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
C2 - 33875384
AN - SCOPUS:85104367771
SN - 1465-3249
VL - 23
SP - 567
EP - 581
JO - Cytotherapy
JF - Cytotherapy
IS - 7
ER -
