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Mesenchymal stromal cells isolated from bronchoalveolar lavage and digest parenchymal lung tissue

ABSTRACT: Stromal support is critical to the achievement of lung homeostasis and the maintenance of an effective epithelial barrier, and yet previous studies have found a positive association between the number of mesenchymal stromal cell populations (MSCs) isolated from the alveolar space and human diseases associated with epithelial dysfunctional. We hypothesised that alveolar MSCs (A-MSCs) represent a dysfunctional population which would be distinct from lung tissue MSCs (LT-MSCs) and which would not be recoverable from healthy humans. In this study, we comprehensively interrogated the phenotype and transcriptome of human A-MSCs and LT-MSCs. We found that MSCs were rarely recoverable from the alveolar space in healthy humans, but were readily isolated from lung transplant recipients, where they expressed a CD90Hi, CD73Hi, CD45Neg, CD105Lo immunophenotype and were bipotent, lacking adipogenic potential. In contrast, MSCs were readily recoverable from healthy lung tissue and were CD90Hi or Lo, CD73Hi, CD45Neg, CD105Int and had full tri-lineage potential. Transcriptome profiling of the two populations confirmed their status as MSCs and revealed a high degree of similarity between each other and the archetypal bone-marrow MSC. 105 genes were differentially expressed, with genes involved in fibroblast activation, extracellular matrix deposition and tissue remodelling being up-regulated in A-MSCs. Finally, we found the fibroblast markers collagen 1 and α-smooth muscle actin was increased in A-MSCs. Our data suggest that in healthy humans, lung MSCs reside within the tissue, but in disease can differentiate to acquire a profibrotic phenotype and so move out of their niche into the alveolar space.

ORGANISM(S): Homo sapiens

PROVIDER: GSE74284 | GEO | 2016/07/04

SECONDARY ACCESSION(S): PRJNA299620

REPOSITORIES: GEO

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Project description:Rationale: Alveolar epithelial type 2 (AT2) cells are stem/progenitor cells in the adult lung and their maintenance and regulation is achieved through their interaction with mesenchymal cells which constitute their niches. However, the precise identity of the niche cells is still elusive. Objectives: To characterize the niche cells capable of supporting the self-renewal of AT2 stem cells in the murine model. Methods: The alveolar organoid model was used to test the efficiency of different subpopulations of mesenchymal cells isolated by FACS from well-established (PdgfraGFP, Axin2LacZ, Fgf10LacZ) reporter mice to support the self-renewal of mature AT2 cells. The reporter-positive cells where pre-sorted based on Cd45neg Cd31neg Epcamneg Sca1pos. Additional selection was achieved using LipidTOX staining for cells containing high level of neutral lipids. Organoid size and colony formation efficiency after 2 weeks in culture were quantified. RNAscope combined with immunofluorescence on adult lungs. qPCR, gene array were used to characterize the niche cells. Measurements and main results: A subset of Sca1+; Fgf10-expressing cells positive for LipidTox staining in the distal mesenchyme is efficient in the self-renewal and differentiation of AT2 stem cells. Co-staining of adult lung by using ISH and IF staining for Fgf10 and Sftpc respectively, indicate that 28% of Fgf10+ cells are located to close to AT2 cells. These cells do not overlap with Fgf7-expressing cells. Gene array comparing MANC (Cd45Neg Cd31Neg EpcamNeg Sca1Pos Axin2LacZ/FDGPos) with Fgf10Pos Lipofibroblasts (Cd45Neg Cd31Neg EpcamNeg Sca1Pos Fgf10LacZ/FDGPos) support that these two cell subsets are different and express differential markers that can be further used for the respective characterization of these cells. Conclusions: We have demonstrated for the first time that Fgf10Pos LIF cells play important role to support AT2 stem cells in terms of self-renewal and differentiation toward the AT1 cell type. These cells appear different from the previously characterized MANC and display a similar activity in eliciting AT2 self-renewal.

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Mesenchymal stromal cells isolated from bronchoalveolar lavage and digest parenchymal lung tissue

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