Chanéle Cyr-Depauw, David P. Cook, Ivana Mizik, Flore Legase, Arul Vadivel, Laurent Renesme, Yupu Deng, Shumei Zhong, Pauline Bardin, Liqun Xu, Marius A. Möbius, Jenny Marzahn, Daniel Freund, Duncan J. Stewart, Barbara C. Vanderhyden, Mario Rüdiger, Bernard Thébaud
Ottawa Hospital Research Institute. University of Ottawa. Universitätsklinikum Carl Gustav Carus. Technische Universität Dresden. Children’s Hospital of Eastern Ontario.
Canada and Germany
American Journal of Respiratory and Critical Care Medicine
Am J Respir Crit Care Med 2024;
DOI: 10.1164/rccm.202310-1975OC
Abstract
Rationale: The chronic lung disease bronchopulmonary dysplasia (BPD) is the most severe complication of extreme prematurity. BPD results in impaired lung alveolar and vascular development and long-term respiratory morbidity, for which only supportive therapies exist. Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) improve lung structure and function in experimental BPD. Results of clinical trials with MSCs for many disorders do not yet match the promising preclinical studies. A lack of specific criteria to define functionally distinct MSCs persists.
Objectives: To determine and correlate single-cell UC-MSC transcriptomic profile with therapeutic potential.
Methods: UC-MSCs from five term donors and human neonatal dermal fibroblasts (HNDFs, control cells of mesenchymal origin) transcriptomes were investigated by single-cell RNA sequencing analysis (scRNA-seq). The lung-protective effect of UC-MSCs with a distinct transcriptome and control HNDFs was tested in vivo in hyperoxia-induced neonatal lung injury in rats.
Measurements and main results: UC-MSCs showed limited transcriptomic heterogeneity, but were different from HNDFs. Gene ontology enrichment analysis revealed distinct – progenitor-like and fibroblast-like – UC-MSC subpopulations. Only the treatment with progenitor-like UC-MSCs improved lung function and structure and attenuated pulmonary hypertension in hyperoxia-exposed rat pups. Moreover, scRNA-seq identified major histocompatibility complex class I as a molecular marker of non-therapeutic cells and associated with decreased lung retention.
Conclusions: UC-MSCs with a progenitor-like transcriptome, but not with a fibroblast-like transcriptome, provide lung protection in experimental BPD. High expression of major histocompatibility complex class I is associated with reduced therapeutic benefit. scRNA-seq may be useful to identify subsets of MSCs with superior repair capacity for clinical application.
Category
Class III. Pulmonary Hypertension Associated with Lung Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
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