Butyrate modulates adipose-derived stem cells isolated from polygenic obese and diabetic mice to drive enhanced immunosuppression

Wan Tseng Hsu; Wei Jan Huang; Bor Luen Chiang; Ping Huei Tseng

doi:10.1016/j.jcyt.2021.01.007

Butyrate modulates adipose-derived stem cells isolated from polygenic obese and diabetic mice to drive enhanced immunosuppression

Wan Tseng Hsu
, Wei Jan Huang
, Bor Luen Chiang
, Ping Huei Tseng

Research output: Contribution to journal › Article › peer-review

5 Citations (Scopus)

Abstract

Background aims: Adipose-derived stem cells (ASCs) offer promising therapeutic possibilities for immunomodulation. Butyrate (BA) exerts potent anti-inflammatory effects and exhibits multiple regulatory functionalities in adipose tissue (AT). The authors aimed to explore whether BA modulates ASCs to augment their immunosuppressive capabilities. Methods: The authors examined the potency of BA and ASCs for controlling anti-CD3 plus CD28-stimulated splenocyte proliferation in vitro, both in combination and with pre-treatment. Further, the authors investigated genes specifically upregulated by BA-treated ASCs, which were harvested from ASC-splenocyte co-culture after the removal of floating splenocytes. In addition, the authors investigated the influence of oral BA supplementation on the ex vivo immunosuppressive potency of ASCs from BALB/c and Tsumura, Suzuki, obese, diabetes (TSOD) mice. Results: BA enhanced the immunosuppressive potency of ASCs when directly added to ASC-splenocyte co-cultures or via pre-conditioning treatment. The percentages of ASC-induced Foxp3⁺ regulatory T cells increased, whereas the numbers of ASC-suppressed T helper 17 cells further decreased after BA exposure. The messenger RNA expression levels of inducible nitric oxide (NO) synthase (iNOS), chemokines, IL-10 and amphiregulin in ASCs co-cultured with activated splenocytes were upregulated after incubation with BA. This was accompanied by an amplification of iNOS-inducing cytokines, interferon gamma and tumor necrosis factor alpha in the ASC-splenocyte co-culture, triggering ASCs to produce high NO levels under the influence of BA. Mechanistically, the authors detected BA-mediated acetylated histone H3 in ASCs. BA treatment consistently improved the immunosuppressive potency of ASCs derived from both BALB/c and TSOD mice. Conclusions: The use of BA to counteract metaflammation by restoring the defective immunomodulation of ASCs from dysregulated AT in obese donors is recommended.

Original language	English
Pages (from-to)	567-581
Number of pages	15
Journal	Cytotherapy
Volume	23
Issue number	7
DOIs	https://doi.org/10.1016/j.jcyt.2021.01.007
Publication status	Published - Jul 2021

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

adipose-derived stem cells
amphiregulin
butyrate
immunomodulation
inducible nitric oxide synthase
metaflammation

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Oncology
Genetics(clinical)
Cell Biology
Transplantation
Cancer Research

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10.1016/j.jcyt.2021.01.007

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@article{386478ccd7b14762baf0dfa7f9a46e83,

title = "Butyrate modulates adipose-derived stem cells isolated from polygenic obese and diabetic mice to drive enhanced immunosuppression",

abstract = "Background aims: Adipose-derived stem cells (ASCs) offer promising therapeutic possibilities for immunomodulation. Butyrate (BA) exerts potent anti-inflammatory effects and exhibits multiple regulatory functionalities in adipose tissue (AT). The authors aimed to explore whether BA modulates ASCs to augment their immunosuppressive capabilities. Methods: The authors examined the potency of BA and ASCs for controlling anti-CD3 plus CD28-stimulated splenocyte proliferation in vitro, both in combination and with pre-treatment. Further, the authors investigated genes specifically upregulated by BA-treated ASCs, which were harvested from ASC-splenocyte co-culture after the removal of floating splenocytes. In addition, the authors investigated the influence of oral BA supplementation on the ex vivo immunosuppressive potency of ASCs from BALB/c and Tsumura, Suzuki, obese, diabetes (TSOD) mice. Results: BA enhanced the immunosuppressive potency of ASCs when directly added to ASC-splenocyte co-cultures or via pre-conditioning treatment. The percentages of ASC-induced Foxp3+ regulatory T cells increased, whereas the numbers of ASC-suppressed T helper 17 cells further decreased after BA exposure. The messenger RNA expression levels of inducible nitric oxide (NO) synthase (iNOS), chemokines, IL-10 and amphiregulin in ASCs co-cultured with activated splenocytes were upregulated after incubation with BA. This was accompanied by an amplification of iNOS-inducing cytokines, interferon gamma and tumor necrosis factor alpha in the ASC-splenocyte co-culture, triggering ASCs to produce high NO levels under the influence of BA. Mechanistically, the authors detected BA-mediated acetylated histone H3 in ASCs. BA treatment consistently improved the immunosuppressive potency of ASCs derived from both BALB/c and TSOD mice. Conclusions: The use of BA to counteract metaflammation by restoring the defective immunomodulation of ASCs from dysregulated AT in obese donors is recommended.",

keywords = "adipose-derived stem cells, amphiregulin, butyrate, immunomodulation, inducible nitric oxide synthase, metaflammation",

author = "Hsu, \{Wan Tseng\} and Huang, \{Wei Jan\} and Chiang, \{Bor Luen\} and Tseng, \{Ping Huei\}",

note = "Funding Information: This study was supported by research grants from the Ministry of Science and Technology (MOST-106-2320-B-002-060, MOST-107-2320-B-002-025, MOST-108-2320-B-002-077), National Health Research Institute (CS-109-PP-14) and National Taiwan University Hospital (UN108-019). Publisher Copyright: {\textcopyright} 2021 International Society for Cell \& Gene Therapy",

year = "2021",

month = jul,

doi = "10.1016/j.jcyt.2021.01.007",

language = "English",

volume = "23",

pages = "567--581",

journal = "Cytotherapy",

issn = "1465-3249",

publisher = "Elsevier B.V.",

number = "7",

}

TY - JOUR

T1 - Butyrate modulates adipose-derived stem cells isolated from polygenic obese and diabetic mice to drive enhanced immunosuppression

