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11β hydroxysteroid dehydrogenase type 1 transgenic mesenchymal stem cells attenuate inflammation in models of sepsis.

ABSTRACT:

Background

Human bone marrow mesenchymal stem cell (MSC) administration reduces inflammation in pre-clinical models of sepsis and sepsis-related lung injury, however clinical efficacy in patients has not yet been demonstrated. We previously showed that Alveolar Macrophage (AM) 11β-hydroxysteroid dehydrogenase type-1 (HSD-1) autocrine signalling is impaired in critically ill sepsis patients, which promotes inflammatory injury. Administration of transgenic MSCs (tMSCs) which overexpress HSD-1 may enhance the anti-inflammatory effects of local glucocorticoids and be more effective at reducing inflammation in sepsis than cellular therapy alone.

Methods

MSCs were transfected using a recombinant lentiviral vector containing the HSD-1 and GPF transgenes under the control of a tetracycline promoter. Thin layer chromatography assessed HSD-1 reductase activity in tMSCs. Mesenchymal stem cell phenotype was assessed by flow cytometry and bi-lineage differentiation. HSD-1 tMSCs were co-cultured with LPS-stimulated monocyte-derived macrophages (MDMs) from healthy volunteers prior to assessment of pro-inflammatory cytokine release. HSD-1 tMSCs were administered intravenously to mice undergoing caecal ligation and puncture (CLP).

Results

MSCs were transfected with an efficiency of 91.1%, and maintained an MSC phenotype. Functional HSD-1 activity was demonstrated in tMSCs, with predominant reductase cortisol activation (peak 8.23 pM/hour/100,000 cells). HSD-1 tMSC co-culture with LPS-stimulated MDMs suppressed TNFα and IL-6 release. Administration of transgene activated HSD-1 tMSCs in a murine model of CLP attenuated neutrophilic inflammation more effectively than transgene inactive tMSCs (medians 0.403 v 1.36 × 10⁶/ml, p = 0.033).

Conclusion

The synergistic impact of HSD-1 transgene expression and MSC therapy attenuated neutrophilic inflammation in a mouse model of peritoneal sepsis more effectively than MSC therapy alone. Future studies investigating the anti-inflammatory capacity of HSD-1 tMSCs in models of sepsis-related direct lung injury and inflammatory diseases are required.

SUBMITTER: Mahida RY

PROVIDER: S-EPMC11257926 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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Publications

11β hydroxysteroid dehydrogenase type 1 transgenic mesenchymal stem cells attenuate inflammation in models of sepsis.

Mahida Rahul Y RY Yuan Zhengqiang Z Kolluri Krishna K KK Scott Aaron A Parekh Dhruv D Hardy Rowan S RS Matthay Michael A MA Perkins Gavin D GD Janes Sam M SM Thickett David R DR

Frontiers in bioengineering and biotechnology 20240705

<h4>Background</h4>Human bone marrow mesenchymal stem cell (MSC) administration reduces inflammation in pre-clinical models of sepsis and sepsis-related lung injury, however clinical efficacy in patients has not yet been demonstrated. We previously showed that Alveolar Macrophage (AM) 11β-hydroxysteroid dehydrogenase type-1 (HSD-1) autocrine signalling is impaired in critically ill sepsis patients, which promotes inflammatory injury. Administration of transgenic MSCs (tMSCs) which overexpress HS ...[more]

PMID: 39036559

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Dataset Information

11β hydroxysteroid dehydrogenase type 1 transgenic mesenchymal stem cells attenuate inflammation in models of sepsis.

Background

Methods

Results

Conclusion

Publications

11β hydroxysteroid dehydrogenase type 1 transgenic mesenchymal stem cells attenuate inflammation in models of sepsis.

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