Mesenchymal Stem Cells Pretreated with Interferon-gamma Attenuate Renal Fibrosis by Enhancing Regulatory T Cell Induction

Overview

Journal Sci Rep

Specialty Science

Date 2024 May 4

PMID 38704512

Authors

So Kurawaki

Ayumu Nakashima

Naoki Ishiuchi

Ryo Kanai

Satoshi Maeda

Kensuke Sasaki

Takao Masaki

Affiliations

Soon will be listed here.

Abstract

Mesenchymal stem cells (MSCs) exert their anti-inflammatory and anti-fibrotic effects by secreting various humoral factors. Interferon-gamma (IFN-γ) can enhance these effects of MSCs, and enhancement of regulatory T (Treg) cell induction is thought to be an underlying mechanism. However, the extent to which Treg cell induction by MSCs pretreated with IFN-γ (IFN-γ MSCs) ameliorates renal fibrosis remains unknown. In this study, we investigated the effects of Treg cell induction by IFN-γ MSCs on renal inflammation and fibrosis using an siRNA knockdown system. Administration of IFN-γ MSCs induced Treg cells and inhibited infiltration of inflammatory cells in ischemia reperfusion injury (IRI) rats more drastically than control MSCs without IFN-γ pretreatment. In addition, administration of IFN-γ MSCs more significantly attenuated renal fibrosis compared with control MSCs. Indoleamine 2,3-dioxygenase (IDO) expression levels in conditioned medium from MSCs were enhanced by IFN-γ pretreatment. Moreover, IDO1 knockdown in IFN-γ MSCs reduced their anti-inflammatory and anti-fibrotic effects in IRI rats by reducing Treg cell induction. Our findings suggest that the increase of Treg cells induced by enhanced secretion of IDO by IFN-γ MSCs played a pivotal role in their anti-fibrotic effects. Administration of IFN-γ MSCs may potentially be a useful therapy to prevent renal fibrosis progression.

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References

Huang B, Cheng X, Wang H, Huang W, la Ga Hu Z, Wang D . Mesenchymal stem cells and their secreted molecules predominantly ameliorate fulminant hepatic failure and chronic liver fibrosis in mice respectively. J Transl Med. 2016; 14:45. PMC: 4746907. DOI: 10.1186/s12967-016-0792-1. View

Doreille A, Azzi F, Lariviere-Beaudoin S, Karakeussian-Rimbaud A, Trudel D, Hebert M . Acute Kidney Injury, Microvascular Rarefaction, and Estimated Glomerular Filtration Rate in Kidney Transplant Recipients. Clin J Am Soc Nephrol. 2021; 16(3):415-426. PMC: 8011007. DOI: 10.2215/CJN.07270520. View

Casiraghi F, Azzollini N, Cassis P, Imberti B, Morigi M, Cugini D . Pretransplant infusion of mesenchymal stem cells prolongs the survival of a semiallogeneic heart transplant through the generation of regulatory T cells. J Immunol. 2008; 181(6):3933-46. DOI: 10.4049/jimmunol.181.6.3933. View

Shi Y, Hu G, Su J, Li W, Chen Q, Shou P . Mesenchymal stem cells: a new strategy for immunosuppression and tissue repair. Cell Res. 2010; 20(5):510-8. DOI: 10.1038/cr.2010.44. View

Krampera M, Cosmi L, Angeli R, Pasini A, Liotta F, Andreini A . Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells. 2005; 24(2):386-98. DOI: 10.1634/stemcells.2005-0008. View

Casiraghi F, Azzollini N, Todeschini M, Cavinato R, Cassis P, Solini S . Localization of mesenchymal stromal cells dictates their immune or proinflammatory effects in kidney transplantation. Am J Transplant. 2012; 12(9):2373-83. DOI: 10.1111/j.1600-6143.2012.04115.x. View

Li P, Burdmann E, Mehta R . Acute kidney injury: global health alert. Kidney Int. 2013; 83(3):372-6. DOI: 10.1038/ki.2012.427. View

Morigi M, Introna M, Imberti B, Corna D, Abbate M, Rota C . Human bone marrow mesenchymal stem cells accelerate recovery of acute renal injury and prolong survival in mice. Stem Cells. 2008; 26(8):2075-82. DOI: 10.1634/stemcells.2007-0795. View

Kern S, Eichler H, Stoeve J, Kluter H, Bieback K . Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells. 2006; 24(5):1294-301. DOI: 10.1634/stemcells.2005-0342. View

10.

Munn D, Mellor A . IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance. Trends Immunol. 2016; 37(3):193-207. PMC: 4916957. DOI: 10.1016/j.it.2016.01.002. View

11.

Rubtsov Y, Rasmussen J, Chi E, Fontenot J, Castelli L, Ye X . Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity. 2008; 28(4):546-58. DOI: 10.1016/j.immuni.2008.02.017. View

12.

Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts A . Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell. 2008; 2(2):141-50. DOI: 10.1016/j.stem.2007.11.014. View

13.

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

14.

Vignali D, Collison L, Workman C . How regulatory T cells work. Nat Rev Immunol. 2008; 8(7):523-32. PMC: 2665249. DOI: 10.1038/nri2343. View

15.

Curti A, Pandolfi S, Valzasina B, Aluigi M, Isidori A, Ferri E . Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25- into CD25+ T regulatory cells. Blood. 2006; 109(7):2871-7. DOI: 10.1182/blood-2006-07-036863. View

16.

Munn D, Mellor A . Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest. 2007; 117(5):1147-54. PMC: 1857253. DOI: 10.1172/JCI31178. View

17.

An J, Song W, Li Q, Kim S, Yang J, Ryu M . Prostaglandin E secreted from feline adipose tissue-derived mesenchymal stem cells alleviate DSS-induced colitis by increasing regulatory T cells in mice. BMC Vet Res. 2018; 14(1):354. PMC: 6245895. DOI: 10.1186/s12917-018-1684-9. View

18.

Kanai R, Nakashima A, Doi S, Kimura T, Yoshida K, Maeda S . Interferon-γ enhances the therapeutic effect of mesenchymal stem cells on experimental renal fibrosis. Sci Rep. 2021; 11(1):850. PMC: 7807061. DOI: 10.1038/s41598-020-79664-6. View

19.

Sun J, Han Z, Liao W, Yang S, Yang Z, Yu J . Intrapulmonary delivery of human umbilical cord mesenchymal stem cells attenuates acute lung injury by expanding CD4+CD25+ Forkhead Boxp3 (FOXP3)+ regulatory T cells and balancing anti- and pro-inflammatory factors. Cell Physiol Biochem. 2011; 27(5):587-96. DOI: 10.1159/000329980. View

20.

Liu Y . Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol. 2011; 7(12):684-96. PMC: 4520424. DOI: 10.1038/nrneph.2011.149. View