Full Text:   <2950>

CLC number: Q27

On-line Access: 2010-01-06

Received: 2010-03-06

Revision Accepted: 2010-06-04

Crosschecked: 2010-12-12

Cited: 12

Clicked: 6681

Citations:  Bibtex RefMan EndNote GB/T7714

-   Go to

Article info.
1. Reference List
Open peer comments

Journal of Zhejiang University SCIENCE B 2011 Vol.12 No.1 P.18-27


Immunomodulative effects of mesenchymal stem cells derived from human embryonic stem cells in vivo and in vitro

Author(s):  Zhou Tan, Zhong-yuan Su, Rong-rong Wu, Bin Gu, Yu-kan Liu, Xiao-li Zhao, Ming Zhang

Affiliation(s):  Institute of Cell Biology and Genetics, College of Life Sciences, Zhejiang University, Hangzhou 310058, China, Institute of Developmental and Regenerative Biology, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China

Corresponding email(s):   zhangming_ls@zju.edu.cn

Key Words:  Human embryonic stem cells, Mesenchymal stem cells, Differentiation, Immunomodulative effects

Zhou Tan, Zhong-yuan Su, Rong-rong Wu, Bin Gu, Yu-kan Liu, Xiao-li Zhao, Ming Zhang. Immunomodulative effects of mesenchymal stem cells derived from human embryonic stem cells in vivo and in vitro[J]. Journal of Zhejiang University Science B, 2011, 12(1): 18-27.

@article{title="Immunomodulative effects of mesenchymal stem cells derived from human embryonic stem cells in vivo and in vitro",
author="Zhou Tan, Zhong-yuan Su, Rong-rong Wu, Bin Gu, Yu-kan Liu, Xiao-li Zhao, Ming Zhang",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Immunomodulative effects of mesenchymal stem cells derived from human embryonic stem cells in vivo and in vitro
%A Zhou Tan
%A Zhong-yuan Su
%A Rong-rong Wu
%A Bin Gu
%A Yu-kan Liu
%A Xiao-li Zhao
%A Ming Zhang
%J Journal of Zhejiang University SCIENCE B
%V 12
%N 1
%P 18-27
%@ 1673-1581
%D 2011
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1000074

T1 - Immunomodulative effects of mesenchymal stem cells derived from human embryonic stem cells in vivo and in vitro
A1 - Zhou Tan
A1 - Zhong-yuan Su
A1 - Rong-rong Wu
A1 - Bin Gu
A1 - Yu-kan Liu
A1 - Xiao-li Zhao
A1 - Ming Zhang
J0 - Journal of Zhejiang University Science B
VL - 12
IS - 1
SP - 18
EP - 27
%@ 1673-1581
Y1 - 2011
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B1000074

Objective: human embryonic stem cells (hESCs) have recently been reported as an unlimited source of mesenchymal stem cells (MSCs). The present study not only provides an identical and clinically compliant MSC source derived from hESCs (hESC-MSCs), but also describes the immunomodulative effects of hESC-MSCs in vitro and in vivo for a carbon tetrachloride (CCl4)-induced liver inflammation model. Methods: Undifferentiated hESCs were treated with Rho-associated kinase (ROCK) inhibitor and induced to fibroblast-looking cells. These cells were tested for their surface markers and multilineage differentiation capability. Further more, we analyzed their immune characteristics by mixed lymphocyte reactions (MLRs) and animal experiments. Results: hESC-MSCs show a homogenous fibroblastic morphology that resembles bone marrow-derived MSCs (BM-MSCs). The cell markers and differentiation potential of hESC-MSCs are also similar to those of BM-MSCs. Unlike their original cells, hESC-MSCs possess poor immunogenicity and can survive and be engrafted into a xenogenic immunocompetent environment. Conclusions: The hESC-MSCs demonstrate strong inhibitory effects on lymphocyte proliferation in vitro and anti-inflammatory infiltration properties in vivo. This study offers information essential to the applications of hESC-MSC-based therapies and evidence for the therapeutic mechanisms of action.

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1]Azpiroz, A., Fano, E., Garmendia, L., Arregi, A., Cacho, R., Beitia, G., Brain, P.F., 1999. Effects of chronic mild stress (CMS) and imipramine administration, on spleen mononuclear cell proliferative response, serum corticosterone level and brain norepinephrine content in male mice. Psychoneuroendocrinology, 24(3):345-361.

[2]Barberi, T., Willis, L.M., Socci, N.D., Studer, L., 2005. Derivation of multipotent mesenchymal precursors from human embryonic stem cells. PLoS Med., 2(6):e161.

[3]Bartholomew, A., Sturgeon, C., Siatskas, M., Ferrer, K., McIntosh, K., Patil, S., Hardy, W., Devine, S., Ucker, D., Deans, R., et al., 2002. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp. Hematol., 30(1):42-48.

