Comparison of angiogenic, cytoprotective, and immunosuppressive properties of human amnion- and chorion-derived mesenchymal stem cells
Kenichi Yamahara, Kazuhiko Harada, Makiko Ohshima, Shin Ishikane, Shunsuke Ohnishi, Hidetoshi Tsuda, Kentaro Otani, Akihiko Taguchi, Toshihiro Soma, Hiroyasu Ogawa, Shinji Katsuragi, Jun Yoshimatsu, Mariko Harada-Shiba, Kenji Kangawa, Tomoaki Ikeda, Kenichi Yamahara, Kazuhiko Harada, Makiko Ohshima, Shin Ishikane, Shunsuke Ohnishi, Hidetoshi Tsuda, Kentaro Otani, Akihiko Taguchi, Toshihiro Soma, Hiroyasu Ogawa, Shinji Katsuragi, Jun Yoshimatsu, Mariko Harada-Shiba, Kenji Kangawa, Tomoaki Ikeda
Abstract
Although mesenchymal stem cells (MSCs) can be obtained from the fetal membrane (FM), little information is available regarding biological differences in MSCs derived from different layers of the FM or their therapeutic potential. Isolated MSCs from both amnion and chorion layers of FM showed similar morphological appearance, multipotency, and cell-surface antigen expression. Conditioned media obtained from amnion- and chorion-derived MSCs inhibited cell death caused by serum starvation or hypoxia in endothelial cells and cardiomyocytes. Amnion and chorion MSCs secreted significant amounts of angiogenic factors including HGF, IGF-1, VEGF, and bFGF, although differences in the cellular expression profile of these soluble factors were observed. Transplantation of human amnion or chorion MSCs significantly increased blood flow and capillary density in a murine hindlimb ischemia model. In addition, compared to human chorion MSCs, human amnion MSCs markedly reduced T-lymphocyte proliferation with the enhanced secretion of PGE2, and improved the pathological situation of a mouse model of acute graft-versus-host disease. Our results highlight that human amnion- and chorion-derived MSCs, which showed differences in their soluble factor secretion and angiogenic/immuno-suppressive function, could be ideal cell sources for regenerative medicine.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
Figures
![Figure 1. Characterization of human amnion- and…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3925106/bin/pone.0088319.g001.jpg)
![Figure 2. Growth factor secretion and the…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3925106/bin/pone.0088319.g002.jpg)
Figure 3. Angiogenic potential of amnion and…
Figure 3. Angiogenic potential of amnion and chorion MSCs against hindlimb ischemia.
(A) Representative images…
Figure 4. Immunosuppressive property of amnion and…
Figure 4. Immunosuppressive property of amnion and chorion MSCs.
(A) Inhibition of human CD4+ T…
- Comparative study of regenerative effects of mesenchymal stem cells derived from placental amnion, chorion and umbilical cord on dermal wounds.Ertl J, Pichlsberger M, Tuca AC, Wurzer P, Fuchs J, Geyer SH, Maurer-Gesek B, Weninger WJ, Pfeiffer D, Bubalo V, Parvizi D, Kamolz LP, Lang I. Ertl J, et al. Placenta. 2018 May;65:37-46. doi: 10.1016/j.placenta.2018.04.004. Epub 2018 Apr 10. Placenta. 2018. PMID: 29908640
- Transplantation of mesenchymal cells rejuvenated by the overexpression of telomerase and myocardin promotes revascularization and tissue repair in a murine model of hindlimb ischemia.Madonna R, Taylor DA, Geng YJ, De Caterina R, Shelat H, Perin EC, Willerson JT. Madonna R, et al. Circ Res. 2013 Sep 13;113(7):902-14. doi: 10.1161/CIRCRESAHA.113.301690. Epub 2013 Jun 18. Circ Res. 2013. PMID: 23780385
- Self-assembled GFFYK peptide hydrogel enhances the therapeutic efficacy of mesenchymal stem cells in a mouse hindlimb ischemia model.Huang A, Liu D, Qi X, Yue Z, Cao H, Zhang K, Lei X, Wang Y, Kong D, Gao J, Li Z, Liu N, Wang Y. Huang A, et al. Acta Biomater. 2019 Feb;85:94-105. doi: 10.1016/j.actbio.2018.12.015. Epub 2018 Dec 11. Acta Biomater. 2019. PMID: 30550934
- Chorion Mesenchymal Stem Cells Show Superior Differentiation, Immunosuppressive, and Angiogenic Potentials in Comparison With Haploidentical Maternal Placental Cells.González PL, Carvajal C, Cuenca J, Alcayaga-Miranda F, Figueroa FE, Bartolucci J, Salazar-Aravena L, Khoury M. González PL, et al. Stem Cells Transl Med. 2015 Oct;4(10):1109-21. doi: 10.5966/sctm.2015-0022. Epub 2015 Aug 13. Stem Cells Transl Med. 2015. PMID: 26273064 Free PMC article.
