Mesenchymal Stromal Cells are Readily Recoverable from Lung Tissue, but not the Alveolar Space, in Healthy Humans

Stromal support is critical for lung homeostasis and the maintenance of an effective epithelial barrier. Despite this, previous studies have found a positive association between the number of mesenchymal stromal cells (MSCs) isolated from the alveolar compartment and human lung diseases associated w...

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Published in:Stem cells (Dayton, Ohio) Ohio), 2016-10, Vol.34 (10), p.2548-2558
Main Authors: Sinclair, K. A., Yerkovich, S. T., Chen, T., McQualter, J. L., Hopkins, P. M‐A., Wells, C. A., Chambers, D. C.
Format: Article
Language:English
Subjects:
Actins - metabolism
Aged
Bronchoalveolar Lavage Fluid
Cell Differentiation
Cell Lineage
Cell Separation
Cluster Analysis
Collagen Type I - genetics
Collagen Type I - metabolism
Colony-Forming Units Assay
Endoglin - metabolism
Female
Fibroblasts
Flow Cytometry
Fluorescence
Gene Expression Profiling
Healthy Volunteers
Humans
Lung
Lung - cytology
Lung Transplantation
Male
Mesenchymal stem cells
Mesenchymal stromal cells
Mesenchymal Stromal Cells - cytology
Microarray
Middle Aged
Pulmonary Alveoli - cytology
Transcriptome
Transcriptome - genetics
Young Adult
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Summary:Stromal support is critical for lung homeostasis and the maintenance of an effective epithelial barrier. Despite this, previous studies have found a positive association between the number of mesenchymal stromal cells (MSCs) isolated from the alveolar compartment and human lung diseases associated with epithelial dysfunction. We hypothesised that bronchoalveolar lavage derived MSCs (BAL‐MSCs) are dysfunctional and distinct from resident lung tissue MSCs (LT‐MSCs). In this study, we comprehensively interrogated the phenotype and transcriptome of human BAL‐MSCs and LT‐MSCs. We found that MSCs were rarely recoverable from the alveolar space in healthy humans, but could be readily isolated from lung transplant recipients by bronchoalveolar lavage. BAL‐MSCs exhibited a CD90Hi, CD73Hi, CD45Neg, CD105Lo immunophenotype and were bipotent, lacking adipogenic potential. In contrast, MSCs were readily recoverable from healthy human lung tissue and were CD90Hi or Lo, CD73Hi, CD45Neg, CD105Int and had full tri‐lineage potential. Transcriptional profiling of the two populations confirmed their status as bona fide MSCs and revealed a high degree of similarity between each other and the archetypal bone‐marrow MSC. 105 genes were differentially expressed; 76 of which were increased in BAL‐MSCs including genes involved in fibroblast activation, extracellular matrix deposition and tissue remodelling. Finally, we found the fibroblast markers collagen 1A1 and α‐smooth muscle actin were increased in BAL‐MSCs. Our data suggests that in healthy humans, lung MSCs reside within the tissue, but in disease can differentiate to acquire a profibrotic phenotype and migrate from their in‐tissue niche into the alveolar space. Stem Cells 2016;34:2548–2558 Human mesenchymal stromal cells were isolated from healthy parenchymal lung tissue (LT‐MSCs, n = 24, 4 samples from six patients) and lung allograft bronchoalveolar lavage fluid (BAL‐MSCs, n = 12, 1 sample from 12 patients) and gene expression was analysed by microarray. Using Significance Analysis of Microarrays, 105 differentially expressed genes were identified. When visualized as a hierarchical cluster, MSC populations segregate into two distinct groups when samples and probes are clustered using Pearson correlation. Genes that were upregulated in BAL‐MSCs include those associated with cellular migration, transforming growth factor‐β activation and fibroblastic differentiation. Our findings suggested that BAL‐MSCs are a dysregulated p
ISSN:1066-5099
1549-4918
DOI:10.1002/stem.2419