Fibroblast-T cell crosstalk as a driver of cardiometabolic HFpEF

• Applicant: Dr. Ramona Emig
• Subject Area: Immunology ; Cardiology, Angiology ; Cell Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 539486371

Heart failure with preserved ejection fraction (HFpEF) is a complex cardiovascular syndrome and among the leading causes of hospitalization in developed countries. HFpEF is usually associated with confounders such as obesity or hypertension. It is characterized by preserved ejection fraction and increased left ventricular end diastolic pressure-volume relationship, which causes reduced filling of the left ventricle during diastole. Treatments that efficiently ameliorate symptoms in other types of heart failure do not provide benefit in patients with HFpEF. To enable the development of specific treatment strategies to improve cardiac function in HFpEF patients, we need to better understand the unique, underlying mechanisms. Cardiac fibroblasts are interstitial cells responsible for extracellular matrix maintenance, thereby providing mechanical stability to the heart. Many cardiac diseases are accompanied by fibrosis, excessive accumulation of extracellular matrix by activated fibroblast, which leads to tissue stiffening. Additionally, fibroblasts contribute to inflammation by secreting cytokines and by presenting antigens to T cells under inflammatory conditions. T cells are part of the adaptive immune system and contribute to the regulation of the immune response. Based on the role of fibroblasts in mechanical tissue remodeling and preliminary data illustrating a crucial role for T cells for HFpEF, I propose to investigate the involvement of fibroblast-T cell crosstalk in a murine model of cardiometabolic HFpEF. In this model, systemic inflammation and diastolic dysfunction are triggered by the combination of high fat diet and hypertension. First of all, I propose to perform in depth longitudinal characterization of left ventricular fibrosis using 3D imaging of the extracellular matrix, investigation of mechanical properties of living cardiac tissue and mass spectrometry-based assessment of extracellular matrix composition. To probe the importance of T cells for extracellular matrix remodeling, these studies will be performed in parallel in wildtype and T cell-deficient mice. Additionally, T cell depletion at different time points after onset of tissue remodeling will show whether T cell-dependent tissue remodeling is reversible. In the second part of the study, in vitro experiments using isolated fibroblasts and T cells will assess the bidirectional communication between fibroblasts and T cells. This will answer whether and, if so, under which conditions T cells can activate fibroblasts and vice versa. Special emphasis will be given to the role of fibroblast mechano-sensing as an amplifier of their response to T cells interactions. Taken together, the study proposed here will answer my central hypothesis that diastolic dysfunction in cardiometabolic HFpEF is induced by mechanically-regulated fibroblast-T cell crosstalk. If true, this would open up new avenues for therapeutic development to treat diastolic dysfunction in HFpEF patients.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Dr. Pilar Alcaide