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Perivascular cells at the crossroads of inflammation, regeneration and fibrosis

Periodic Reporting for period 5 - PERIF (Perivascular cells at the crossroads of inflammation, regeneration and fibrosis)

Reporting period: 2021-11-01 to 2023-04-30

The survival of organisms requires the ability to repair tissues upon injury, as well as, after birth, to fight foreign invaders that may have contaminated the wound. This last function is mediated by a complex host response involving innate immune cells, blood vessels and inflammatory mediators that collectively intend to neutralize the harmful agent and eliminate damaged/necrotic tissue. Initially beneficial, this massive inflammatory response comes with a cost, and adult injured tissues usually heal with a scar, which is an area of fibrous tissue that transiently replaces normal tissue. This is in contrast to the complete tissue repair with no signs of scarring observed during fetal development until late stages of organogenesis, resembling regeneration. In chronic settings, scarring can become excessive in a process called fibrosis, to the point of preventing functional recovery of the injured organ and be life threatening.

Nearly half of all deaths in industrialized world are due to diseases involving inappropriate, often chronic, inflammatory and fibrotic responses, including chronic lung, kidney and liver diseases, scleroderma, inflammatory bowel diseases, muscular dystrophies, cardiovascular diseases, and desmoplastic tumors. However, our current knowledge of the biological processes regulating fibrosis is partial, which has hindered therapeutic advances in the field. Recent data from our team and others drew new attention on a discrete population of mesenchymal cells that wraps around vessels, variously called mural cells, perivascular cells or pericytes, as a major source for profibrotic stromal cells generating scar tissue. Previously known for their vascular protective functions, increasing evidence suggests new and unexpected roles for these cells also in inflammation, repair/regeneration, and cancer. These new findings raise a number of challenging questions relative to their functional diversity, and mechanisms of activation/ regulation in disease.

In this project, we used different experimental approaches to uncover novel cellular partners in the perivascular niche and molecular pathways across several organs that lead to dysregulated repair responses, pathological inflammation and fibrosis. At the translational level, results obtained in this project are expected to pave the way for the development of novel (co)-therapeutic strategies in inflammatory diseases, regenerative medicine and cancer.
In this project, we used a multidisciplinary approach based on new experimental models of lineage tracing and inducible cell ablation in vivo, to uncover novel cellular and molecular stromal pathways across organs that lead to pathological inflammation and fibrosis. By using different approaches including transcriptomics, flow cytometry and functional assays, our results identified several new stromal pathways and cellular interaction that are key in inflammation and cancer. In the long term, results obtained in this project are expected to lead to the discovery of new stromal targets and/or improve current therapies to treat cancer and inflammatory/fibrotic diseases. Molecular profiling of perivascular mesenchymal progenitors obtained in this project is expected to generate new interest to further exploit the translational potential of these findings. Altogether, these results will allow to better decipher the coordination of different cell types in vivo, in particular tissue resident cells, tipping the balance toward healing or chronic repair/fibrosis.
This research project addresses current challenges in the field of tissue repair and chronic diseases, with emerging medical applications in fibrosis, regenerative medicine and cancer. Chronic fibrotic diseases are a huge burden for our societies, and still represent a major cause of mortality, nevertheless efficient treatments are rare. In this project, we are addressing the role of resident perivascular mesenchymal cells as key sensors of tissue injury and upstream organizers of inflammation. It is known since a long time that resident mesenchymal/stromal cells that form the structure of our organs and vessels are activated upon injury and foster chronic diseases. However, the underlying mechanisms remain unclear, which has prevented development of new therapeutic approaches. One of the major roadblock is the paucity of specific markers and tools to study these cells. In this project, we generated different genetic tools and experimental systems that allow us to study the function of specific subsets of mesenchymal cells in disease. Using these tools, we shed new light on the fundamental process of tissue repair, which is still not fully understood. The long-term aim is to target specific subsets of “pathology-associated” mesenchymal cells to ameliorate current therapies in fibrotic diseases and cancer.