- Fetal membranes as a source of stem cells.Kmiecik G, Niklińska W, Kuć P, Pancewicz-Wojtkiewicz J, Fil D, Karwowska A, Karczewski J, Mackiewicz Z. Kmiecik G, et al. Adv Med Sci. 2013;58(2):185-95. doi: 10.2478/ams-2013-0007. Adv Med Sci. 2013. PMID: 24327530 Review.
- Human Amniotic Mesenchymal Stem Cells Alleviate aGVHD after allo-HSCT by Regulating Interactions between Gut Microbiota and Intestinal Immunity.Bu X, Wang J, Yin Z, Pan W, Liu L, Jin H, Liu Q, Zheng L, Sun H, Gao Y, Ping B. Bu X, et al. Stem Cell Rev Rep. 2023 Mar 4. doi: 10.1007/s12015-023-10522-4. Online ahead of print. Stem Cell Rev Rep. 2023. PMID: 36870009
- Secretion pattern of canine amniotic stem cells derived extracellular vesicles.Karam RG, Motta LCB, de Almeida MF, Bridi A, da Silveira JC, Ambrósio CE. Karam RG, et al. Anim Reprod. 2022 Nov 14;19(4):e20220063. doi: 10.1590/1984-3143-AR2022-0063. eCollection 2022. Anim Reprod. 2022. PMID: 36425401 Free PMC article.
- Mesenchymal stem cells and their microenvironment.Liu J, Gao J, Liang Z, Gao C, Niu Q, Wu F, Zhang L. Liu J, et al. Stem Cell Res Ther. 2022 Aug 20;13(1):429. doi: 10.1186/s13287-022-02985-y. Stem Cell Res Ther. 2022. PMID: 35987711 Free PMC article. Review.
- Significance of Placental Mesenchymal Stem Cell in Placenta Development and Implications for Preeclampsia.Zhang Y, Zhong Y, Zou L, Liu X. Zhang Y, et al. Front Pharmacol. 2022 Jun 1;13:896531. doi: 10.3389/fphar.2022.896531. eCollection 2022. Front Pharmacol. 2022. PMID: 35721156 Free PMC article. Review.
