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Genome-wide lung transcriptional profiling of mouse models for pneumonia given human adipose-derived mesenchymal stem cells treatment or Prekallikrein

ABSTRACT: Adult mesenchymal stem cells exert immunomodulatory effects that might improve the host response during sepsis. Knowledge on the effect of adipocyte-derived mesenchymal stem cells (ASCs) in sepsis is limited. Klebsiella (K.) pneumoniae is a common cause of gram-negative pneumonia and sepsis. The aim of this study was to determine the effect of human ASCs on the host response during pneumosepsis in mice. For this mice were infected with K. pneumoniae via the airways to induce a gradually evolving infection in the lung cumulating in pneumosepsis. One or 6 hours (h) after infection, mice were infused intravenously with ASCs or vehicle, and euthanized after 16h or 48h respectively. The effects of freshly cultured and cryopreserved ASCs were compared, the latter formulation being more clinically relevant. Intravenously administered ASCs were visualized in lung tissue by immunostaining at 1 and 3h, but not at 15h after infusion. While early after infection ASCs did not or only modestly influence bacterial loads, they reduced bacterial burdens in lungs and distant organs at 48h. ASCs reduced the lung levels of pro-inflammatory cytokines and attenuated lung pathology, but did not influence distant organ injury. ASCs strongly modified the lung transcriptome in both uninfected mice and mice with pneumosepsis, especially affecting. Cryopreserved and cultured ASCs induced largely similar effects. These data indicate that human ASCs induce profound immune modulatory effects in the lungs, resulting in reduced bacterial burdens and lung inflammation during pneumosepsis caused by a common human pathogen, suggesting that ASCs may be an adjunctive therapeutic in this condition. Experimental groups were defined as follows: (1) plac_cryo, placebo treated and K.pneumoniae infected control mice for cryopreserved MSCs; (2) plac_cult, placebo treated and K.pneumoniae infected control mice for cultured MSCs; (3) cryo, K.pneumoniae infected mice treated with cryopreserved MSCs; (4) cult, K.pneumoniae infected mice treated with cultured MSCs; (5) n_cult, non-infected control mice for cultured MSCs; (6) n_cryo, non-infected control mice for cryopreserved MSCs; (7) n, normal mouse lung baseline. In a separate experiment, mice were treated with a selective prekallikrein (PKK) directed antisense oligonucleotide (ASO) or a scrambled control ASO for 3 weeks prior to infection. Host response readouts were determined at 12 or 36 hours postinfection, including genome-wide messenger RNA profiling of lungs, or mice were followed for survival Pre-processing and quality control of the scans were performed by using the oligo method (version 1.44) and probes were annotated using the platform design info for Affymetrix Clariom_S_Mouse_HT available through Bioconductor. Array data were background corrected by Robust Multi-array Average (RMA) and quantiles-normalized. Microarray quality control was performed by means of the array quality metrics method (version 3.36.0). The occurrence of non-experimental chip effects was evaluated by the surrogate variable analysis method (version 3.28.0) and corrected using the combat method.

ORGANISM(S): Mus musculus

PROVIDER: GSE121970 | GEO | 2018/10/31

REPOSITORIES: GEO

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Genome-wide lung transcriptional profiling of mouse models for pneumonia given human adipose-derived mesenchymal stem cells treatment or Prekallikrein

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