Immunomodulatory Properties of Mouse Mesenchymal Stromal/Stem Cells Upon Ectopic Expression of Immunoregulator Nanos2.
Ectopic expression
Immunomodulatory
Innate immunity
Mesenchymal stromal/stem cells
Nanos2
Journal
Stem cell reviews and reports
ISSN: 2629-3277
Titre abrégé: Stem Cell Rev Rep
Pays: United States
ID NLM: 101752767
Informations de publication
Date de publication:
04 2023
04 2023
Historique:
accepted:
07
09
2022
medline:
5
4
2023
pubmed:
9
11
2022
entrez:
8
11
2022
Statut:
ppublish
Résumé
Mesenchymal stromal/stem cells (MSCs) are known for their involvement in modulating the immune system of mammals. This potency could be enhanced by different strategies, including regulation of key proteins, in order to meet desirable therapeutic properties. Nanos2, encoding an RNA-binding protein involved in regulation of key spermatogonial signaling pathways, has been demonstrated to downregulate a range of immune related genes in mouse embryonic fibroblasts (MEFs). Accordingly, it was hypothesized that Nanos2 functions as a potent immunosuppressing factor. This study was aimed to measure the expression profile of the immune-related genes in mouse mesenchymal stromal/stem cells (mMSCs) and assess their functional properties after Nanos2 ectopic expression. As inflammatory mediators, interferon (IFN-γ) and poly(I:C) were used to provoke an immune response. The interactions between the control and engineered mMSCs overexpressing Nanos2, with mouse peripheral blood mononuclear cells (mPBMCs) were then compared. The sensitivity of these cells to an inflammatory environment was assessed by using a conditioned medium containing high levels of inflammatory cytokines. Finally, the functional properties of the cells were investigated both in vivo and in vitro in presence of tumor and immune cells. Deep transcriptome analysis indicated that numerous genes were downregulated as a result of higher Nanos2 expression. Most of the genes subjected to gene expression alteration, were responsible for controlling responses to external stimuli, cell-cell adhesion, and wound healing. In comparison to the control cells, Nanos2-overexpressing cells showed lower expression of several immune-related genes after pretreatment with IFN-γ and poly(I:C). They also exhibited inhibitory effects against mPBMCs proliferation. Tumor growth rate, in B16-F0 administered mice was obviously increased upon their treatment with the Nanos2-mMSCs, while no tumor or very small ones were developed in the control group. In addition, the cytotoxic environment had no significant effects on Nanos2-mMSCs. According to the literature, MSCs are believed to be tuned very precisely by their internal and external conditions to act as either pro-inflammatory or anti-inflammatory agents. We show here that Nanos2 plays a significant role in promoting anti-inflammatory properties when expressed at higher levels by MSCs. This approach could be adopted for controlling the excessive inflammatory conditions in clinical programs, however more experiments are required to confirm it. In Brief Viral transduction was used to over express Nanos2 in mouse mesenchymal stromal/stem cells (mMSCs). Induced expression of Nanos2 downregulated the expression of immune-related genes and proteins. These modified mMSCs switched to an immunosuppressive state, even in the presence of pro-inflammatory cytokines; and could also contribute to tumor progression in a mouse model.
Sections du résumé
BACKGROUND
Mesenchymal stromal/stem cells (MSCs) are known for their involvement in modulating the immune system of mammals. This potency could be enhanced by different strategies, including regulation of key proteins, in order to meet desirable therapeutic properties. Nanos2, encoding an RNA-binding protein involved in regulation of key spermatogonial signaling pathways, has been demonstrated to downregulate a range of immune related genes in mouse embryonic fibroblasts (MEFs). Accordingly, it was hypothesized that Nanos2 functions as a potent immunosuppressing factor. This study was aimed to measure the expression profile of the immune-related genes in mouse mesenchymal stromal/stem cells (mMSCs) and assess their functional properties after Nanos2 ectopic expression.
METHODS
As inflammatory mediators, interferon (IFN-γ) and poly(I:C) were used to provoke an immune response. The interactions between the control and engineered mMSCs overexpressing Nanos2, with mouse peripheral blood mononuclear cells (mPBMCs) were then compared. The sensitivity of these cells to an inflammatory environment was assessed by using a conditioned medium containing high levels of inflammatory cytokines. Finally, the functional properties of the cells were investigated both in vivo and in vitro in presence of tumor and immune cells.
RESULTS
Deep transcriptome analysis indicated that numerous genes were downregulated as a result of higher Nanos2 expression. Most of the genes subjected to gene expression alteration, were responsible for controlling responses to external stimuli, cell-cell adhesion, and wound healing. In comparison to the control cells, Nanos2-overexpressing cells showed lower expression of several immune-related genes after pretreatment with IFN-γ and poly(I:C). They also exhibited inhibitory effects against mPBMCs proliferation. Tumor growth rate, in B16-F0 administered mice was obviously increased upon their treatment with the Nanos2-mMSCs, while no tumor or very small ones were developed in the control group. In addition, the cytotoxic environment had no significant effects on Nanos2-mMSCs.
CONCLUSIONS
According to the literature, MSCs are believed to be tuned very precisely by their internal and external conditions to act as either pro-inflammatory or anti-inflammatory agents. We show here that Nanos2 plays a significant role in promoting anti-inflammatory properties when expressed at higher levels by MSCs. This approach could be adopted for controlling the excessive inflammatory conditions in clinical programs, however more experiments are required to confirm it. In Brief Viral transduction was used to over express Nanos2 in mouse mesenchymal stromal/stem cells (mMSCs). Induced expression of Nanos2 downregulated the expression of immune-related genes and proteins. These modified mMSCs switched to an immunosuppressive state, even in the presence of pro-inflammatory cytokines; and could also contribute to tumor progression in a mouse model.
Identifiants
pubmed: 36348161
doi: 10.1007/s12015-022-10451-8
pii: 10.1007/s12015-022-10451-8
doi:
Substances chimiques
Cytokines
0
Anti-Inflammatory Agents
0
Nanos2 protein, mouse
0
RNA-Binding Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
734-753Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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