Remodelling and Regeneration


Understanding the developmental biology of airway branching and lung parenchymal morphogenesis is still incomplete, but several key morphogenetic pathways have been identified. In contrast, there is a virtual complete lack of knowledge as to the sensing and control mechanism, the engagement of key cellular players and the (re-)activation of signaling pathways that underlie the architectural maintenance and the (assumedly continuous) re-shaping of the lung parenchyma under conditions of permanent noxious attack via the large epithelial surface area. Designed to enable the rendezvous of large air and vascular surfaces while minimizing the structural backbone of the organ, control of pulmonary cellularity and matrix homeostasis is of fundamental importance for the lung.

Uncontrolled hyperplasia and hypertrophy of various cells types and extracellular matrix accumulation/malcomposition are not compatible with the functional requirement of this organ. We assume that epigenetic setting and chromatin-mediated processes play key roles in orchestrating the architectural control of the lung and its resilience to structural distortion.

Loss of the lung architectural homeostasis may on the one hand result in “plus” variants of lung parenchymal diseases, characterized by changes in cellular phenotypes (activation vs quiescence, proliferation vs differentiation, engagement of the various stem/progenitor cells and morphogenetic pathways) and an overall or spatially accentuated accumulation of cells and matrix. Pulmonary hypertension (vascular compartment), interstitial lung diseases/lung fibrosis (interstitial and/or alveolar compartment), progressive scarring processes in chronic infectious states (all compartments) and lung cancer (in particular lung adenocarcinoma assumed to originate from distal lung epithelial stem cells) represent the prominent diseases in this context. On the other hand, “minus” variants of lung diseases may arise form enhanced apoptotic, necroptotic or necrotic cell death as well as loss of replicative competence (epigenetic “misguidance”, boosted senescence, and stem/progenitor pool exhaustion as putative underlying events) with loss of essential lung structural components. Emphysema (complete loss of alveolar units), but also “pruning” types of pulmonary hypertension with loss of peripheral lung vasculature represent diseases with such background. Interestingly, components of “plus” and “minus” pathological processes often co-exist in different or even overlapping lung areas, with “Combined Pulmonary Fibrosis and Emphysema (CPFE)” representing a prominent clinical example.

Deciphering the key cellular and molecular players of such aberrant lung parenchymal remodeling will provide novel targets to be harnessed for preventive, anti-remodeling, reverse-remodeling and regenerative strategies. Indeed, recent evidence indicates that even major distortions of lung architecture may be reversed, at least to some extent, by activation of stem/progenitor cells, cellular plasticity allowing de-differentiation/re-differentiation cycles and reengagement of morphogenetic pathways.


Long-term Scientific and Structural Objectives

Deciphering the key cellular and molecular players of aberrant remodeling processes in the lung parenchyma will profoundly broaden our current scope of understanding the pathogenesis of chronic distorting lung diseases. Most importantly, combining such knowledge with advanced therapeutic intervention tools will result in novel preventive, anti-remodeling, reverse-remodeling and regenerative strategies. To this end, transgenic mouse technology and advanced animal models, cutting edge “omics”, extensive biomaterials from deeply phenotyped patient cohorts, bioinformatics capacity and clinical trial competence are to be combined as outlined in the work packages above. Restoration of fully functioning lung parenchymal architecture is the obvious long term goal of this Research Area, not to be achieved by transplantation of healthy organs, but by induction of remodeling, repair and regeneration processes inherently available in this organ, but handicapped under the specific disease conditions.