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Kidney Week

Abstract: TH-PO418

Mesenchymal Stem Cells Overexpressing Tumor Necrosis Factor α-Induced Protein 6 Have an Enhanced Inhibitory Effect on Kidney Fibrosis

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 600 Development, Stem Cells, and Regenerative Medicine

Authors

  • Morimoto, Keisuke, Hiroshima Daigaku Daigakuin Ikei Kagaku Kenkyuka, Hiroshima, Hiroshima, Japan
  • Nakashima, Ayumu, Yamanashi Daigaku, Kofu, Yamanashi, Japan
  • Ishiuchi, Naoki, Hiroshima Daigaku Byoin, Hiroshima, Hiroshima, Japan
  • Miyasako, Kisho, Hiroshima Daigaku Daigakuin Ikei Kagaku Kenkyuka, Hiroshima, Hiroshima, Japan
  • Tanaka, Yoshiki, Hiroshima Daigaku Daigakuin Ikei Kagaku Kenkyuka, Hiroshima, Hiroshima, Japan
  • Sasaki, Kensuke, Hiroshima Daigaku Byoin, Hiroshima, Hiroshima, Japan
  • Masaki, Takao, Hiroshima Daigaku Byoin, Hiroshima, Hiroshima, Japan
Background

Acute kidney injury (AKI) is involved in subsequent chronic kidney disease (CKD) development, and effective treatments to prevent AKI to CKD progression are lacking. Mesenchymal stem cells (MSCs) are emerging as a promising cellular therapy to impede such progression. MSCs repair injured tissue through secretion of various humoral factors. Among these factors, tumor necrosis factor-α-induced protein 6 (TSG-6) has a central role in the anti-inflammatory effects of MSCs. However, the mechanisms by which MSCs secrete TSG-6 and exert anti-inflammatory effects are not fully clarified. In this study, we investigated these mechanisms using TSG-6-overexpressing MSCs.

Methods

MSCs infected with an adeno-associated virus carrying TSG-6 cDNA or an empty adeno-associated virus were designed as TSG-6 MSCs and null MSCs, respectively. Extracellular vesicles (EVs) were isolated from MSC culture supernatants by ultracentrifugation. MSCs were injected through the abdominal aorta into rats with ischemia-reperfusion injury (IRI) to evaluate their anti-inflammatory and anti-fibrotic effects. We also examined whether TSG-6 secreted from MSCs affected polarization of monocytic THP-1 cell-derived macrophages to the immunosuppressive M2 phenotype. Additionally, we explored natural compounds that increased TSG-6 expression in MSCs.

Results

Most TSG-6 was immediately secreted in EVs and was not stored intracellularly. Administration of TSG-6 MSCs more strongly suppressed renal fibrosis and inflammation in IRI rats than null MSCs. Although EVs and conditioned medium from TSG-6 MSCs (TSG-6 MSC-CM) strongly promoted polarization of M2 macrophages, TSG-6 MSC-CM after EV depletion promoted it only slightly. Moreover, TSG-6 MSC-CM enhanced regulatory T cell induction. Additionally, MSCs treated with indole-3-carbinol had enhanced TSG-6 expression and markedly suppressed IRI-induced renal fibrosis.

Conclusion

TSG-6 is secreted in EVs from MSCs and exerts potent anti-inflammatory effects by promoting M2 macrophage polarization and regulatory T cell induction. Administration of MSCs with enhanced TSG-6 secretion is a promising therapeutic strategy to impede AKI to CKD progression.