- Letter to the Editor
- Open Access
iPSC-derived mesenchymal stromal cells are less supportive than primary MSCs for co-culture of hematopoietic progenitor cells
- Theresa Vasko†1, 2,
- Joana Frobel†1, 2,
- Richard Lubberich1, 2,
- Tamme W. Goecke3 and
- Wolfgang Wagner1, 2Email author
© Vasko et al. 2016
- Received: 2 March 2016
- Accepted: 13 April 2016
- Published: 21 April 2016
In vitro culture of hematopoietic stem and progenitor cells (HPCs) is supported by a suitable cellular microenvironment, such as mesenchymal stromal cells (MSCs)—but MSCs are heterogeneous and poorly defined. In this study, we analyzed whether MSCs derived from induced pluripotent stem cells (iPS-MSCs) provide a suitable cellular feeder layer too. iPS-MSCs clearly supported proliferation of HPCs, maintenance of a primitive immunophenotype (CD34+, CD133+, CD38-), and colony-forming unit (CFU) potential of CD34+ HPCs. However, particularly long-term culture-initiating cell (LTC-IC) frequency was lower with iPS-MSCs as compared to primary MSCs. Relevant genes for cell-cell interaction were overall expressed at similar level in MSCs and iPS-MSCs, whereas VCAM1 was less expressed in the latter. In conclusion, our iPS-MSCs support in vitro culture of HPCs; however, under the current differentiation and culture conditions, they are less suitable than primary MSCs from bone marrow.
- Mesenchymal Stromal Cell
- Publish Gene Expression
- Carboxyfluorescein Succinimidyl Ester
- Stromal Support
- Hematopoietic Stem Cell Niche
We assessed the CFU frequency in freshly isolated HPCs or upon culture-expansion for 7 days: without stromal support, there was no expansion of CFUs, whereas CFU frequency was significantly increased under co-culture conditions with MSCs or iPS-MSCs (Fig. 1d). CFU frequency was not significantly affected if HPCs were co-cultured either with MSCs or iPS-MSCs, and there was no bias towards specific types of colonies (Fig. 1d). However, if HPCs were cultured for 5 weeks in a long-term culture-initiating cell (LTC-IC) assay , different hematopoiesis supporting capacities of MSCs and iPS-MSCs became evident: long-term culture of HPCs gave rise to a significantly higher number of colonies on MSCs compared to iPS-MSCs (Fig. 1e).
Taken together, our iPS-MSCs provide a less hematopoiesis supportive microenvironment than primary MSCs, particularly after long-term co-culture. This tendency was not observed in a recent study by Moslem et al. , but these authors did not test for maintenance of LTC-ICs. It is conceivable that optimized differentiation procedures of iPSCs towards cellular components of the hematopoietic stem cell niche as well as 3D-culture systems will further enhance stromal support to ultimately facilitate in vitro expansion of HPCs.
This work was supported by the Else Kröner-Fresenius Stiftung (2014_A193), by the German Research Foundation (WA/1706/2-1), and by the Interdisciplinary Center for Clinical Research (IZKF) in the Faculty of Medicine at the RWTH Aachen University (O1-1).
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Frobel J, Hemeda H, Lenz M, Abagnale G, Joussen S, Denecke B, Saric T, Zenke M, Wagner W. Epigenetic rejuvenation of mesenchymal stromal cells derived from induced pluripotent stem cells. Stem Cell Reports. 2014;3:414–22.View ArticlePubMedPubMed CentralGoogle Scholar
- Walenda T, Bork S, Horn P, Wein F, Saffrich R, Diehlmann A, Eckstein V, Ho AD, Wagner W. Co-culture with mesenchymal stromal cells increases proliferation and maintenance of hematopoietic progenitor cells. J Cell Mol Med. 2010;14:337–50.View ArticlePubMedPubMed CentralGoogle Scholar
- Jing D, Fonseca AV, Alakel N, Fierro FA, Muller K, Bornhauser M, Ehninger G, Corbeil D, Ordemann R. Hematopoietic stem cells in co-culture with mesenchymal stromal cells—modeling the niche compartments in vitro. Haematologica. 2010;95:542–50.View ArticlePubMedPubMed CentralGoogle Scholar
- Wagner W, Saffrich R, Wirkner U, Eckstein V, Blake J, Ansorge A, Schwager C, Wein F, Miesala K, Ansorge W, Ho AD. Hematopoietic progenitor cells and cellular microenvironment: behavioral and molecular changes upon interaction. Stem Cells. 2005;23:1180–91.View ArticlePubMedGoogle Scholar
- Wein F, Pietsch L, Saffrich R, Wuchter P, Walenda T, Bork S, Horn P, Diehlmann A, Eckstein V, Ho AD, Wagner W. N-cadherin is expressed on human hematopoietic progenitor cells and mediates interaction with human mesenchymal stromal cells. Stem Cell Res. 2010;4:129–39.View ArticlePubMedGoogle Scholar
- Wagner W, Ansorge A, Wirkner U, Eckstein V, Schwager C, Blake J, Miesala K, Selig J, Saffrich R, Ansorge W, Ho AD. Molecular evidence for stem cell function of the slow-dividing fraction among human hematopoietic progenitor cells by genome-wide analysis. Blood. 2004;104:675–86.View ArticlePubMedGoogle Scholar
- Giebel B, Corbeil D, Beckmann J, Hohn J, Freund D, Giesen K, Fischer J, Kogler G, Wernet P. Segregation of lipid raft markers including CD133 in polarized human hematopoietic stem and progenitor cells. Blood. 2004;104:2332–8.View ArticlePubMedGoogle Scholar
- Charbord P, Oostendorp R, Pang W, Herault O, Noel F, Tsuji T, Dzierzak E, Peault B. Comparative study of stromal cell lines derived from embryonic, fetal, and postnatal mouse blood-forming tissues. Exp Hematol. 2002;30:1202–10.View ArticlePubMedGoogle Scholar
- Wagner W, Roderburg C, Wein F, Diehlmann A, Frankhauser M, Schubert R, Eckstein V, Ho AD. Molecular and secretory profiles of human mesenchymal stromal cells and their abilities to maintain primitive hematopoietic progenitors. Stem Cells. 2007;10:2638–57.View ArticleGoogle Scholar
- Mabuchi Y, Morikawa S, Harada S, Niibe K, Suzuki S, Renault-Mihara F, Houlihan DD, Akazawa C, Okano H, Matsuzaki Y. LNGFR(+)THY-1(+)VCAM-1(hi+) cells reveal functionally distinct subpopulations in mesenchymal stem cells. Stem Cell Reports. 2013;1:152–65.View ArticlePubMedPubMed CentralGoogle Scholar
- Yang ZX, Han ZB, Ji YR, Wang YW, Liang L, Chi Y, Yang SG, Li LN, Luo WF, Li JP, Chen DD, Du WJ, Cao XC, Zhuo GS, Wang T, Han ZC. CD106 identifies a subpopulation of mesenchymal stem cells with unique immunomodulatory properties. PLoS One. 2013;8:e59354.View ArticlePubMedPubMed CentralGoogle Scholar
- Moslem M, Eberle I, Weber I, Henschler R, Cantz T. Mesenchymal stem/stromal cells derived from induced pluripotent stem cells support CD34(pos) hematopoietic stem cell propagation and suppress inflammatory reaction. Stem Cells Int. 2015;2015:843058.View ArticlePubMedPubMed CentralGoogle Scholar