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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.

SUBMITTER: Busch SM

PROVIDER: S-EPMC8149957 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Integrins provide the primary link between mesenchymal stem cells (MSCs) and their surrounding extracellular matrix (ECM), with different integrin pairs having specificity for different ECM molecules or peptide sequences contained within them. It is widely acknowledged that the type of ECM present can influence MSC differentiation; however, it is yet to be determined how specific integrin-ECM interactions may alter this or how they change during differentiation. We determined that human bone marrow-derived mesenchymal stem cells (hMSCs) express a broad range of integrins in their undifferentiated state and show a dramatic, but transient, increase in the level of ?5 integrin on day 7 of osteogenesis and an increase in ?6 integrin expression throughout adipogenesis. We used a nonfouling polystyrene-block-poly(ethylene oxide)-copolymer (PS-PEO) surface to present short peptides with defined integrin-binding capabilities (RGD, IKVAV, YIGSR, and RETTAWA) to hMSCs and investigate the effects of such specific integrin-ECM contacts on differentiation. hMSCs cultured on these peptides displayed different morphologies and had varying abilities to differentiate along the osteogenic and adipogenic lineages. The peptide sequences most conducive to differentiation (IKVAV for osteogenesis and RETTAWA and IKVAV for adipogenesis) were not necessarily those that were bound by those integrin subunits seen to increase during differentiation. Additionally, we also determined that presentation of RGD, which is bound by multiple integrins, was required to support long-term viability of hMSCs. Overall we confirm that integrin-ECM contacts change throughout hMSC differentiation and show that surfaces presenting defined peptide sequences can be used to target specific integrins and ultimately influence hMSC differentiation. This platform also provides information for the development of biomaterials capable of directing hMSC differentiation for use in tissue engineering therapies.

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

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