Regulating cell fate of human amnion epithelial cells using natural compounds: an example of enhanced neural and pigment differentiation by 3,4,5-tri-O-caffeoylquinic acid

doi:10.1186/s12964-020-00697-5

. 2021 Feb 24;19(1):26.

doi: 10.1186/s12964-020-00697-5.

Regulating cell fate of human amnion epithelial cells using natural compounds: an example of enhanced neural and pigment differentiation by 3,4,5-tri-O-caffeoylquinic acid

Meriem Bejaoui^{1

2}, Farhana Ferdousi^{1

2

3}, Yun-Wen Zheng^{2

4}, Tatsuya Oda^{2

4}, Hiroko Isoda^{5

6

7}

Affiliations

¹ Alliance for Research On the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba, Japan.
² AIST-University of Tsukuba Open Innovation Laboratory for Food and Medicinal Resource Engineering (FoodMed-OIL), AIST, University of Tsukuba, Tsukuba, Japan.
³ Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8572, Japan.
⁴ Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
⁵ Alliance for Research On the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba, Japan. isoda.hiroko.ga@u.tsukuba.ac.jp.
⁶ AIST-University of Tsukuba Open Innovation Laboratory for Food and Medicinal Resource Engineering (FoodMed-OIL), AIST, University of Tsukuba, Tsukuba, Japan. isoda.hiroko.ga@u.tsukuba.ac.jp.
⁷ Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8572, Japan. isoda.hiroko.ga@u.tsukuba.ac.jp.

PMID: 33627134
PMCID: PMC7903623
DOI: 10.1186/s12964-020-00697-5

Regulating cell fate of human amnion epithelial cells using natural compounds: an example of enhanced neural and pigment differentiation by 3,4,5-tri-O-caffeoylquinic acid

Meriem Bejaoui et al. Cell Commun Signal. 2021.

. 2021 Feb 24;19(1):26.

doi: 10.1186/s12964-020-00697-5.

Authors

Meriem Bejaoui^{1

2}, Farhana Ferdousi^{1

2

3}, Yun-Wen Zheng^{2

4}, Tatsuya Oda^{2

4}, Hiroko Isoda^{5

6

7}

Affiliations

¹ Alliance for Research On the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba, Japan.
² AIST-University of Tsukuba Open Innovation Laboratory for Food and Medicinal Resource Engineering (FoodMed-OIL), AIST, University of Tsukuba, Tsukuba, Japan.
³ Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8572, Japan.
⁴ Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
⁵ Alliance for Research On the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba, Japan. isoda.hiroko.ga@u.tsukuba.ac.jp.
⁶ AIST-University of Tsukuba Open Innovation Laboratory for Food and Medicinal Resource Engineering (FoodMed-OIL), AIST, University of Tsukuba, Tsukuba, Japan. isoda.hiroko.ga@u.tsukuba.ac.jp.
⁷ Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8572, Japan. isoda.hiroko.ga@u.tsukuba.ac.jp.

PMID: 33627134
PMCID: PMC7903623
DOI: 10.1186/s12964-020-00697-5

Abstract

Over the past years, Human Amnion Epithelial Cells (hAECs), a placental stem cell, are gaining higher attention from the scientific community as they showed several advantages over other types of stem cells, including availability, easy accessibility, reduced rejection rate, non-tumorigenicity, and minimal legal constraint. Recently, natural compounds are used to stimulate stem cell differentiation and proliferation and to enhance their disease-treating potential. A polyphenolic compound 3,4,5-Tri-O-Caffeoylquinic Acid (TCQA) has been previously reported to induce human neural stem cell differentiation and may affect melanocyte stem cell differentiation as well. In this study, TCQA was tested on 3D cultured hAECs after seven days of treatment, and then, microarray gene expression profiling was conducted of TCQA-treated and untreated control cells on day 0 and day 7. Analyses revealed that TCQA treatment significantly enriched pigment and neural cells sets; besides, genes linked with neurogenesis, oxidation-reduction process, epidermal development, and metabolism were positively regulated. Interestingly, TCQA stimulated cell cycle arrest-related pathways and differentiation signaling. On the other hand, TCQA decreased interleukins and cytokines expression and this due to its anti-inflammatory properties as a polyphenolic compound. Results were validated to highlight the main activities of TCQA on hAECs, including differentiation, cell cycle arrest, and anti-inflammatory. This study highlights the important role of hAECs in regenerative medicine and the use of natural compounds to regulate their fate. Video abstract.

Keywords: 3,4,5-tri-O-caffeoylquinic acid (TCQA); Cell cycle arrest; Differentiation; Human amniotic epithelial stem cells (hAECs); Inflammation; Neurogenesis; Pigment cell.

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Conflict of interest statement

The authors declare that they have no financial or commercial conflicts of interest.

