Implications for Extracellular Matrix Interactions With Human Lung Basal Stem Cells in Lung Development, Disease, and Airway Modeling

Abstract

The extracellular matrix (ECM) is not simply a quiescent scaffold. This three-dimensional network of extracellular macromolecules provides structural, mechanical, and biochemical support for the cells of the lung. Throughout life, the ECM forms a critical component of the pulmonary stem cell niche. Basal cells (BCs), the primary stem cells of the airways capable of differentiating to all luminal cell types, reside in close proximity to the basolateral ECM. Studying BC-ECM interactions is important for the development of therapies for chronic lung diseases in which ECM alterations are accompanied by an apparent loss of the lung’s regenerative capacity. The complexity and importance of the native ECM in the regulation of BCs is highlighted as we have yet to create an in vitro culture model that is capable of supporting the long-term expansion of multipotent BCs. The interactions between the pulmonary ECM and BCs are, therefore, a vital component for understanding the mechanisms regulating BC stemness during health and disease. If we are able to replicate these interactions in airway models, we could significantly improve our ability to maintain basal cell stemness ex vivo for use in in vitro models and with prospects for cellular therapies. Furthermore, successful, and sustained airway regeneration in an aged or diseased lung by small molecules, novel compounds or via cellular therapy will rely upon both manipulation of the airway stem cells and their immediate niche within the lung. This review will focus on the current understanding of how the pulmonary ECM regulates the basal stem cell function, how this relationship changes in chronic disease, and how replicating native conditions poses challenges for ex vivo cell culture.

Airway Basal Cells, Protectors of Epithelial Walls in Health and Respiratory Diseases

“…Indeed, upon damage, the neighboring epithelial cells will undergo phenotypic changes, due to loss of contact inhibition from neighboring cells and an increasing gradient of factors (e.g., cytokines and growth factors) from the wound site, which enable them to migrate over and seal the wound ( 47 ). Gene expression analysis of those spreading cells in human showed that these cells were positive for vimentin and KRT14, illustrating the important role of basal cells in the initial phase after injury ( 48 , 49 ). Interestingly, secretory epithelial cells (i.e., goblet and club cells) have the capacity to dedifferentiate in absence of basal cells and become functional TP63 + and KRT5 + airway progenitor cells ( 49 – 51 ).…”

“…The degradation is primarily performed by matrix metalloproteinases (i.e., MMP-3, MMP-9, and MMP-11), that are mainly released by the migratory basal cells ( 28 , 37 ). In addition, those migratory basal cells also deposit new ECM compounds that ease their migration and provide a temporary provisional barrier that covers the wound in attendance of full resolution, a mechanism that is again proposed to be initiated by TGF-β ( 48 , 65 ). While colonizing the denuded epithelium, the migratory progenitor cells start to proliferate to completely cover the damaged site.…”

“…Using intestinal organoids, it has been shown that both cocultures with Tregs and treatment with its main cytokine IL-10 result in intestinal stem cell expansion, while cocultures with other Th cell subgroups or cytokine treatments caused a decrease of intestinal stem cell numbers ( 132 ). Lastly, TGF-β induces phenotypic changes in basal cells upon injury, leading to more motile progenitors, and deposition of ECM compounds in order to generate a provisional barrier that covers the wound ( 48 , 65 ).…”

Reconstructing the pulmonary niche with stem cells: a lung story

“…It is immediately obvious that the ECM provides an elaborate framework that maintains structural integrity during lung organogenesis. However, it also plays a critical role in defining stem cell fate and maturation of the lung [ 20 , 110 ]. The pulmonary ECM is a nexus of biochemical and mechanical cues that instructs stem cell behavior during lung development and regeneration [ 111 ].…”

Development of a physiomimetic model of acute respiratory distress syndrome by using ECM hydrogels and organ-on-a-chip devices

“…Two different technologies have recently gained popularity for creating physiomimetic models to recreate the ECM ( Busch, Lorenzana, and Ryan 2021 ) and the mechanobiological signals in vitro : 3D cell cultures ( Habanjar et al, 2021 ) and organ-on-a-chip devices ( Mertz, Ahmed, and Takayama 2018 ; Benam, Burgess, and Stewart 2021 ). Indeed, it has been shown that lung ECM can be obtained by decellularizing the native tissues with detergents and enzymes ( Nonaka et al, 2014 ) and then pulverized and reconstituted in the form of hydrogels suitable for 3D cell culture ( Pati and Cho 2017 ).…”