Adipose-derived stem cells inhibit dermal fibroblast growth and induce apoptosis in keloids through the arachidonic acid-derived cyclooxygenase-2/prostaglandin E2 cascade by paracrine

Jinxiu Yang; Shiyi Li; Leren He; Minliang Chen

doi:10.1093/burnst/tkab020

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Adipose-derived stem cells inhibit dermal fibroblast growth and induce apoptosis in keloids through the arachidonic acid-derived cyclooxygenase-2/prostaglandin E2 cascade by paracrine

更新时间：2022-06-14

- Adipose-derived stem cells inhibit dermal fibroblast growth and induce apoptosis in keloids through the arachidonic acid-derived cyclooxygenase-2/prostaglandin E2 cascade by paracrine
- Adipose-derived stem cells inhibit dermal fibroblast growth and induce apoptosis in keloids through the arachidonic acid-derived cyclooxygenase-2/prostaglandin E2 cascade by paracrine
- Burns & Trauma 2021年9卷第1期
- 作者机构：
  
  1. Department of Burn and Plastic Surgery
  2. Chinese People’s Liberation Army General Hospital
  3. 7th Department of Plastic Surgery
- 作者简介：
- 基金信息：
  
  The current study was supported by grant from the National Natural Science Foundation of China (No. 81772085).
- DOI：10.1093/burnst/tkab020
  中图分类号：
- 纸质出版日期：2021，
  
  网络出版日期：2021-9-11，
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Jinxiu Yang, Shiyi Li, Leren He, 等. Adipose-derived stem cells inhibit dermal fibroblast growth and induce apoptosis in keloids through the arachidonic acid-derived cyclooxygenase-2/prostaglandin E2 cascade by paracrine[J]. Burns & Trauma, 2021,9(1).

Jinxiu Yang, Shiyi Li, Leren He, Minliang Chen, Adipose-derived stem cells inhibit dermal fibroblast growth and induce apoptosis in keloids through the arachidonic acid-derived cyclooxygenase-2/prostaglandin E2 cascade by paracrine, Burns & Trauma, Volume 9, 2021, tkab020, https://doi.org/10.1093/burnst/tkab020
Jinxiu Yang, Shiyi Li, Leren He, 等. Adipose-derived stem cells inhibit dermal fibroblast growth and induce apoptosis in keloids through the arachidonic acid-derived cyclooxygenase-2/prostaglandin E2 cascade by paracrine[J]. Burns & Trauma, 2021,9(1). DOI： 10.1093/burnst/tkab020.

Jinxiu Yang, Shiyi Li, Leren He, Minliang Chen, Adipose-derived stem cells inhibit dermal fibroblast growth and induce apoptosis in keloids through the arachidonic acid-derived cyclooxygenase-2/prostaglandin E2 cascade by paracrine, Burns & Trauma, Volume 9, 2021, tkab020, https://doi.org/10.1093/burnst/tkab020 DOI：

摘要

Abstract

BackgroundThe clinical features of keloids consist of aberrant proliferation

secretion

differentiation and apoptosis of keloid dermis-derived fibroblasts (KFBs). Notably

the apoptosis rate of KFBs is lower than the proliferation rate. Though the anti-fibrotic effect of adipose-derived stem cells (ADSCs) on keloids has become a hot topic of research

the exact anti-fibrotic mechanism of the paracrine effect remains unclear. This study aimed to find out how the conditioned medium of ADSCs (ADSC-CM) exerts an anti-fibrotic effect in KFBs.MethodsKFBs and ADSCs were extracted and cultured. Then

ADSC-CM was prepared. Whether ADSC-CM could inhibit KFB growth and induce apoptosis was verified by the use of a cell counting kit-8

an 5-Ethynyl-2-deoxyuridine (Edu) kit and flow cytometry. The expressions of cyclooxygenase-1 (COX-1)

COX-2

caspase 3 and B-cell lymphoma-2 (Bcl-2) in ADSC-CM-cultured KFBs were tested by real-time PCR and western blotting. To clarify the role of COX-2 in ADSC-CM-induced KFB apoptosis

a specific COX-2 inhibitor

celecoxib

was applied to KFBs cultured in ADSC-CM. Moreover

we tested the production of arachidonic acid (AA) and prostaglandin E2 (PGE2) by ELISA. Then

we established a keloid transplantation model in a nude mouse to validate the therapeutic effect in vivo.ResultsThe proliferation ability of KFBs cultured in ADSC-CM was found to be weakened and apoptosis was significantly increased. Caspase 3 expression was significantly upregulated and Bcl-2 was downregulated in ADSC-CM-cultured KFBs. Furthermore