[4]Bruder, S.P., Kurth, A.A., Shea, M., Hayes, W.C., Jaiswal, N., Kadiyala, S., 1998. Bone regeneration by implantation of purified, culture-expanded human mesenchymal stem cells. J. Orthop. Res., 16(2):155-162.

[5]Campagnoli, C., Roberts, I.A., Kumar, S., Bennett, P.R., Bellantuono, I., Fisk, N.M., 2001. Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood, 98(8):2396-2402.

[6]Carpenter, M., Inokuma, M., Denham, J., Mujtaba, T., Chiu, C.P., Rao, M., 2001. Enrichment of neurons and neural precursors from human embryonic stem cells. Exp. Neurol., 172(2):383-397.

[7]Chen, X., Song, X.H., Yin, Z., Zou, X.H., Wang, L.L., Hu, H., Cao, T., Zheng, M., Ouyang, H.W., 2009. Stepwise differentiation of human embryonic stem cells promotes tendon regeneration by secreting fetal tendon matrix and differentiation factors. Stem Cells, 27(6):1276-1287.

[8]Corcione, A., Benvenuto, F., Ferretti, E., Giunti, D., Cappiello, V., Cazzanti, F., Risso, M., Gualandi, F., Mancardi, G.L., Pistoia, V., et al., 2006. Human mesenchymal stem cells modulate B-cell functions. Blood, 107(1):367-372.

[9]da Silva Meirelles, L., Chagastelles, P.C., Nardi, N.B., 2006. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J. Cell Sci., 119(11):2204-2213.

[10]di Nicola, M., Carlo-Stella, C., Magni, M., Milanesi, M., Longoni, P.D., Matteucci, P., Grisanti, S., Gianni, A.M., 2002. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood, 99(10):3838-3843.

[11]Friedenstein, A.J., Chailakhyan, R.K., Latsinik, N.V., Panasyuk, A.F., Keiliss-Borok, I.V., 1974. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation, 17(4):331-340.

[12]Grinnemo, K.H., Kumagai-Braesch, M., Mansson-Broberg, A., Skottman, H., Hao, X., Siddiqui, A., Andersson, A., Stromberg, A.M., Lahesmaa, R., Hovatta, O., et al., 2006. Human embryonic stem cells are immunogenic in allogeneic and xenogeneic settings. Reprod. Biomed. Online, 13(5):712-724.

[13]Haynesworth, S.E., Goshima, J., Goldberg, V.M., Caplan, A.I., 1992. Characterization of cells with osteogenic potential from human marrow. Bone, 13(1):81-88.

[14]Hwang, N.S., Varghese, S., Lee, H.J., Zhang, Z., Ye, Z., Bae, J., Cheng, L., Elisseeff, J., 2008. In vivo commitment and functional tissue regeneration using human embryonic stem cell-derived mesenchymal cells. PNAS, 105(52):20641-20646.

[15]in′t Anker, P.S., Noort, W.A., Scherjon, S.A., Kleijburg-van der Keur, C., Kruisselbrink, A.B., van Bezooijen, R.L., Beekhuizen, W., Willemze, R., Kanhai, H.H., Fibbe, W.E., 2003. Mesenchymal stem cells in human second-trimester bone marrow, liver, lung, and spleen exhibit a similar immunophenotype but a heterogeneous multilineage differentiation potential. Haematologica, 88(8):845-852.

[16]Karlsson, C., Emanuelsson, K., Wessberg, F., Kajic, K., Axell, M.Z., Eriksson, P.S., Lindahl, A., Hyllner, J., Strehl, R., 2009. Human embryonic stem cell-derived mesenchymal progenitors—potential in regenerative medicine. Stem Cell Res., 3(1):39-50.

[17]Kehat, I., Amit, M., Gepstein, A., Huber, I., Itskovitz-Eldor, J., Gepstein, L., 2003. Development of cardiomyocytes from human ES cells. Methods Enzymol., 365(2):461-473.

[18]Klyushnenkova, E., Mosca, J.D., Zernetkina, V., Majumdar, M.K., Beggs, K.J., Simonetti, D.W., Deans, R.J., McIntosh, K.R., 2005. T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression. J. Biomed. Sci., 12(1):47-57.

[19]Koç, O.N., Day, J., Nieder, M., Gerson, S.L., Lazarus, H.M., Krivit, W., 2002. Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH). Bone Marrow Transplant., 30(4):215-222.

[20]Lavon, N., Yanuka, O., Benvenisty, N., 2004. Differentiation and isolation of hepatic-like cells from human embryonic stem cells. Differentiation, 72(5):230-238.

[21]le Blanc, K., Tammik, L., Sundberg, B., Haynesworth, S.E., Ringdén, O., 2003. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand. J. Immunol., 57(1):11-20.

[22]Lian, Q., Lye, E., Suan Yeo, K., Khia Way Tan, E., Salto-Tellez, M., Liu, T.M., Palanisamy, N., El Oakley, R.M., Lee, E.H., Lim, B., et al., 2007. Derivation of clinically compliant MSCs from CD105+, CD24 differentiated human ESCs. Stem Cells, 25(2):425-436.

