From Clones to Buds and Branches: The Use of Lung Organoids to Model Branching Morphogenesis Ex Vivo.

Ana Ivonne Vazquez-Armendariz,Susanne Herold

doi:10.3389/fcell.2021.631579

Abstract

Three-dimensional (3D) organoid culture systems have rapidly emerged as powerful tools to study organ development and disease. The lung is a complex and highly specialized organ that comprises more than 40 cell types that offer several region-specific roles. During organogenesis, the lung goes through sequential and morphologically distinctive stages to assume its mature form, both structurally and functionally. As branching takes place, multipotent epithelial progenitors at the distal tips of the growing/bifurcating epithelial tubes progressively become lineage-restricted, giving rise to more differentiated and specialized cell types. Although many cellular and molecular mechanisms leading to branching morphogenesis have been explored, deeper understanding of biological processes governing cell-fate decisions and lung patterning is still needed. Given that these distinct processes cannot be easily analyzed in vivo, 3D culture systems have become a valuable platform to study organogenesis in vitro. This minireview focuses on the current lung organoid systems that recapitulate developmental events occurring before and during branching morphogenesis. In addition, we also discuss their limitations and future directions.

Highlights

Organoids are 3D structures derived from stem cells that proliferate and give rise to organ-specific cells types capable to form structures that recapitulate the cellular architecture and functions of the native organ
Most of the lung organoids derived from adult stem cells lack proximal to distal patterning, these models have been proven useful for studying cell-fate decisions happening at later stages of branching morphogenesis
3D culture of bronchioalveolar stem cells (BASCs) (EpCAMhighSCA-1+secretoglobin family 1A member 1 (SCGB1A1)+surfactant Protein C (SFTPC)+) and lung resident mesenchymal cells (CD45−CD31−epithelial cell adhesion molecule (EpCAM)− stem cell antigen-1 (SCA-1)+) isolated from adult mouse lungs gave rise to mainly bronchioalveolar lung organoids (BALO) that exhibit distinct bronchiolar-like structures containing basal, club, goblet, and ciliated cells and alveolar-like structures comprising differentiated alveolar epithelial cells type 1 (AECI) and alveolar epithelial cells type 2 (AECII) that resembled the proximodistal pattering of the lung (Figure 1D) (Vazquez-Armendariz et al, 2020)

Summary

Introduction

Organoids are 3D structures derived from stem cells that proliferate and give rise to organ-specific cells types capable to form structures that recapitulate the cellular architecture and functions of the native organ. McCauley and colleagues reported a hPSC-derived lung bud tip organoid model using NKX2-1+ progenitors that could give rise to either proximal airway or alveolar lineages (McCauley et al, 2017).

Results

Conclusion