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Single-cell RNA sequencing analysis of murine lung epithelial cells and fibroblasts derived from bleomycin-injured alveolospheres

ABSTRACT: Pulmonary fibrosis is a devatating lung disease with limited effective treatment. Because fibrotic responses are considered to be regulated by complex cellular and molecular circuits, it is difficult to demonstrate a causal relationship of cells, molecules, and cell-cell interactions with diseases in vivo. To overcome this issue, we established bleomycin (BLM)-stimulated alveolosphere model as an ex vivo culture model. To clarify whether our ex vivo model recapitulates the cellular and molecular response to BLM-induced lung injury, we performed single-cell RNA-seq (scRNA-seq) analysis of the BLM-stimulated alveolospheres generated by co-culturing murine lung epithelial cells and lung fibroblasts.

ORGANISM(S): Mus musculus

PROVIDER: GSE200298 | GEO | 2024/04/01

REPOSITORIES: GEO

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Project description:Background Bleomycin (BLM)-induced lung injury is characterized by the mixed histopathologic changes with inflammation and fibrosis. These changes are also observed in human patients with bronchopulmonary dysplasia, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease. Although no curative therapies for these lung vsdiseases exist, stem cell therapy has emerged as a potential therapeutic option. Multilineage-differentiating stress-enduring (Muse) cells are endogenous pluripotent-like/macrophage-like stem cells distributed in various adult and fetal tissues as stage-specific embryonic antigen-3-positive cells. They selectively home to damaged tissue by sensing sphingosine-1-phosphate and replace the damaged/apoptotic cells by in vivo differentiation. Clinical trials for some human diseases suggest the safety and therapeutic efficacy of intravenously injected human leukocyte antigen-mismatched allogenic-Muse cells from adult bone marrow (BM) without immunosuppressant. Here, we evaluated the therapeutic effects of human Muse cells from preterm- and term-umbilical cord (UC), and adult BM in a rat BLM-induced lung injury model. Methods Rats were endotracheally administered BLM to induce lung injury on day 0. On day 3, human preterm UC-Muse, term UC-Muse, or adult BM-Muse cells were administered intravenously without immunosuppressants, and rats were subjected to histopathologic analysis on day 21. Body weight, serum surfactant protein D (SP-D) levels, and oxygen saturation (SpO2) were monitored. Histopathologic lung injury scoring by the Ashcroft and modified American Thoracic Society document scales, quantitative characterization of engrafted Muse cells, RNA sequencing analysis, and in vitro migration assay of infused Muse cells were performed. Results Rats administered preterm- and term-UC-Muse cells exhibited a significantly better recovery based on weight loss, serum SP-D levels, SpO2, and histopathologic lung injury scores, and a significantly higher rate of Muse cell homing to the lung and alveolar marker expression (podoplanin and prosurfactant protein-C) than those administered BM-Muse cells. Rats receiving preterm-UC-Muse cells showed statistically superior results to those receiving term-UC-Muse cells in many of the measures. These findings are thought to be due to higher expression of genes related to cell migration, lung differentiation, and cell adhesion. Conclusion Preterm UC-Muse cells deliver more efficient therapeutic effects than term UC- and BM-Muse cells for treating the BLM-induced lung injury in a rat model.

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Single-cell RNA sequencing analysis of murine lung epithelial cells and fibroblasts derived from bleomycin-injured alveolospheres

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