A1: Organ-specific specialization and functional heterogeneity of pericytes
Blood vessels provide a versatile and adaptable transport system, but recent work has established that endothelial cells, which form the innermost lining of the vascular network, are also a source of molecular signals controlling the behavior of non-vascular cell types in the surrounding tissue. This paracrine (also termed ‘angiocrine’) function of endothelial cells regulates morphogenesis, homeostasis and regeneration of different organs including lung, liver, heart, and bone. Pericytes, capillary-associated mesenchymal cells, are another essential component of the vessel wall and help to preserve vascular integrity. Ongoing research in my laboratory has established that pulmonary pericytes are a critical source of growth factor signals that control the proliferation of epithelial cells and are indispensable for alveologenesis in the postnatal lung. We have also found that pericytes exhibit organ-specific gene expression profiles, which result in highly specialized expression signatures for potential angiocrine signals. Here, we propose a systematic analysis of pericyte-derived molecular cues in multiple organs. We will define critical common and specialized properties of pericytes, and will investigate the relevance of different growth factor signals in 2D and 3D co-culture assays. Our work will also involve the unbiased investigation of the molecular heterogeneity of pericytes at the single cell level. Finally, we will use genetic approaches in mice to gain deeper insight into the function of pericytes as angiocrine regulators in organ growth, maintenance and in response to tissue damage. Together, the results obtained from the proposed experiments will establish that pericytes function as important signaling centers, a function that might be impaired in pathological settings. Our findings are likely to be relevant for many other organs and might facilitate the development of future therapeutic strategies to promote tissue regeneration.
Genetic labeling of pericyte (GFP, green) in adult (8 week-old) Pdgfrb-CreERT2 lung. Epithelial cells (RAGE, red); endothelial cells (CD31, blue).