AU - Hsu, Wan Tseng

AU - Huang, Wei Jan

AU - Chiang, Bor Luen

AU - Tseng, Ping Huei

N1 - Funding Information: This study was supported by research grants from the Ministry of Science and Technology (MOST-106-2320-B-002-060, MOST-107-2320-B-002-025, MOST-108-2320-B-002-077), National Health Research Institute (CS-109-PP-14) and National Taiwan University Hospital (UN108-019). Publisher Copyright: © 2021 International Society for Cell & Gene Therapy

PY - 2021/7

Y1 - 2021/7

N2 - Background aims: Adipose-derived stem cells (ASCs) offer promising therapeutic possibilities for immunomodulation. Butyrate (BA) exerts potent anti-inflammatory effects and exhibits multiple regulatory functionalities in adipose tissue (AT). The authors aimed to explore whether BA modulates ASCs to augment their immunosuppressive capabilities. Methods: The authors examined the potency of BA and ASCs for controlling anti-CD3 plus CD28-stimulated splenocyte proliferation in vitro, both in combination and with pre-treatment. Further, the authors investigated genes specifically upregulated by BA-treated ASCs, which were harvested from ASC-splenocyte co-culture after the removal of floating splenocytes. In addition, the authors investigated the influence of oral BA supplementation on the ex vivo immunosuppressive potency of ASCs from BALB/c and Tsumura, Suzuki, obese, diabetes (TSOD) mice. Results: BA enhanced the immunosuppressive potency of ASCs when directly added to ASC-splenocyte co-cultures or via pre-conditioning treatment. The percentages of ASC-induced Foxp3+ regulatory T cells increased, whereas the numbers of ASC-suppressed T helper 17 cells further decreased after BA exposure. The messenger RNA expression levels of inducible nitric oxide (NO) synthase (iNOS), chemokines, IL-10 and amphiregulin in ASCs co-cultured with activated splenocytes were upregulated after incubation with BA. This was accompanied by an amplification of iNOS-inducing cytokines, interferon gamma and tumor necrosis factor alpha in the ASC-splenocyte co-culture, triggering ASCs to produce high NO levels under the influence of BA. Mechanistically, the authors detected BA-mediated acetylated histone H3 in ASCs. BA treatment consistently improved the immunosuppressive potency of ASCs derived from both BALB/c and TSOD mice. Conclusions: The use of BA to counteract metaflammation by restoring the defective immunomodulation of ASCs from dysregulated AT in obese donors is recommended.

AB - Background aims: Adipose-derived stem cells (ASCs) offer promising therapeutic possibilities for immunomodulation. Butyrate (BA) exerts potent anti-inflammatory effects and exhibits multiple regulatory functionalities in adipose tissue (AT). The authors aimed to explore whether BA modulates ASCs to augment their immunosuppressive capabilities. Methods: The authors examined the potency of BA and ASCs for controlling anti-CD3 plus CD28-stimulated splenocyte proliferation in vitro, both in combination and with pre-treatment. Further, the authors investigated genes specifically upregulated by BA-treated ASCs, which were harvested from ASC-splenocyte co-culture after the removal of floating splenocytes. In addition, the authors investigated the influence of oral BA supplementation on the ex vivo immunosuppressive potency of ASCs from BALB/c and Tsumura, Suzuki, obese, diabetes (TSOD) mice. Results: BA enhanced the immunosuppressive potency of ASCs when directly added to ASC-splenocyte co-cultures or via pre-conditioning treatment. The percentages of ASC-induced Foxp3+ regulatory T cells increased, whereas the numbers of ASC-suppressed T helper 17 cells further decreased after BA exposure. The messenger RNA expression levels of inducible nitric oxide (NO) synthase (iNOS), chemokines, IL-10 and amphiregulin in ASCs co-cultured with activated splenocytes were upregulated after incubation with BA. This was accompanied by an amplification of iNOS-inducing cytokines, interferon gamma and tumor necrosis factor alpha in the ASC-splenocyte co-culture, triggering ASCs to produce high NO levels under the influence of BA. Mechanistically, the authors detected BA-mediated acetylated histone H3 in ASCs. BA treatment consistently improved the immunosuppressive potency of ASCs derived from both BALB/c and TSOD mice. Conclusions: The use of BA to counteract metaflammation by restoring the defective immunomodulation of ASCs from dysregulated AT in obese donors is recommended.

KW - adipose-derived stem cells

KW - amphiregulin

KW - butyrate

KW - immunomodulation

KW - inducible nitric oxide synthase

KW - metaflammation

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U2 - 10.1016/j.jcyt.2021.01.007

DO - 10.1016/j.jcyt.2021.01.007

M3 - Article

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SN - 1465-3249

VL - 23

SP - 567

EP - 581

JO - Cytotherapy

JF - Cytotherapy

IS - 7

ER -

Butyrate modulates adipose-derived stem cells isolated from polygenic obese and diabetic mice to drive enhanced immunosuppression

Abstract

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