Interferon-γ Enhances the Therapeutic Effect of Mesenchymal Stem Cells on Experimental Renal Fibrosis

Overview

Journal Sci Rep

Specialty Science

Date 2021 Jan 14

PMID 33441701

Citations 27

Authors

Ryo Kanai

Ayumu Nakashima

Shigehiro Doi

Tomoe Kimura

Ken Yoshida

Satoshi Maeda

Naoki Ishiuchi

Yumi Yamada

Takeshi Ike

Toshiki Doi

Yukio Kato

Takao Masaki

Affiliations

Soon will be listed here.

Abstract

Mesenchymal stem cells (MSCs) administered for therapeutic purposes can be activated by interferon-γ (IFN-γ) secreted from natural killer cells in injured tissues and exert anti-inflammatory effects. These processes require a substantial period of time, leading to a delayed onset of MSCs' therapeutic effects. In this study, we investigated whether pretreatment with IFN-γ could potentiate the anti-fibrotic ability of MSCs in rats with ischemia-reperfusion injury (IRI) and unilateral ureter obstruction. Administration of MSCs treated with IFN-γ strongly reduced infiltration of inflammatory cells and ameliorated interstitial fibrosis compared with control MSCs without IFN-γ treatment. In addition, conditioned medium obtained from IFN-γ-treated MSCs decreased fibrotic changes in cultured cells induced by transforming growth factor-β1 more efficiently than that from control MSCs. Most notably, secretion of prostaglandin E2 from MSCs was significantly increased by treatment with IFN-γ. Increased prostaglandin E2 in conditioned medium obtained from IFN-γ-treated MSCs induced polarization of immunosuppressive CD163 and CD206-positive macrophages. In addition, knockdown of prostaglandin E synthase weakened the anti-fibrotic effects of MSCs treated with IFN-γ in IRI rats, suggesting the involvement of prostaglandin E2 in the beneficial effects of IFN-γ. Administration of MSCs treated with IFN-γ might represent a promising therapy to prevent the progression of renal fibrosis.

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References

English K . Mechanisms of mesenchymal stromal cell immunomodulation. Immunol Cell Biol. 2012; 91(1):19-26. DOI: 10.1038/icb.2012.56. View

Lee S, Kalluri R . Mechanistic connection between inflammation and fibrosis. Kidney Int Suppl. 2010; (119):S22-6. PMC: 4067095. DOI: 10.1038/ki.2010.418. View

Luan B, Yoon Y, Le Lay J, Kaestner K, Hedrick S, Montminy M . CREB pathway links PGE2 signaling with macrophage polarization. Proc Natl Acad Sci U S A. 2015; 112(51):15642-7. PMC: 4697393. DOI: 10.1073/pnas.1519644112. View

Matsui F, Babitz S, Rhee A, Hile K, Zhang H, Meldrum K . Mesenchymal stem cells protect against obstruction-induced renal fibrosis by decreasing STAT3 activation and STAT3-dependent MMP-9 production. Am J Physiol Renal Physiol. 2016; 312(1):F25-F32. PMC: 5283885. DOI: 10.1152/ajprenal.00311.2016. View

Jin L, Deng Z, Zhang J, Yang C, Liu J, Han W . Mesenchymal stem cells promote type 2 macrophage polarization to ameliorate the myocardial injury caused by diabetic cardiomyopathy. J Transl Med. 2019; 17(1):251. PMC: 6683374. DOI: 10.1186/s12967-019-1999-8. View

He Q, You H, Li X, Liu T, Wang P, Wang B . HMGB1 promotes the synthesis of pro-IL-1β and pro-IL-18 by activation of p38 MAPK and NF-κB through receptors for advanced glycation end-products in macrophages. Asian Pac J Cancer Prev. 2012; 13(4):1365-70. DOI: 10.7314/apjcp.2012.13.4.1365. View

Lu B, Wang C, Wang M, Li W, Chen F, Tracey K . Molecular mechanism and therapeutic modulation of high mobility group box 1 release and action: an updated review. Expert Rev Clin Immunol. 2014; 10(6):713-27. PMC: 4056343. DOI: 10.1586/1744666X.2014.909730. View

