Interleukin‐10 secreted by mesenchymal stem cells attenuates acute liver failure through inhibiting pyroptosis

Wang, Jinglin; Ren, Haozhen; Yuan, Xianwen; Ma, Hucheng; Shi, Xiaolei; Ding, Yitao

doi:10.1111/hepr.12969

Cited by 81 publications

(68 citation statements)

References 31 publications

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“…For example, secretion of EGF by MSCs attenuated apoptosis in podocytes 31 and IL-10 secretion by MSC ameliorated liver injury in mice. 16 Collectively, the results from these studies and our own data suggest that beyond P3, AD-MSCs may exhibit reduced potency while for BM-MSCs, culturing them to P5 might augment their potency.…”

Section: Discussionmentioning

confidence: 72%

“…In contrast, BM‐MSCs secreted only two (IL‐8 and RANTES) cytokines at higher amounts at P3 compared to P1, and secretion of six cytokines and growth factors (fractalkine, PGDF‐BB, IL‐2, IL‐6, IL‐8, and RANTES) was significantly increased at P5 compared to P1. Multiple studies indicate that the biologic functions mediated by MSCs are dependent on cytokine release by the MSC . Since the cytokine secretion profiles of both AD‐MSC and BM‐MSC seem to be passage dependent, it stands to reason that MSC passage number would also influence their biological potency.…”

Section: Resultsmentioning

confidence: 99%

“…Multiple studies indicate that the biologic functions mediated by MSCs are dependent on cytokine release by the MSC. [14][15][16] Since the cytokine secretion profiles of both AD-MSC and BM-MSC seem to be passage dependent, it stands to reason that MSC passage number would also influence their biological potency. When we compared overall cytokine and growth factor secretion by AD-MSCs with BM-MSCs at P3, we found that AD-MSCs significantly secreted a higher number of cytokines and growth factors at greater concentrations.…”

Section: Cytokine Secretion Profiles Differ Between Ad-mscs and Bm-mscsmentioning

confidence: 99%

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Modifiers of mesenchymal stem cell quantity and quality

et al. 2018

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Section: Discussionmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 99%

Section: Cytokine Secretion Profiles Differ Between Ad-mscs and Bm-mscsmentioning

confidence: 99%

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Modifiers of mesenchymal stem cell quantity and quality

et al. 2018

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“…Besides, blocking IL-1 signaling by treatment with the recombinant human IL-1 receptor antagonist (IL-1ra) anakinra alleviated DGalN/LPS leaded liver injury [30,40]. Moreover, the NLRP3 inhibitor MCC950 has also shown to protect mice from chemically-induced liver injury [41,42]. Here, we found that although NLRP3 de ciency decreased serum and hepatic IL1β levels in DGalN/LPS treated mice, the liver injury is not improved, suggesting that IL1β may have a limited role in DGalN/LPS induced liver injury.…”

Section: Discussionmentioning

confidence: 99%

NLRP3 is dispensable for D-galactosamine/Lipopolysaccharide-induced fulminant hepatitis

Zhang

Tao

Wang

et al. 2020

Preprint

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Background: The NOD-like receptor family protein 3 (NLRP3) inflammasome is involved in the progression of liver inflammation. NLRP3 inactivation has been shown to protect mice against multiple types of experimental liver injury. However, it is unclear whether NLRP3 contributes to D-Galactosamine (DGalN) plus lipopolysaccharide (LPS) induced fatal hepatitis. This study aims to examine the function of NLRP3 inflammasome in DGalN/LPS induced acute liver failure.Method: The expression of inflammasomes was detected by quantitative PCR. Wild type (WT) mice and NLRP3 knockout mice were given an intraperitoneal injection of DGalN plus LPS. Liver damage was examined at 6 h post DGalN/LPS administration by histological analysis and serum aminotransferases measurement. Hepatocyte apoptosis and pyroptosis was detected with TUNEL assay, immunohistochemistry (IHC) staining, and western blot. Hepatic macrophages (F4/80+) and neutrophils (Ly6G+) were analyzed by IHC staining. The proinflammatory cytokines levels in serum and liver were examined using cytometric bead array and quantitative PCR. Hepatic IL1β level was further detected by western blot.Result: The hepatic NLRP3 activity was upregulated in WT mice treated with DGalN/LPS. Nlrp3−/− and WT mice showed similar mortality against lethal dose of DGalN/LPS. Serum aminotransferases levels and liver necrosis area of Nlrp3−/− mice did not differ from that in WT mice after DGalN/LPS injection. The numbers of liver TUNEL positive cells and cleaved caspase3 positive hepatocytes were comparable between Nlrp3−/− and WT mice. The hepatic GSDMDNterm peptide production also showed no difference between Nlrp3−/− and WT mice. Mice treated with DGalN/LPS displayed significantly increased numbers of intrahepatic F4/80+ cells and Ly6G+ cells, but the cell numbers in Nlrp3−/− mice livers were similar to those in WT mice. Consistently, serum and hepatic TNFα, IL6, and MCP-1 levels were similar between Nlrp3−/− and WT mice upon DGalN/LPS administration, but serum IL1β and hepatic mature IL1β level in Nlrp3−/− mice was reduced.Conclusions: NLRP3 ablation does not protect mice from DGalN/LPS induced acute liver failure, nor affect hepatocyte apoptosis and pyroptosis. Deficiency of NLRP3 has a limited effect on intrahepatic inflammatory response induced by DGalN/LPS treatment. NLRP3 inflammasome does not appear to be a major contributor to DGalN/LPS induced fatal hepatitis.