ADSC-CM strikingly elevated COX-2 mRNA and protein expressions

but COX-1 expression was unaltered. COX-2 inhibitors reduced ADSC-CM-induced apoptosis. Additionally

COX-2 inhibition blocked the elevation of caspase 3 and reversed the decrease in Bcl-2 expression. ADSC-CM increased PGE2 levels by 1.5-fold and this effect was restrained by COX-2 inhibition. In the nude mouse model

expressions of AA

COX-2 and PGE2 were higher in the translated keloid tissues after ADSC-CM injection than in the controls.ConclusionsWe showed activation of the COX-2/PGE2 cascade in KFBs in response to ADSC-CM. By employing a specific COX-2 inhibitor

COX-2/PGE2 cascade activation played a crucial role in mediating the ADSC-CM-induced KFB apoptosis and anti-proliferation effects.

关键词

Keywords

KeloidsAdipose-derived stem cellsFibroblastsApoptosisAnti-fibrosis cyclooxygenase-2Arachidonic acid

references

1.Jumper N, Paus R, Bayat A. Functional histopathology of keloid disease. Histol Histopathol. 2015;30:1033–57.

2.Tan S, Khumalo N, Bayat A. Understanding keloid pathobiology from a quasi-neoplastic perspective: less of a scar and more of a chronic inflammatory disease with cancer-like tendencies. Front Immunol. 2019;10:1810:1–15.

3.Xu X, Lai L, Zhang X, Chen J, Chen J, Wang F, et al. Autologous chyle fat grafting for the treatment of hypertrophic scars and scar-related conditions. Stem Cell Res Ther. 2018;9(1):64:1–8.

4.Chen J, Lai L, Ma K, Xu X, Huang Z, Zhou G, et al. The effect of chyle fat injection on human hypertrophic scars in an animal model: a new strategy for the treatment of hypertrophic scars. Ann Plast Surg. 2019;82:622–7.

5.Zhang W, Bai X, Zhao B, Li Y, Zhang Y, Li Z, et al. Cell-free therapy based on adipose tissue stem cell-derived exosomes promotes wound healing via the PI3K/Akt signaling pathway. Exp Cell Res. 2018;370:333–42.

6.Bajek A, Gurtowska N, Olkowska J, Kazmierski L, Maj M, Drewa T. Adipose-derived stem cells as a tool in cell-based therapies. Arch Immunol Ther Exp (Warsz). 2016;64:443–54.

7.Louw L. Keloids in rural black South Africans. Part 3: a lipid model for the prevention and treatment of keloid formations. Prostaglandins Leukot Essent Fatty Acids. 2000;63:255–62.

8.Calder PC. Omega-3 fatty acids and inflammatory processes: from molecules to man. Biochem Soc Trans. 2017;45:1105–15.

9.Hayashi T, Nishihira J, Koyama Y, Sasaki S, Yamamoto Y. Decreased prostaglandin E2 production by inflammatory cytokine and lower expression of EP2 receptor result in increased collagen synthesis in keloid fibroblasts. J Invest Dermatol. 2006;126:990–7.

10.Carantino I, Florescu IP, Carantino A. Overview about the keloid scars and the elaboration of a non-invasive, unconventional treatment. J Med Life. 2010;3:122–7.

11.Duan C, Chen K, Yang G, Li T, Liu L. HIF-1α regulates Cx40-dependent vasodilatation following hemorrhagic shock in rats. Am J Transl Res 2017;9:1277–86.

12.Doong H, Dissanayake S, Gowrishankar TR, LaBarbera MC, Lee RC. The 1996 Lindberg award. Calcium antagonists alter cell shape and induce procollagenase synthesis in keloid and normal human dermal fibroblasts. J Burn Care Rehabil. 1996;17:497–514.

13.Philandrianos C, Kerfant N, Jaloux C, Jr, Martinet L, Bertrand B, Casanova D. Keloid scars (part I): clinical presentation, epidemiology, histology and pathogenesis. Ann Chir Plast Esthet. 2016;61:128–35.

