Immune modulation via adipose derived Mesenchymal Stem cells is driven by donor sex in vitro

Abstract Mesenchymal stromal/stem cells (MSCs) are currently being used in clinical trials as proposed treatments for a large range of genetic, immunological, orthopaedic, cardiovascular, endocrine and neurological disorders. MSCs are potent anti-inflammatory mediators which are considered immune ev...

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Autores principales:	Flyn Mckinnirey, Benjamin Herbert, Graham Vesey, Sharon McCracken
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e5a54ba5e62144d4baeb75b79d590f27
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spelling	oai:doaj.org-article:e5a54ba5e62144d4baeb75b79d590f272021-12-02T17:41:04ZImmune modulation via adipose derived Mesenchymal Stem cells is driven by donor sex in vitro10.1038/s41598-021-91870-42045-2322https://doaj.org/article/e5a54ba5e62144d4baeb75b79d590f272021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91870-4https://doaj.org/toc/2045-2322Abstract Mesenchymal stromal/stem cells (MSCs) are currently being used in clinical trials as proposed treatments for a large range of genetic, immunological, orthopaedic, cardiovascular, endocrine and neurological disorders. MSCs are potent anti-inflammatory mediators which are considered immune evasive and employ a large range of secreted vesicles to communicate and repair damaged tissue. Despite their prolific use in therapy, sex specific mechanism of action is rarely considered as a potential confounding factor for use. The purpose of this study was to examine the potency and functionality of both female and male adipose derived MSCs in order to gain further insights into donor selection. Methods MSC were expanded to passage 4, secretome was harvested and stored at − 80c. To assess potency MSC were also primed and assessed via functional immune assays, ELISA, multiplex and immunophenotyping. Results Female MSCs (fMSC), consistently suppressed Peripheral blood mononuclear cell (PBMC) proliferation significantly (p < 0.0001) more than male MSC (mMSC). In co-culture mPBMCs, showed 60.7 ± 15.6% suppression with fMSCs compared with 22.5 ± 13.6% suppression with mMSCs. Similarly, fPBMCs were suppressed by 67.9 ± 10.4% with fMSCs compared to 29.4 ± 9.3% with mMSCs. The enhanced immunosuppression of fMSCs was attributed to the production of higher concentrations of the anti-inflammatory mediators such as IDO1 (3301 pg/mL vs 1699 pg/mL) and perhaps others including IL-1RA (1025 pg/mL vs 701 pg/mL), PGE-2 (6142 pg/mL vs 2448 pg/mL) and prolonged expression of VCAM-1 post activation relative to mMSCs. In contrast, mMSCs produces more inflammatory G-CSF than fMSCs (806 pg/mL vs 503 pg/mL). Moreover, IDO1 expression was correlated to immune suppression and fMSCs, but not mMSCs induced downregulation of the IL-2 receptor and sustained expression of the early T cell activation marker, CD69 in PBMCs further highlighting the differences in immunomodulation potentials between the sexes. Conclusion In conclusion, our data shows that female MSC are more potent in vitro than their male counterparts. The inability of male MSC to match female MSC driven immunomodulation and to use the inflammatory microenvironment to their advantage is evident and is likely a red flag when using allogeneic male MSC as a therapeutic for disease states.Flyn MckinnireyBenjamin HerbertGraham VeseySharon McCrackenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Flyn Mckinnirey Benjamin Herbert Graham Vesey Sharon McCracken Immune modulation via adipose derived Mesenchymal Stem cells is driven by donor sex in vitro
description	Abstract Mesenchymal stromal/stem cells (MSCs) are currently being used in clinical trials as proposed treatments for a large range of genetic, immunological, orthopaedic, cardiovascular, endocrine and neurological disorders. MSCs are potent anti-inflammatory mediators which are considered immune evasive and employ a large range of secreted vesicles to communicate and repair damaged tissue. Despite their prolific use in therapy, sex specific mechanism of action is rarely considered as a potential confounding factor for use. The purpose of this study was to examine the potency and functionality of both female and male adipose derived MSCs in order to gain further insights into donor selection. Methods MSC were expanded to passage 4, secretome was harvested and stored at − 80c. To assess potency MSC were also primed and assessed via functional immune assays, ELISA, multiplex and immunophenotyping. Results Female MSCs (fMSC), consistently suppressed Peripheral blood mononuclear cell (PBMC) proliferation significantly (p < 0.0001) more than male MSC (mMSC). In co-culture mPBMCs, showed 60.7 ± 15.6% suppression with fMSCs compared with 22.5 ± 13.6% suppression with mMSCs. Similarly, fPBMCs were suppressed by 67.9 ± 10.4% with fMSCs compared to 29.4 ± 9.3% with mMSCs. The enhanced immunosuppression of fMSCs was attributed to the production of higher concentrations of the anti-inflammatory mediators such as IDO1 (3301 pg/mL vs 1699 pg/mL) and perhaps others including IL-1RA (1025 pg/mL vs 701 pg/mL), PGE-2 (6142 pg/mL vs 2448 pg/mL) and prolonged expression of VCAM-1 post activation relative to mMSCs. In contrast, mMSCs produces more inflammatory G-CSF than fMSCs (806 pg/mL vs 503 pg/mL). Moreover, IDO1 expression was correlated to immune suppression and fMSCs, but not mMSCs induced downregulation of the IL-2 receptor and sustained expression of the early T cell activation marker, CD69 in PBMCs further highlighting the differences in immunomodulation potentials between the sexes. Conclusion In conclusion, our data shows that female MSC are more potent in vitro than their male counterparts. The inability of male MSC to match female MSC driven immunomodulation and to use the inflammatory microenvironment to their advantage is evident and is likely a red flag when using allogeneic male MSC as a therapeutic for disease states.
format	article
author	Flyn Mckinnirey Benjamin Herbert Graham Vesey Sharon McCracken
author_facet	Flyn Mckinnirey Benjamin Herbert Graham Vesey Sharon McCracken
author_sort	Flyn Mckinnirey
title	Immune modulation via adipose derived Mesenchymal Stem cells is driven by donor sex in vitro
title_short	Immune modulation via adipose derived Mesenchymal Stem cells is driven by donor sex in vitro
title_full	Immune modulation via adipose derived Mesenchymal Stem cells is driven by donor sex in vitro
title_fullStr	Immune modulation via adipose derived Mesenchymal Stem cells is driven by donor sex in vitro
title_full_unstemmed	Immune modulation via adipose derived Mesenchymal Stem cells is driven by donor sex in vitro
title_sort	immune modulation via adipose derived mesenchymal stem cells is driven by donor sex in vitro
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/e5a54ba5e62144d4baeb75b79d590f27
work_keys_str_mv	AT flynmckinnirey immunemodulationviaadiposederivedmesenchymalstemcellsisdrivenbydonorsexinvitro AT benjaminherbert immunemodulationviaadiposederivedmesenchymalstemcellsisdrivenbydonorsexinvitro AT grahamvesey immunemodulationviaadiposederivedmesenchymalstemcellsisdrivenbydonorsexinvitro AT sharonmccracken immunemodulationviaadiposederivedmesenchymalstemcellsisdrivenbydonorsexinvitro
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Immune modulation via adipose derived Mesenchymal Stem cells is driven by donor sex in vitro

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