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Abstract
SummaryMesenchymal stromal cells (MSCs) have broad-ranging therapeutic properties, including the ability to inhibit bacterial growth and resolve infection. However, the genetic mechanisms regulating these antibacterial properties in MSCs are largely unknown. Here, we utilized a systems-based approach to compare MSCs from different genetic backgrounds that displayed differences in antibacterial activity. Although both MSCs satisfied traditional MSC-defining criteria, comparative transcriptomics and quantitative membrane proteomics revealed two unique molecular profiles. The antibacterial MSCs responded rapidly to bacterial lipopolysaccharide (LPS) and had elevated levels of the LPS co-receptor CD14. CRISPR-mediated overexpression of endogenous CD14 in MSCs resulted in faster LPS response and enhanced antibacterial activity. Single-cell RNA sequencing of CD14-upregulated MSCs revealed a shift in transcriptional ground state and a more uniform LPS-induced response. Our results highlight the impact of genetic background on MSC phenotypic diversity and demonstrate that overexpression of CD14 can prime these cells to be more responsive to bacterial challenge.
Highlights
The emergence of drug-resistant microorganisms is a significant threat to human health that requires the development of new and alternative therapies
CRISPR-mediated overexpression of endogenous CD14 in Mesenchymal stromal cells (MSCs) resulted in faster LPS response and enhanced antibacterial activity
Single-cell RNA sequencing of CD14-upregulated MSCs revealed a shift in transcriptional ground state and a more uniform LPS-induced response
Summary
The emergence of drug-resistant microorganisms is a significant threat to human health that requires the development of new and alternative therapies. MSCs have the potential for broad-acting cell-based antimicrobial therapy; the mechanistic basis for antimicrobial activity, and the molecular tools and strategies required to generate and maintain MSC populations of uniform phenotype, a requirement for their safe and reliable use in clinical applications, are not fully understood One such strategy to direct, or enhance, MSC therapeutic properties is through ‘‘priming’’ these cells by exposing them to specific stimuli or growth conditions (Yin et al, 2019; Noronha et al, 2019; Pittenger et al, 2019; Redondo-Castro et al, 2018; Showalter et al, 2019; Qiu et al, 2017b; Park et al, 2016, 2020; Najar et al, 2017; Luo et al, 2019; Liu et al, 2017b; Bartosh et al, 2010; Ho et al, 2016).
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