CXCL12 and tissue regeneration: Mechanisms of action and therapeutic potential – chemrepair

The chemokine CXCL12 is unique among chemokines by the pleiotropic roles that it plays in embryo and adult life. The exceptional conservation of CXCL12 structure & function in mammalians announces the essential roles played by this singular chemokine. To this regard the contribution of CXCL12/CXCR4 chemokine axis in the recruitment of stem cells from bone marrow and non bone marrow origins is of paramount importance and occupying a predominant hierarchic role in the orchestration of tissue regeneration. Notably, CXCL12 regulates with unchallenged capacity both the tissue homing and survival of circulating tissue-specific progenitors, hematopoietic- and bone marrow stem cells as well as triggers inflammatory cells infiltration. Subsequently, the ?involvement or the contribution of CXCL12 to stem-cell-based tissue repair has been investigated in several models of ischemia or tissue injure among which, cardiac or limb ischemia, liver or renal injury.
Beyond the binding to its cognate receptor CXCR4, the interaction of chemokines with the glycanic moiety of proteoglycans, in particular with?heparan sulfates (HS), is supposed to enable the formation of chemokine gradients which determine the orientated migration and tissue recruitment of circulating cells. In a former project supported by the ANR, we investigated the structural and functional characterization of the interactions of the CXCL12 chemokine with HS and we identified the novel CXCL12? isoform as the paradigm of proteins with hapotactic capacity in vivo. The work accomplished has also enabled the development of an animal model where Cxcl12 gene has been selectively mutated (knock-in) in the critical binding sites that disable CXCL12-HS interactions (CxcL12 HS-/- mice) supported by ANR-05-NT05-4_41968,
It is the purpose of this project to pursue and implement the investigation of this important mechanism in both homeostasis and pathological situations where the contribution of CXCL12 is hierarchical and critically involved in the successful return to homeostasis.
The project will focus on, on one hand, the investigation of tissue homeostasis during development and adult life in Cxcl12 HS-/- animals, to provide a detailed histological analysis in Cxcl12 HS-/- embryo and adult animals and characterize the trafficking of leukocytes between blood and primary lymphoid organs. On the other hand, we will assess the role played by CXCL12/HS interactions in the physiopathology of tissue repair and analyze the therapeutic potential of CXCL12 isoforms differing by their capacity to interact with HS proteoglycans. For this purpose we will use, three different models of tissue regeneration including skeletal muscular repair following notexin injury; vessel growth and remodeling after hindlimb ischemia and woundhealing and will analyze the kinetic of the spontaneous tissue reparation in these settings models of tissue regeneration in the Cxcl12 HS-/- animal model. Finally, we will analyze the therapeutic potential of CXCL12 and in particular this of CXCL12?, which binds with unsupassed affinity to HS proteoglycans an is the paradigm of haptotactic proteins.
Overall, our project aim to investigate the paradigm of chemokine HS-immobilisation and gradient formation during pathological situations associated with tissue regeneration and we believe that the proposed physiopathological settings are ideally suited for investigating the postulate that CXCL12 plays a hierarchical and non redundant role in the orchestration of tissue repair. The consortium will conduct this project with an open-laboratory phylosophy sharing approaches and ressources and exploiting results in a partnership warranted by the ongoing collaboartion and the tight links between our host institutions