Inhibition of glycogen synthase kinase 3β protects liver against ischemia/reperfusion injury by activating 5′ adenosine monophosphate‐activated protein kinase‐mediated autophagy

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 264.7 cells (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.

show abstract

“…The primary mice hepatocytes were isolated and cultured as previously described [19]. UMSCs were cultured in DMEM/F12 supplemented with 10% FBS.…”

Section: Cell Isolation and Culturementioning

confidence: 99%

Co-encapsulation of HNF4α overexpressing UMSCs and human primary hepatocytes ameliorates mouse acute liver failure

Kong

Chen

et al. 2020

Stem Cell Res Ther

Self Cite

View full text Add to dashboard Cite

show abstract

“…The primary mice hepatocytes were isolated from the livers as previously described. (19) Isolation and cultureof UMSCs were performed as described in the previous report. 15 UMSCs were cultured in DMEM/F12 supplemented with 10% FBS.…”

Section: Cell Isolation and Culturementioning

confidence: 99%

“…The histopathological changes were given scores according to a classic liver injury score standard. 19 Immunohistochemistry analyses were performed as previously described. (20) Next, the liver sections were incubated with primary antibodies against MPO for overnight at 4 °C.…”

Section: Histopathology Immunohistochemistry and Immunofluorescence mentioning

confidence: 99%

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

Kong

Chen

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

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 from liver and umbilical cord separately, 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 of conditioned mediums (CMs) of UMSCs and HNF4α-UMSCs were used to define the important paracrine factors 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 response in ALF mice by promoting M2 macrophage polarization and inflammatory resolution effect mainly modulated by the paracrine factor HB-EGF from HNF4α-UMSCs.Conclusions: The present study confirms that the co-encapsulation of HNF4α-UMSC and hepatocytes could exert an efficient effect on ALF mainly by HB-EGF and provides a novel therapeutic strategy for the treatment of ALF.

show abstract

“…The primary mice hepatocytes were isolated and cultured as previously described. (19) UMSCs were cultured in DMEM/F12 supplemented with 10% FBS. UMSCs between passage 3 (P3) and P5 were used in the following experiments.…”

Section: Cell Isolation and Culturementioning

confidence: 99%

“…The histopathological changes were given scores according to a classic liver injury score standard. 19 Immunohistochemistry analyses were performed as previously described. (20) For immunohistochemistry, the liver sections were incubated with primary antibodies against MPO (Abcam, Cambridge, UK) or F4/80 (Abcam).…”

Section: Histopathology Immunohistochemistry and Immuno Uorescence Amentioning

confidence: 99%

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

Kong

Chen

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Inhibition of glycogen synthase kinase 3β protects liver against ischemia/reperfusion injury by activating 5′ adenosine monophosphate‐activated protein kinase‐mediated autophagy

Cited by 14 publications

References 34 publications

Co-encapsulation of HNF4α overexpressing UMSCs and human primary hepatocytes ameliorates mouse acute liver failure

Co-encapsulation of HNF4α overexpressing UMSCs and human primary hepatocytes ameliorates mouse acute liver failure

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

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

Contact Info

Product

Resources

About