iPSC-derived co-culture model to investigate lymphatic-epithelial interactions in sporadic-LAM (lymphangioleiomyomatosis)

• Applicant: Dr. Sinem Koc-Günel
• Subject Area: Pneumology, Thoracic Surgery ; Structural Biology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 428935778

Sporadic Lymphangioleiomyomatosis (S-LAM) is a rare progressive multi-systemic and cystic disease of the lung characterized by an abnormal, tumorous proliferation of smooth muscle-like cells (SMC) leading to an invasion of bronchioles, blood and lymphatic vessels, causing severe obstructive lung disease and involving the lymphatic system. There is no proven therapeutic intervention currently available to slow or prevent the ensuing progressive cystic destruction of the lung. A significant increase in morbidity and mortality is observed in young premenopausal women which results in death due to respiratory failure within 20 years of symptom onset. The paucity of therapeutic development is augmented by a lack of in vitro and in vivo models that recapitulate the human disease. Investigating rare diseases is indisputably challenging with a lack of disease relevant tissues available. This proposal addresses a critical need to develop a reproducible, disease and species specific model of LAM to accelerate our understanding of its pathogenesis and facilitate therapeutic development. In order to understand the abhorrent cell signaling and cellular interactions that may activate LAM cells and favor metastatic spread, we need to develop a patient specific co-culture system which we will first use to investigate the role for VEGF signaling in driving a pathogenic regulation of the lung epithelium by the disease lymphatic endothelium. Currently available animal model systems do not recapitulate the LAM-phenotype where epithelioid LAM cells are found in pleural effusions and blood and recur in transplanted lungs supporting a metastatic character to the disease. Serum levels of VEGF-D have been associated with disease progression, which may indicate a role for VEGFR-3 signaling in LAM cell-induction via autocrine regulation of the lymphatic epithelium or paracrine effects on the epithelium. Deciphering whether lymphatic dysfunction and VEGFR-3 signaling are key drivers of the invasive proliferation of LAM cells requires the development of an in vitro model using patient specific and relevant cell types. IPSC-derived models of LAM are a novelty and will broaden our understanding of the disease and will significantly improve deciphering the pathophysiology during embryogenesis in a dish and will help to find new therapeutic targets and hopefully will help to give appropriate therapy to hold the progression of the disease.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Privatdozentin Amy Ryan, Ph.D.