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Human Placental Mesenchymal Stem Cells Ameliorate Liver Fibrosis in Mice by Upregulation of Caveolin1 in Hepatic Stellate Cells
Hongxin Deng
West China Hospital, Sichuan University , and Collaborative Innovation Center for Biotherapy
Corresponding Author
ORCiD: https://orcid.org/0000-0002-8875-4493
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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.
Keywords
Liver fibrosis, hPMSCs, HSCs, Caveolin-1, TGF-β/Smad pathway
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This preprint is under consideration at Stem Cell Research & Therapy. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Human Placental Mesenchymal Stem Cells Ameliorate Liver Fibrosis in Mice by Upregulation of Caveolin1 in Hepatic Stellate Cells
Hongxin Deng
West China Hospital, Sichuan University , and Collaborative Innovation Center for Biotherapy
Corresponding Author
ORCiD: https://orcid.org/0000-0002-8875-4493
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 07 Jan, 2021
No community comments so far
Reviewer #6 agreed
On 10 Jan, 2021
Review #3 received
Received 07 Jan, 2021
Reviewer #5 agreed
On 06 Jan, 2021
Reviewer #4 agreed
On 06 Jan, 2021
Review #1 received
Received 05 Jan, 2021
Reviewer #3 agreed
On 04 Jan, 2021
Reviewer #2 agreed
On 03 Jan, 2021
Reviewers invited
Invitations sent on 03 Jan, 2021
Reviewer #1 agreed
On 03 Jan, 2021
Editor assigned
On 01 Jan, 2021
Submission checks complete
On 01 Jan, 2021
Editor invited
On 01 Jan, 2021
First submitted
On 30 Dec, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Stem Cell & Developmental Cell Biology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
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