and limit the development of pro-inflammatory areas and fibrosis. This project is supported by European and regional funds.
Florent Morfoisse is focusing on microenvironment. Fibrosis, the pathological accumulation and disorganization of extracellular matrix (ECM), worsens lymphedema but has been poorly investigated. His project characterizes lymphedema—induced modifications of ECM, to determine how this pathological ECM disrupts lymphatic vessels and identify the molecular actor of fibrosis development. This project is expected to provide new strategies to treat lymphedema by normalizing its microenvironment.