[23]Liechty, K.W., MacKenzie, T.C., Shaaban, A.F., Radu, A., Moseley, A.M., Deans, R., Marshak, D.R., Flake, A.W., 2000. Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep. Nat. Med., 6(11):1282-1286.

[24]Mishra, P.K., 2008. Bone marrow-derived mesenchymal stem cells for treatment of heart failure: is it all paracrine actions and immunomodulation? J. Cardiovasc. Med. (Hagerstown), 9(2):122-128.

[25]Niemeyer, P., Vohrer, J., Schmal, H., Kasten, P., Fellenberg, J., Suedkamp, N.P., Mehlhorn, A.T., 2008. Survival of human mesenchymal stromal cells from bone marrow and adipose tissue after xenogenic transplantation in immunocompetent mice. Cytotherapy, 10(8):784-795.

[26]Olivier, E.N., Rybicki, A.C., Bouhassira, E.E., 2006. Differentiation of human embryonic stem cells into bipotent mesenchymal stem cells. Stem Cells, 24(8):1914-1922.

[27]Pittenger, M.F., Mackay, A.M., Beck, S.C., Jaiswal, R.K., Douglas, R., Mosca, J.D., Moorman, M.A., Simonetti, D.W., Craig, S., Marshak, D.R., 1999. Multilineage potential of adult human mesenchymal stem cells. Science, 284(5411):143-147.

[28]Rao, M.S., Mattson, M.P., 2001. Stem cells and aging: expanding the possibilities. Mech. Ageing Dev., 122(7):713-734.

[29]Ringdén, O., Uzunel, M., Rasmusson, I., Remberger, M., Sundberg, B., Lönnies, H., Marschall, H.U., Dlugosz, A., Szakos, A., Hassan, Z., et al., 2006. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation, 81(10):1390-1397.

[30]Ryan, J.M., Barry, F.P., Murphy, J.M., Mahon, B.P., 2005. Mesenchymal stem cells avoid allogeneic rejection. J. Inflamm., 2(1):8.

[31]Sabatini, F., Petecchia, L., Tavian, M., Jodon de Villeroche, V., Rossi, G.A., Brouty-Boye, D., 2005. Human bronchial fibroblasts exhibit a mesenchymal stem cell phenotype and multilineage differentiating potentialities. Lab. Invest., 85(8):962-971.

[32]Sakaida, I., Terai, S., Yamamoto, N., Aoyama, K., Ishikawa, T., Nishina, H., Okita, K., 2004. Transplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice. Hepatology, 40(6):1304-1311.

[33]Seeberger, K.L., Dufour, J.M., Shapiro, A.M., Lakey, J.R., Rajotte, R.V., Korbutt, G.S., 2006. Expansion of mesenchymal stem cells from human pancreatic ductal epithelium. Lab. Invest., 86(2):141-153.

[34]Spaggiari, G.M., Capobianco, A., Abdelrazik, H., Becchetti, F., Mingari, M.C., Moretta, L., 2008. Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood, 111(3):1327-1333.

[35]Thomson, J.A., Itskovitz-Eldor, J., Shapiro, S.S., Waknitz, M.A., Swiergiel, J.J., Marshall, V.S., Jones, J.M., 1998. Embryonic stem cell lines derived from human blastocysts. Science, 282(5391):1145-1147.

[36]Toma, C., Pittenger, M.F., Cahill, K.S., Byrne, B.J., Kessler, P.D., 2002. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation, 105(1):93-98.

[37]Trivedi, P., Hematti, P., 2008. Derivation and immunological characterization of mesenchymal stromal cells from human embryonic stem cells. Exp. Hematol., 36(3):350-359.

[38]Tse, W.T., Pendleton, J.D., Beyer, W.M., Egalka, M.C., Guinan, E.C., 2003. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation, 75(3):389-397.

[39]Wang, X.J., Li, Q.P., 2007. The roles of mesenchymal stem cells (MSCs) therapy in ischemic heart diseases. Biochem. Biophys. Res. Commun., 359(2):189-193.

[40]Watanabe, K., Ueno, M., Kamiya, D., Nishiyama, A., Matsumura, M., Wataya, T., Takahashi, J.B., Nishikawa, S., Nishikawa, S., Muguruma, K., et al., 2007. A ROCK inhibitor permits survival of dissociated human embryonic stem cells. Nat. Biotechnol., 25(6):681-686.

[41]Yen, B.L., Chang, C.J., Liu, K.J., Chen, Y.C., Hu, H.I., Bai, C.H., Yen, M.L., 2009. Brief report—human embryonic stem cell-derived mesenchymal progenitors possess strong immunosuppressive effects toward natural killer cells as well as T lymphocytes. Stem Cells, 27(2):451-456.

Open peer comments: Debate/Discuss/Question/Opinion


Please provide your name, email address and a comment

Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2024 Journal of Zhejiang University-SCIENCE