Figures

**Fig. 1**
Microarray profiling of D7 TCQA-treated versus D0 control hAECs. a Scatter plot showing the DEGs. X-axis represents the average signal intensities (log2) in D0 control. Y-axis represents the average signal intensities (log2) in D7 TCQA-treated hAECs. The red color represents the upregulated DEGs, green color represents the downregulated DEGs, and grey color represents the nonsignificant genes. b Significantly enriched GOs by upregulated (analyzed using GSEA). c Significantly enriched KEGG pathways by upregulated DEGs (analyzed using DAVID and GSEA). d Significantly enriched GOs by downregulated (analyzed using GSEA). e Top significantly enriched KEGG pathways by the downregulated DEGs (analyzed using DAVID and GSEA). Each bar is arranged according to significance (p-values) and represents the number of DEGs

**Fig. 2**
Comparison of gene profiling between D7 TCQA-treated versus D7 control hAECs with D7 control versus D0 control. a Venn diagram showing common and unique sets of DEGs between each exposure. b Heat map showing the significance of biological processes in two comparison sets—D7 control versus D0 control and D7 TCQA-treated versus D7 control hAECs. Heat map was generated using Morpheus online software (https://software.broadinstitute.org/morpheus)

**Fig. 3**
Gene expression profiling of D7 TCQA-treated versus D7 control hAECs. a Significantly enriched GOs by upregulated DEGs. b Significantly enriched KEGG pathways by upregulated DEGs. c Top functional categories of upregulated DEGs. d Significantly enriched GOs by downregulated DEGs. e Significantly enriched KEGG pathways by downregulated DEGs. f Top functional categories of downregulated DEGs

**Fig. 4**
Molecular functions induced in D7 TCQA-treated compared with D7 control hAECs. a Heat map showing relative expression intensities of DEGs. Heat map was generated using Morpheus software. b Gene expression of *CTNNB1, MC1R, VCAN, DMKN, IL6*, and *TNFα* in D7 TCQA-treated and D7 control hAECs. The mRNA level was quantified using TaqMan real-time PCR. Results represent the mean ± SD of three independent experiments. The Student’s t-test was used to compare the mean values of two groups. *P ≤ 0.05; **P ≤ 0.01. c Possible protein interactions among the genes classified in the heat map. Figure was generated using an online software STRING (https://string-db.org/)

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References

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1. Visweswaran M, Pohl S, Arfuso F, Newsholme P, Dilley R, Pervaiz S, et al. Multi-lineage differentiation of mesenchymal stem cells—to Wnt, or not Wnt. Int J Biochem Cell Biol. 2015;68:139–147. doi: 10.1016/j.biocel.2015.09.008. - DOI - PubMed
1. McDonald C, Siatskas C, Bernard CA. The emergence of amnion epithelial stem cells for the treatment of Multiple Sclerosis. Inflamm Regen. 2011;31:256–271.
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[1] Maymó JL, Riedel R, Pérez-Pérez A, Magatti M, Maskin B, Dueñas JL, et al. Proliferation and survival of human amniotic epithelial cells during their hepatic differentiation. PLoS ONE. 2018;13:1–28. - PMC - PubMed

[2] Maymó JL, Riedel R, Pérez-Pérez A, Magatti M, Maskin B, Dueñas JL, et al. Proliferation and survival of human amniotic epithelial cells during their hepatic differentiation. PLoS ONE. 2018;13:1–28. - PMC - PubMed

[3] Visweswaran M, Pohl S, Arfuso F, Newsholme P, Dilley R, Pervaiz S, et al. Multi-lineage differentiation of mesenchymal stem cells—to Wnt, or not Wnt. Int J Biochem Cell Biol. 2015;68:139–147. doi: 10.1016/j.biocel.2015.09.008. - DOI - PubMed

[4] Visweswaran M, Pohl S, Arfuso F, Newsholme P, Dilley R, Pervaiz S, et al. Multi-lineage differentiation of mesenchymal stem cells—to Wnt, or not Wnt. Int J Biochem Cell Biol. 2015;68:139–147. doi: 10.1016/j.biocel.2015.09.008. - DOI - PubMed

[5] McDonald C, Siatskas C, Bernard CA. The emergence of amnion epithelial stem cells for the treatment of Multiple Sclerosis. Inflamm Regen. 2011;31:256–271.

[6] McDonald C, Siatskas C, Bernard CA. The emergence of amnion epithelial stem cells for the treatment of Multiple Sclerosis. Inflamm Regen. 2011;31:256–271.

[7] Li JY, Christophersen NS, Hall V, Soulet D, Brundin P. Critical issues of clinical human embryonic stem cell therapy for brain repair. Trends Neurosci. 2008;31:146–153. - PubMed

[8] Li JY, Christophersen NS, Hall V, Soulet D, Brundin P. Critical issues of clinical human embryonic stem cell therapy for brain repair. Trends Neurosci. 2008;31:146–153. - PubMed

[9] Miki T. Amnion-derived stem cells: in quest of clinical applications. Stem Cell Res Ther. 2011;2:25. - PMC - PubMed

[10] Miki T. Amnion-derived stem cells: in quest of clinical applications. Stem Cell Res Ther. 2011;2:25. - PMC - PubMed

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Regulating cell fate of human amnion epithelial cells using natural compounds: an example of enhanced neural and pigment differentiation by 3,4,5-tri-O-caffeoylquinic acid

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Regulating cell fate of human amnion epithelial cells using natural compounds: an example of enhanced neural and pigment differentiation by 3,4,5-tri-O-caffeoylquinic acid

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