14.Chen ZY, Yu XF, Huang JQ, Li DL. The mechanisms of β-catenin on keloid fibroblast cells proliferation and apoptosis. Eur Rev Med Pharmacol. Sci 2018;22:888–95.

15.Wang X, Ma Y, Gao Z, Yang J. Human adipose-derived stem cells inhibit bioactivity of keloid fibroblasts. Stem Cell Res Ther. 2018;9:40:1–8.

16.Zhang MZ, Liu YF, Ding N, Zhao PX, Zhang X, Liu MY, et al. 2-Methoxyestradiol improves the apoptosis level in keloid fibroblasts through caspase-dependent mechanisms in vitro. Am J Transl Res. 2018;10:4017–29.

17.Zhu S, Pabla N, Tang C, He L, Dong Z. DNA damage response in cisplatin-induced nephrotoxicity. Arch Toxicol. 2015;89:2197–205.

18.Mukherjee A, Williams DW. More alive than dead: non-apoptotic roles for caspases in neuronal development, plasticity and disease. Cell Death Differ. 2017;24:1411–21.

19.Roset R, Ortet L, Gil-Gomez G. Role of Bcl-2 family members on apoptosis: what we have learned from knock-out mice. Front Biosci. 2007;12:4722–30.

20.Liu J, Ren J, Su L, Cheng S, Zhou J, Ye X, et al. Human adipose tissue-derived stem cells inhibit the activity of keloid fibroblasts and fibrosis in a keloid model by paracrine signaling. Burns. 2018;44:370–85.

21.Wilgus TA, Bergdall VK, Tober KL, Hill KJ, Mitra S, Flavahan NA, et al. The impact of cyclooxygenase-2 mediated inflammation on scarless fetal wound healing. Am J Pathol. 2004;165:753–61.

22.Abd El-Aleem SA, Abdelwahab S, Am-Sherief H, Sayed A. Cellular and physiological upregulation of inducible nitric oxide synthase, arginase, and inducible cyclooxygenase in wound healing. J Cell Physiol. 2019;234:23618–32.

23.Greenhough A, Smartt HJ, Moore AE, Roberts HR, Williams AC, Paraskeva C, et al. The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis. 2009;30:377–86.

24.Kim KN, Ko YJ, Yang HM, Ham YM, Roh SW, Jeon YJ, et al. Anti-inflammatory effect of essential oil and its constituents from fingered citron (Citrus medica L. var. sarcodactylis) through blocking JNK, ERK and NF-κB signaling pathways in LPS-activated RAW 264.7 cells. Food Chem Toxicol. 2013;57:126–31.

25.Wilgus TA, Vodovotz Y, Vittadini E, Clubbs EA, Oberyszyn TM. Reduction of scar formation in full-thickness wounds with topical celecoxib treatment. Wound Repair Regen. 2003;11:25–34.

26.McAnulty RJ, Hernández-Rodriguez NA, Mutsaers SE, Coker RK, Laurent GJ. Indomethacin suppresses the anti-proliferative effects of transforming growth factor-beta isoforms on fibroblast cell cultures. Biochem J. 1997;321:639–43.

27.Cheng Q, Li N, Chen M, Zheng J, Qian Z, Wang X, et al. Cyclooxygenase-2 promotes hepatocellular apoptosis by interacting with TNF-α and IL-6 in the pathogenesis of nonalcoholic steatohepatitis in rats. Dig Dis Sci. 2013;58:2895–902.

28.Su WH, Cheng MH, Lee WL, Tsou TH, Chang WH, Chen CS, et al. Nonsteroidal anti-inflammatory drugs for wounds: pain relief or excessive scar formation? Mediators Inflamm. 2010;2010:413238:1–8.

29.Yeh FL, Shen HD, Lin MW, Chang CY, Tai HY, Huang MH. Keloid-derived fibroblasts have a diminished capacity to produce prostaglandin E2. Burns. 2006;32:299–304.

30.Renò F, Grazianetti P, Cannas M. Effects of mechanical compression on hypertrophic scars: prostaglandin E2 release. Burns. 2001;27:215–8.

31.Wang T, Guo S, Liu X, Xv N, Zhang S. Protective effects of adipose-derived stem cells secretome on human dermal fibroblasts from ageing damages. Int J Clin Exp Pathol. 2015;8:15739–48.

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