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“…Mounting evidence showed that MSCs secretions exerted a bene cial effect by reducing the in ammatory response, promoting the survival and proliferation of injured cells, and ameliorating liver injury. (21,(44)(45)(46)(47) In the present study, microcapsules were used as carriers to encapsulate UMSCs and hepatocytes to persistently release the secretory factors contributing to the repair of impaired liver and the reduction of in ammatory response in ALF. And more, HNF4α-UMSCs signi cantly argument the therapeutic effects on ALF mice (Fig.1-5).…”

Section: Discussionmentioning

confidence: 99%

Co-encapsulation of HNF4α Overexpressing UMSCs and Human Primary Hepatocytes Ameliorates Mouse Acute Liver Failure

Kong

Chen

et al. 2020

Preprint

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Background: Acute liver failure (ALF) is a complicated condition that is characterized by global hepatocyte death and often requires immediate liver transplantation. However, this therapy is limited by shortage of donor organs. Mesenchymal stem cells (MSCs) and hepatocytes are two attractive sources of cell-based therapies to treat ALF. The combined transplantation of hepatocytes and MSCs is considered to be more effective for the treatment of ALF than single-cell transplantation. We have previously demonstrated that HNF4α-overexpressing human umbilical cord MSCs (HNF4α-UMSCs) promoted the expression of hepatic-specific genes. In addition, microencapsulation allows exchange of nutrients, forming a protective barrier to the transplanted cells. Moreover, encapsulation of hepatocytes improves the viability and synthetic ability of hepatocytes and circumvents immune rejection. This study aimed to investigate the therapeutic effect of microencapsulation of hepatocytes and HNF4α-UMSCs in ALF mice.Methods: Human hepatocytes and UMSCs were obtained separately from liver and umbilical cord, followed by co-encapsulation and transplantation into mice by intraperitoneal injection. LPS/D-gal was used to induce ALF by intraperitoneal injection 24 h after transplantation. In addition, Raw 264.7cells (a macrophage cell line) were used to elucidate the effect of HNF4α-UMSCs-hepatocyte microcapsules on polarization of macrophages. The protein chip was used to define the important paracrine factors in the conditioned mediums (CMs) of UMSCs and HNF4α-UMSCs and investigate the possible mechanism of HNF4α-UMSCs for the treatment of ALF in mice.Results: HNF4α-UMSCs can enhance the function of primary hepatocytes in alginate–poly-L-lysine–alginate (APA) microcapsules. The co-encapsulation of both HNF4α-UMSCs and hepatocytes achieved better therapeutic effects in ALF mice by promoting M2 macrophage polarization and reducing inflammatory response mainly mediated by the paracrine factor HB-EGF secreted by HNF4α-UMSCs.Conclusions: The present study confirms that the co-encapsulation of HNF4α-UMSC and hepatocytes could exert therapeutic effect on ALF mainly by HB-EGF secreted by HNF4α-UMSCs and provides a novel strategy for the treatment of ALF.

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Interleukin‐10 secreted by mesenchymal stem cells attenuates acute liver failure through inhibiting pyroptosis

Abstract: Pyroptosis was inhibited after IL-10 infusion and inhibition of NLRP3 by MCC950 reversed liver dysfunction.

Cited by 81 publications

References 31 publications

Modifiers of mesenchymal stem cell quantity and quality

Modifiers of mesenchymal stem cell quantity and quality

NLRP3 is dispensable for D-galactosamine/Lipopolysaccharide-induced fulminant hepatitis

Co-encapsulation of HNF4α Overexpressing UMSCs and Human Primary Hepatocytes Ameliorates Mouse Acute Liver Failure

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