iPSC-Derived Vascularized Human Lung Organoids and Interaction Between Lung Endothelial Cells and Alveolar Epithelial Cells

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Principal Investigator: Preetish  Kadur Lakshminarasim
Organization: UNIVERSITY OF ILLINOIS AT CHICAGO
Fiscal Year: 2024
Award: $715,989
Funding agency: National Heart Lung and Blood Institute

ABSTRACT
 Human induced pluripotent stem cells (iPSCs) can be used to generate 3-dimensional lung organoid
structures. However, most lung organoid studies have focused on human iPSC-derived lung epithelial subtypes.
They have not to date included human iPSC-derived endothelial cells and systematically addressed the critical
role of lung vascular endothelial cells and vascular perfusion itself in the generation and maturation of lung
organoids which model human lung structures. The alveolar units consist of two predominant cell types –
epithelial cells (EpiC)(40-45% of total cells) and endothelial cells (EC) (45-50% of total cells). Our key
Supporting Data support the critical and heretofore underestimated role of human lung vascular endothelial
cells in guiding differentiation of human lung epithelial progenitor cells and formation of vascularized human lung
organoid. We propose to use this novel platform generated by integration of hiPSC-derived epithelial and
endothelial cells to address the following aims: Aim 1 tests the hypothesis that endothelial cell-derived
angiocrine signals in lung organoids activate Wnt signaling and mediate the maturation of lung alveolar units and
the corollary hypothesis that reciprocal epicrine signaling of EpiC regulates lung EC fate, generation of recently
described specific lung EC populations and lung microvessel patterning at the level of alveoli. Aim 2 will test
the hypothesis that the vascularized and perfused human lung organoid serves as a translationally relevant
reductionist model for teasing apart the elusive signaling and molecular mechanisms of inflammatory injury at
the level of the alveolar unit and resolution of injury. Aim 3 will test the hypothesis that lung EC signaling through
the upregulation of ACE2 in alveolar Type II epithelial cells promotes SARS-CoV-2 entry and infection of lungs.
Together the proposed studies through their focus on lung EC and vascularization of human lung organoid and
incorporation of alveolar epithelial cells in this system will uncover fundamental mechanisms of how the
vascularized alveolar unit functions in health to maintain homeostasis and how defective cross-talk between EC
and alveolar epithelial cells contributes to inflammatory lung disease.

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health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Selection for Treatments><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Structure of parenchyma of lung><Study models><System><Testing><Therapeutic><Type II Cell><Type II Epithelial Receptor Cell><Type II Pneumocyte><Up-Regulation><Upregulation><Vascular Endothelial Cell><Vascular Endothelium><Vascularization><WNT Signaling Pathway><WNT signaling><Wuhan coronavirus><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after infection by SARS-CoV-2><after severe acute respiratory distress syndrome CoV-2 infection><alveolar epithelium><alveolar type II cell><angiotensin converting enzyme 2><angiotensin converting enzyme II><biological signal transduction><capsule><cell type><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health 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