- A comparison of isolation and culture protocols for human amniotic mesenchymal stem cells.Naeem A, Gupta N, Naeem U, Khan MJ, Elrayess MA, Cui W, Albanese C. Naeem A, et al. Cell Cycle. 2022 Aug;21(15):1543-1556. doi: 10.1080/15384101.2022.2060641. Epub 2022 Apr 12. Cell Cycle. 2022. PMID: 35412950
-
- Prockop DJ (1997) Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 276: 71–74. - PubMed
-
- Ishikane S, Ohnishi S, Yamahara K, Sada M, Harada K, et al. (2008) Allogeneic injection of fetal membrane-derived mesenchymal stem cells induces therapeutic angiogenesis in a rat model of hind limb ischemia. Stem Cells 26: 2625–2633. - PubMed
-
- Ishikane S, Yamahara K, Sada M, Harada K, Kodama M, et al. (2010) Allogeneic administration of fetal membrane-derived mesenchymal stem cells attenuates acute myocarditis in rats. J Mol Cell Cardiol 49: 753–761. - PubMed
-
- Tsuda H, Yamahara K, Ishikane S, Otani K, Nakamura A, et al. (2010) Allogenic fetal membrane-derived mesenchymal stem cells contribute to renal repair in experimental glomerulonephritis. Am J Physiol Renal Physiol 299: F1004–1013. - PubMed
- Comparative Study
- Research Support, Non-U.S. Gov't
- Amnion / cytology*
- Animals
- Chorion / cytology*
- Cytoprotection*
- Female
- Hindlimb / blood supply
- Hindlimb / pathology
- Human Umbilical Vein Endothelial Cells / cytology
- Humans
- Immunosuppression Therapy*
- Intercellular Signaling Peptides and Proteins / metabolism
- Ischemia / therapy
- Male
- Mesenchymal Stem Cell Transplantation*
- Mesenchymal Stem Cells / cytology*
- Mesenchymal Stem Cells / metabolism
- Mice
- Mice, Nude
- Myocytes, Cardiac / cytology
- Neovascularization, Physiologic*
- Intercellular Signaling Peptides and Proteins
- Full Text Sources
- Other Literature Sources
- Medical
- Miscellaneous
NCBI Literature Resources
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![Figure 3. Angiogenic potential of amnion and…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3925106/bin/pone.0088319.g003.jpg)
Figure 4. Immunosuppressive property of amnion and…
Figure 4. Immunosuppressive property of amnion and chorion MSCs.
(A) Inhibition of human CD4+ T…
- Comparative study of regenerative effects of mesenchymal stem cells derived from placental amnion, chorion and umbilical cord on dermal wounds.Ertl J, Pichlsberger M, Tuca AC, Wurzer P, Fuchs J, Geyer SH, Maurer-Gesek B, Weninger WJ, Pfeiffer D, Bubalo V, Parvizi D, Kamolz LP, Lang I. Ertl J, et al. Placenta. 2018 May;65:37-46. doi: 10.1016/j.placenta.2018.04.004. Epub 2018 Apr 10. Placenta. 2018. PMID: 29908640
- Transplantation of mesenchymal cells rejuvenated by the overexpression of telomerase and myocardin promotes revascularization and tissue repair in a murine model of hindlimb ischemia.Madonna R, Taylor DA, Geng YJ, De Caterina R, Shelat H, Perin EC, Willerson JT. Madonna R, et al. Circ Res. 2013 Sep 13;113(7):902-14. doi: 10.1161/CIRCRESAHA.113.301690. Epub 2013 Jun 18. Circ Res. 2013. PMID: 23780385
- Self-assembled GFFYK peptide hydrogel enhances the therapeutic efficacy of mesenchymal stem cells in a mouse hindlimb ischemia model.Huang A, Liu D, Qi X, Yue Z, Cao H, Zhang K, Lei X, Wang Y, Kong D, Gao J, Li Z, Liu N, Wang Y. Huang A, et al. Acta Biomater. 2019 Feb;85:94-105. doi: 10.1016/j.actbio.2018.12.015. Epub 2018 Dec 11. Acta Biomater. 2019. PMID: 30550934
- Chorion Mesenchymal Stem Cells Show Superior Differentiation, Immunosuppressive, and Angiogenic Potentials in Comparison With Haploidentical Maternal Placental Cells.González PL, Carvajal C, Cuenca J, Alcayaga-Miranda F, Figueroa FE, Bartolucci J, Salazar-Aravena L, Khoury M. González PL, et al. Stem Cells Transl Med. 2015 Oct;4(10):1109-21. doi: 10.5966/sctm.2015-0022. Epub 2015 Aug 13. Stem Cells Transl Med. 2015. PMID: 26273064 Free PMC article.
- Fetal membranes as a source of stem cells.Kmiecik G, Niklińska W, Kuć P, Pancewicz-Wojtkiewicz J, Fil D, Karwowska A, Karczewski J, Mackiewicz Z. Kmiecik G, et al. Adv Med Sci. 2013;58(2):185-95. doi: 10.2478/ams-2013-0007. Adv Med Sci. 2013. PMID: 24327530 Review.
