MSCs interaction with the host lung microenvironment: An overlooked aspect?

Abstract

Mesenchymal stromal cells (MSCs) were identified more than 50 years ago, and research advances have promoted the translation of pre-clinical studies into clinical settings in several diseases. However, we are only starting to uncover the local factors that regulate cell phenotype, cell function, and cell viability across tissues following administration in different diseases. Advances in pre-clinical and translational studies suggest that the host environment, especially inflammatory active environments, plays a significant role in directing the infused MSCs towards different phenotypes with different functions. This can significantly effect their therapeutic efficacy. One way to study this interaction between the host environment and the infused cells is to expose MSCs ex vivo to patient samples such as serum or bronchoalveolar lavage fluid. Using this approach, it has been demonstrated that MSCs are very sensitive to different host factors such as pathogens, inflammatory cytokines, and extra cellular matrix properties. By understanding how different local host factors effect MSC function it will open possibilities to select specific patient sub-groups that are more likely to respond to this type of treatment and will also open possibilities to prime the local host environment to increase viability and to enrich for a specific MSC phenotype. Here, we aim to review the current understanding of the interaction of MSCs with the host microenvironment. To narrow the scope of this mini review, the focus will be on the pulmonary microenvironment, with a specific focus on the diseases acute respiratory distress syndrome (ARDS) and cystic fibrosis (CF).

Keywords: MSCs; Mesenchymal stromal cells; acute respiratory distress syndrome; bronchoalveolar lavage fluid; cell therapy; cystic fibrosis; lung; microenvironment.

Figure 1

A schematic illustration describing how different environmental factors such as microbes (e.g. bacteria, virus, fungi, and PAMPs), inflammation (e.g. inflammatory cells and pro- and anti-inflammatory cytokines), and extracellular matrix properties (e.g. DAMPS, emphysema, fibrosis, elastic tendency of the lung, and oxygen tension) influence the viability, phenotype, and functions of administered human mesenchymal stromal cells (MSCs). MSC, mesenchymal stromal cells; PAMPS; pathogen-associated molecular patterns; DAMPS, danger-associated molecular patterns; ECM, extracellular matrix. Illustration created by Lisa Karlsson.

Figure 2

A schematic illustration summarizing the local host environment found in CF (A) and ARDS patients (B). (A) The CF environment that MSCs encounter after infusion is a hypoxic and acidic environment with thick and sticky mucus that contribute to the increased risk of microbe colonization. This constant infection often results in a chronic inflammation with the release of several cytokines (IL-8 being one of the major cytokines), neutrophil influx, and ROS production leading to tissue damage and decreased lung function. (B) The ARDS environment is a protein rich and inflamed environment with activation of inflammatory cells and the release of pro-inflammatory cytokines (cytokine storm), often combined with injuries to both the alveolar and capillary barrier (which lead to edema). This result in paracellular permeability, impaired fluid clearance, impaired surfactant production, and shedding of anticoagulant molecules and tissue factors. MSCs, mesenchymal stromal cells; CF, cystic fibrosis; ARDS, acute respiratory distress syndrome; IL-8, interleukin 8; ROS, reactive oxygen species; CFTR, cystic fibrosis transmembrane conductance regulator; AT1, alveolar type 1 cells; AT2, alveolar type 2 cells. Illustration created by Lisa Karlsson.