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Analysis of Retinoic Acid-induced Neural Differentiation of Mouse Embryonic Stem Cells in Two and Three-dimensional Embryoid Bodies
Published on: April 22, 2017
Acyclic retinoid induces differentiation and apoptosis of murine hepatic stem cells
Hong-Bin Guan1, Yun-Zhong Nie2, Yun-Wen Zheng3,4
1Department of Regenerative Medicine, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa, 236-0004, Japan. dillonguan277@gmail.com.
Introduction:
The therapeutic potential of acyclic retinoid (ACR), a synthetic retinoid, has been confirmed in experimental and clinical studies. Therapeutic targets include precancerous and cancer stem cells. As ACR is also involved in developmental processes, its effect on normal hepatic stem cells (HpSCs) should be investigated for understanding the underlying mechanisms. Here, we examined effects of the acyclic retinoid peretinoin on fresh isolated murine HpSCs.
Methods:
We isolated c-kit-CD29+CD49f+/lowCD45-Ter119- cells from murine fetal livers using flow cytometry. To evaluate the effect of ACR, we traced clonal expansion and analyzed cell differentiation as well as apoptosis during the induction process by immunofluorescent staining and marker gene expression.
Results:
ACR dose-dependently inhibited HpSCs expansion. Stem cell clonal expansion was markedly inhibited during the culture period. Moreover, ACR showed a significant promotion of HpSC differentiation and induction of cellular apoptosis. The expression of stem cell marker genes, Afp, Cd44, and Dlk, was downregulated, while that of mature hepatocyte genes, Alb and Tat, and apoptosis-related genes, Annexin V and Caspase-3, were upregulated. Flow cytometry showed that the proportion of Annexin V-positive cells increased after ACR incubation compared with the control. Data obtained by immunofluorescent staining for albumin and Caspase-3 corroborated the data on gene expression. Finally, we found that ACR directly regulates the expression of retinoic acid receptors and retinoid X receptors.
Conclusions:
These findings indicate that ACR inhibits the clonal expansion of normal HpSCs in vitro and promotes the differentiation of immature cells by regulating receptors of retinoic acid.
Insights
Acyclic retinoid (ACR) inhibits normal hepatic stem cell (HpSC) expansion and promotes differentiation. This study investigated ACR
Area of Science:
- Hepatology
- Stem Cell Biology
- Retinoid Research
Background:
- Acyclic retinoid (ACR) demonstrates therapeutic potential against precancerous and cancer stem cells.
- ACR's role in development necessitates understanding its impact on normal hepatic stem cells (HpSCs).
Purpose of the Study:
- To investigate the effects of the acyclic retinoid peretinoin on freshly isolated murine HpSCs.
- To elucidate the mechanisms by which ACR influences HpSC behavior.
Main Methods:
- Isolation of murine HpSCs using flow cytometry (c-kit-CD29+CD49f+/lowCD45-Ter119- cells).
- Evaluation of ACR's effects on clonal expansion, differentiation, and apoptosis.
- Analysis of gene expression for stem cell markers, mature hepatocytes, and apoptosis-related genes.
- Immunofluorescent staining and flow cytometry for validation.
Main Results:
- ACR dose-dependently inhibited HpSC expansion and clonal proliferation.
- ACR promoted HpSC differentiation and induced apoptosis.
- Downregulation of stem cell markers (Afp, Cd44, Dlk) and upregulation of mature hepatocyte (Alb, Tat) and apoptosis genes (Annexin V, Caspase-3) observed.
- ACR directly regulates retinoic acid and retinoid X receptors.
Conclusions:
- ACR inhibits normal HpSC clonal expansion in vitro.
- ACR promotes the differentiation of immature hepatic cells.
- Regulation of retinoic acid receptors is a key mechanism.
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