- Human Amniotic Mesenchymal Stem Cells Alleviate aGVHD after allo-HSCT by Regulating Interactions between Gut Microbiota and Intestinal Immunity.Bu X, Wang J, Yin Z, Pan W, Liu L, Jin H, Liu Q, Zheng L, Sun H, Gao Y, Ping B. Bu X, et al. Stem Cell Rev Rep. 2023 Mar 4. doi: 10.1007/s12015-023-10522-4. Online ahead of print. Stem Cell Rev Rep. 2023. PMID: 36870009
- Secretion pattern of canine amniotic stem cells derived extracellular vesicles.Karam RG, Motta LCB, de Almeida MF, Bridi A, da Silveira JC, Ambrósio CE. Karam RG, et al. Anim Reprod. 2022 Nov 14;19(4):e20220063. doi: 10.1590/1984-3143-AR2022-0063. eCollection 2022. Anim Reprod. 2022. PMID: 36425401 Free PMC article.
- Mesenchymal stem cells and their microenvironment.Liu J, Gao J, Liang Z, Gao C, Niu Q, Wu F, Zhang L. Liu J, et al. Stem Cell Res Ther. 2022 Aug 20;13(1):429. doi: 10.1186/s13287-022-02985-y. Stem Cell Res Ther. 2022. PMID: 35987711 Free PMC article. Review.
- Significance of Placental Mesenchymal Stem Cell in Placenta Development and Implications for Preeclampsia.Zhang Y, Zhong Y, Zou L, Liu X. Zhang Y, et al. Front Pharmacol. 2022 Jun 1;13:896531. doi: 10.3389/fphar.2022.896531. eCollection 2022. Front Pharmacol. 2022. PMID: 35721156 Free PMC article. Review.
- A comparison of isolation and culture protocols for human amniotic mesenchymal stem cells.Naeem A, Gupta N, Naeem U, Khan MJ, Elrayess MA, Cui W, Albanese C. Naeem A, et al. Cell Cycle. 2022 Aug;21(15):1543-1556. doi: 10.1080/15384101.2022.2060641. Epub 2022 Apr 12. Cell Cycle. 2022. PMID: 35412950
-
- Prockop DJ (1997) Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 276: 71–74. - PubMed
-
- Ishikane S, Ohnishi S, Yamahara K, Sada M, Harada K, et al. (2008) Allogeneic injection of fetal membrane-derived mesenchymal stem cells induces therapeutic angiogenesis in a rat model of hind limb ischemia. Stem Cells 26: 2625–2633. - PubMed
-
- Ishikane S, Yamahara K, Sada M, Harada K, Kodama M, et al. (2010) Allogeneic administration of fetal membrane-derived mesenchymal stem cells attenuates acute myocarditis in rats. J Mol Cell Cardiol 49: 753–761. - PubMed
-
- Tsuda H, Yamahara K, Ishikane S, Otani K, Nakamura A, et al. (2010) Allogenic fetal membrane-derived mesenchymal stem cells contribute to renal repair in experimental glomerulonephritis. Am J Physiol Renal Physiol 299: F1004–1013. - PubMed
- Comparative Study
- Research Support, Non-U.S. Gov't
- Amnion / cytology*
- Animals
- Chorion / cytology*
- Cytoprotection*
- Female
- Hindlimb / blood supply
- Hindlimb / pathology
- Human Umbilical Vein Endothelial Cells / cytology
- Humans
- Immunosuppression Therapy*
- Intercellular Signaling Peptides and Proteins / metabolism
- Ischemia / therapy
- Male
- Mesenchymal Stem Cell Transplantation*
- Mesenchymal Stem Cells / cytology*
- Mesenchymal Stem Cells / metabolism
- Mice
- Mice, Nude
- Myocytes, Cardiac / cytology
- Neovascularization, Physiologic*
- Intercellular Signaling Peptides and Proteins
- Full Text Sources
- Other Literature Sources
- Medical
- Miscellaneous
![Figure 4. Immunosuppressive property of amnion and…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3925106/bin/pone.0088319.g004.jpg)
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Source: PubMed