Human Placental Mesenchymal Stem Cells Ameliorate Liver Fibrosis in Mice by Upregulation of Caveolin1 in Hepatic Stellate Cells
Background: Liver fibrosis (LF) is a common pathological process characterized by the activation of hepatic stellate cells (HSCs) and accumulation of extracellular matrix. Severe LF causes cirrhosis and even liver failure, a major cause of morbidity and mortality worldwide. Transplantation of human placental mesenchymal stem cells (hPMSCs) has been considered as an alternative therapy, replacing liver transplantation in clinical trials, to treat LF. However, the underlying mechanisms and the appropriate time window for hPMSC transplantation are not well understood.
Methods: We established mouse models of CCL4-injured LF, and administered hPMSCs once a week for 2 weeks. The therapeutic effect of hPMSCs on LF was investigated, according to histopathological and blood biochemical analyses. What’s more, the culture supernatant of hPMSCs were isolated, and the effect of the culture supernatant on the inhibition of activated HSCs was also assessed. RNA sequencing (RNA-seq) analysis, Real-time PCR array, and western blotting were performed to explore possible signaling pathways involved in treatment of IF with hPMSCs.
Results: hPMSC treatment can alleviate experimental hepatic fibrosis, restore liver function, and inhibit inflammation. Furthermore, the therapeutic effect of hPMSCs against mild to moderate LF was significantly greater than against severe disease. Mechanistic dissection studies suggested ameliorating LF using hPMSCs occur partly by restoring Caveolin-1 (Cav1) in activated hepatic stellate cells (HSCs). Upregulation of Cav1 can inhibit the TGF-β/Smad signaling pathway, mainly by reducing Smad2 phosphorylation, resulting in the inhibition of activated HSCs, whereas this effect could be abated if Cav1 was silenced in advance by siRNAs.
Conclusions: Our findings suggest that hPMSCs could provide multifaceted therapeutic benefits for the treatment of LF, and the TGF-β/Cav1 pathway might act as a therapeutic target for hPMSCs in the treatment of LF.
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Posted 07 Jan, 2021
On 10 Jan, 2021
Received 07 Jan, 2021
On 06 Jan, 2021
On 06 Jan, 2021
Received 05 Jan, 2021
On 04 Jan, 2021
On 03 Jan, 2021
Invitations sent on 03 Jan, 2021
On 03 Jan, 2021
On 01 Jan, 2021
On 01 Jan, 2021
On 01 Jan, 2021
On 30 Dec, 2020
Human Placental Mesenchymal Stem Cells Ameliorate Liver Fibrosis in Mice by Upregulation of Caveolin1 in Hepatic Stellate Cells
Posted 07 Jan, 2021
On 10 Jan, 2021
Received 07 Jan, 2021
On 06 Jan, 2021
On 06 Jan, 2021
Received 05 Jan, 2021
On 04 Jan, 2021
On 03 Jan, 2021
Invitations sent on 03 Jan, 2021
On 03 Jan, 2021
On 01 Jan, 2021
On 01 Jan, 2021
On 01 Jan, 2021
On 30 Dec, 2020
Background: Liver fibrosis (LF) is a common pathological process characterized by the activation of hepatic stellate cells (HSCs) and accumulation of extracellular matrix. Severe LF causes cirrhosis and even liver failure, a major cause of morbidity and mortality worldwide. Transplantation of human placental mesenchymal stem cells (hPMSCs) has been considered as an alternative therapy, replacing liver transplantation in clinical trials, to treat LF. However, the underlying mechanisms and the appropriate time window for hPMSC transplantation are not well understood.
Methods: We established mouse models of CCL4-injured LF, and administered hPMSCs once a week for 2 weeks. The therapeutic effect of hPMSCs on LF was investigated, according to histopathological and blood biochemical analyses. What’s more, the culture supernatant of hPMSCs were isolated, and the effect of the culture supernatant on the inhibition of activated HSCs was also assessed. RNA sequencing (RNA-seq) analysis, Real-time PCR array, and western blotting were performed to explore possible signaling pathways involved in treatment of IF with hPMSCs.
Results: hPMSC treatment can alleviate experimental hepatic fibrosis, restore liver function, and inhibit inflammation. Furthermore, the therapeutic effect of hPMSCs against mild to moderate LF was significantly greater than against severe disease. Mechanistic dissection studies suggested ameliorating LF using hPMSCs occur partly by restoring Caveolin-1 (Cav1) in activated hepatic stellate cells (HSCs). Upregulation of Cav1 can inhibit the TGF-β/Smad signaling pathway, mainly by reducing Smad2 phosphorylation, resulting in the inhibition of activated HSCs, whereas this effect could be abated if Cav1 was silenced in advance by siRNAs.
Conclusions: Our findings suggest that hPMSCs could provide multifaceted therapeutic benefits for the treatment of LF, and the TGF-β/Cav1 pathway might act as a therapeutic target for hPMSCs in the treatment of LF.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7