Grange C, Tritta S, Tapparo M, Cedrino M, Tetta C, Camussi G . Stem cell-derived extracellular vesicles inhibit and revert fibrosis progression in a mouse model of diabetic nephropathy. Sci Rep. 2019; 9(1):4468. PMC: 6418239. DOI: 10.1038/s41598-019-41100-9. View

Wei Y, Zhang L, Chi Y, Ren X, Gao Y, Song B . High-efficient generation of VCAM-1 mesenchymal stem cells with multidimensional superiorities in signatures and efficacy on aplastic anaemia mice. Cell Prolif. 2020; 53(8):e12862. PMC: 7445411. DOI: 10.1111/cpr.12862. View

10.

Phanish M, Wahab N, Colville-Nash P, Hendry B, Dockrell M . The differential role of Smad2 and Smad3 in the regulation of pro-fibrotic TGFbeta1 responses in human proximal-tubule epithelial cells. Biochem J. 2005; 393(Pt 2):601-7. PMC: 1360711. DOI: 10.1042/BJ20051106. View

11.

Sakai K, Nozaki Y, Murao Y, Yano T, Ri J, Niki K . Protective effect and mechanism of IL-10 on renal ischemia-reperfusion injury. Lab Invest. 2019; 99(5):671-683. DOI: 10.1038/s41374-018-0162-0. View

12.

Asanuma H, VanderBrink B, Campbell M, Hile K, Zhang H, Meldrum D . Arterially delivered mesenchymal stem cells prevent obstruction-induced renal fibrosis. J Surg Res. 2010; 168(1):e51-9. PMC: 3008314. DOI: 10.1016/j.jss.2010.06.022. View

13.

Lin F, Zhang W, Xue D, Zhu T, Li J, Chen E . Signaling pathways involved in the effects of HMGB1 on mesenchymal stem cell migration and osteoblastic differentiation. Int J Mol Med. 2016; 37(3):789-97. DOI: 10.3892/ijmm.2016.2479. View

14.

Ueno T, Nakashima A, Doi S, Kawamoto T, Honda K, Yokoyama Y . Mesenchymal stem cells ameliorate experimental peritoneal fibrosis by suppressing inflammation and inhibiting TGF-β1 signaling. Kidney Int. 2013; 84(2):297-307. PMC: 3731556. DOI: 10.1038/ki.2013.81. View

15.

Thomas H, Jager M, Mauel K, Brandau S, Lask S, Flohe S . Interaction with mesenchymal stem cells provokes natural killer cells for enhanced IL-12/IL-18-induced interferon-gamma secretion. Mediators Inflamm. 2014; 2014:143463. PMC: 4021755. DOI: 10.1155/2014/143463. View

16.

Nakashima A, Kawamoto T, Honda K, Ueshima T, Noshiro M, Iwata T . DEC1 modulates the circadian phase of clock gene expression. Mol Cell Biol. 2008; 28(12):4080-92. PMC: 2423136. DOI: 10.1128/MCB.02168-07. View

17.

Yoshimura A, Wakabayashi Y, Mori T . Cellular and molecular basis for the regulation of inflammation by TGF-beta. J Biochem. 2010; 147(6):781-92. PMC: 2912031. DOI: 10.1093/jb/mvq043. View

18.

Gregorini M, Corradetti V, Rocca C, Pattonieri E, Valsania T, Milanesi S . Mesenchymal Stromal Cells Prevent Renal Fibrosis in a Rat Model of Unilateral Ureteral Obstruction by Suppressing the Renin-Angiotensin System via HuR. PLoS One. 2016; 11(2):e0148542. PMC: 4750962. DOI: 10.1371/journal.pone.0148542. View

19.

da Silva Meirelles L, Maria Fontes A, Covas D, Caplan A . Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev. 2009; 20(5-6):419-27. DOI: 10.1016/j.cytogfr.2009.10.002. View

20.

Anders H, Schaefer L . Beyond tissue injury-damage-associated molecular patterns, toll-like receptors, and inflammasomes also drive regeneration and fibrosis. J Am Soc Nephrol. 2014; 25(7):1387-400. PMC: 4073442. DOI: 10.1681/ASN.2014010117. View