QIANG LI*, SEI-MYOUNG HAN*, WOO-JIN SONG, SANG-CHUL PARK, MIN-OK RYU and HWA-YOUNG YOUN

Department of Veterinary Internal Medicine, College of Veterinary Medicine,
Seoul National University, Seoul, Republic of Korea

 

Abstract. Background/Aim: The transcription factors Oct4 and Sox2 enhance the proliferation and pluripotency of human adipose tissue-derived mesenchymal stem cells (hATMSCs);
however, the anti-inflammatory effects of Oct4- and
Sox2-overexpressing hAT-MSCs (Oct4/Sox2-hAT-MSCs) are
unclear. Here, we evaluated the anti-inflammatory effects of
Oct4/Sox2-hAT-MSCs in vitro and in vivo. Materials and
Methods: Supernatants from green-fluorescent protein
(GFP)- and Oct4/Sox2-hAT-MSCs were used to treat
lipopolysaccharide (LPS)-stimulated RAW264.7 cells and
inflammatory cytokine expression was determined. In LPSinduced
mice, GFP- and Oct4/Sox2-hAT-MSCs were injected
intraperitoneally and survival rates, as well as sickness
scores of mice, were monitored. Results: Decreased
expression of pro-inflammatory cytokines was observed in
Oct4/Sox2-hAT-MSC supernatant-exposed RAW264.7 cells
compared to that in GFP-hAT-MSC supernatant-exposed
RAW264.7 cells. The sickness score was reduced to 34.9%
and the survival rate was increased by 11.1% in Oct4/Sox2-
hAT-MSC-injected mice compared to that in GFP-hAT-MSCinjected
mice. Conclusion: Our findings provide important
insights into the development of therapies utilizing
Oct4/Sox2-hAT-MSCs in inflammatory diseases.
Inflammation is part of the complex biological response of
vascular tissues to harmful stimuli (1). Macrophages, which
are at the frontline of the innate immune response, are
distributed throughout the circulation system, subsequently
migrating to most tissues of the body and activating
synthesis and release of pro-inflammatory mediators, such
as interleukin (IL)-1β, IL-6 and tumor necrosis factor-α
(TNF-α) (2). In macrophages activated by endotoxin, the
rapid activation of nuclear factor (NF)-ĸB signaling via
Toll-like receptor (TLR) 4 results in the transcription of
immunity effectors (3). Although the inflammatory response
is a universal and essential biological response, excessive
production of pro-inflammatory cytokines may result in
severe inflammation and, even, tissue necrosis.
Although the pathogenesis of systemic inflammation is
not fully understood, numerous cytokines and factors
involved in inflammation have been studied as therapeutic
targets (4-7). However, formerly accepted treatments, such
as anti-TNF-α antibodies (8), IL-1 receptor antagonists (9)
and platelet-activating factor antagonists (10), have failed
to demonstrate therapeutic effects or improve survival rates
in systemic inflammation models. Recent studies on the
effectiveness of cell-based therapy using mesenchymal
stem cells (MSCs) have shown that bone marrow-derived
MSCs may be effective for decreasing both systemic and
local inflammatory responses (11-13).
The pluripotent transcription factors Oct4 and Sox2,
which are involved in self-renewal and pluripotency, are
expressed by MSCs at early passages. In previous studies,
Oct4/Sox2 overexpression has been shown to enhance
proliferation and differentiation ability in human adipose
tissue-derived mesenchymal stem cells (hAT-MSCs) (14, 15).
Based on these findings, we hypothesized that Oct4/Sox2
expression may enhance the anti-inflammatory effects of
hAT-MSCs.
Accordingly, in this study, the anti-inflammatory effects
of lentivirus-transduced Oct4/Sox2-hAT-MSCs were
investigated by determining the expression of
inflammation-related cytokines in macrophage cell lines
treated with conditioned medium in vitro. In addition,
sickness scores (diarrhea, eye condition, activity and fur
condition) and survival rates were used to evaluate the antiinflammatory
effects of the engineered hAT-MSCs in a
mouse model.

발행연도 : 2017. March

저자 : QIANG LI, SEI-MYOUNG HAN, WOO-JIN SONG, SANG-CHUL PARK, MIN-OK RYU and HWA-YOUNG YOUN

출처 : iv.iiarjournals.org

소스 : 지방 MSC