Journal
STEM CELLS AND DEVELOPMENT
Volume 21, Issue 9, Pages 1549-1558Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/scd.2011.0400
Keywords
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Funding
- Innovation and Science Department of the Junta de Andalucia [P08-CTS-3678]
- FIS/FEDER [PI10/00449, PI061267, PS09/02454]
- MICINN [PLE-2009-0111]
- Spanish Association Against Cancer [CI110023]
- Instituto de Salud Carlos III [CP07/00059, CP09/0063, CP09/00228]
- Marie Curie IIF [PIIF-GA-2009236430]
- CSIC [2008201172]
- Community of Asturias [FICYT IB09-106]
- lUOPA-Obra Social Cajastur
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The realization of human embryonic stem cells (hESC) as a model for human developmental hematopoiesis and in potential cell replacement strategies relies on an improved understanding of the extrinsic and intrinsic factors regulating hematopoietic-specific hESC differentiation. Human mesenchymal stem cells (hMSCs) are multipotent cells of mesodermal origin that form a part of hematopoietic stem cell niches and have an important role in the regulation of hematopoiesis through production of secreted factors and/or cell-to-cell interactions. We have previously shown that hESCs may be successfully maintained feeder free using hMSC-conditioned media (MSC-CM). Here, we hypothesized that hESCs maintained in MSC-CM may be more prone to differentiation toward hematopoietic lineage than hESCs grown in standard human foreskin fibroblast-conditioned media. We report that specification into hemogenic progenitors and subsequent hematopoietic differentiation and clonogenic progenitor capacity is robustly enhanced in hESC lines maintained in MSC-CM. Interestingly, co-culture of hESCs on hMSCs fully abrogates hematopoietic specification of hESCs, thus suggesting that the improved hematopoietic differentiation is mediated by MSC-secreted factors rather than by MSC-hESC physical interactions. To investigate the molecular mechanism involved in this process, we analyzed global (LINE-1) methylation and genome-wide promoter DNA methylation. hESCs grown in MSC-CM showed a decrease of 17% in global DNA methylation and a promoter DNA methylation signature consisting of 45 genes commonly hypomethylated and 102 genes frequently hypermethylated. Our data indicate that maintenance of hESCs in MSC-CM robustly augments hematopoietic specification and that the process seems mediated by MSC-secreted factors conferring a DNA methylation signature to undifferentiated hESCs which may influence further predisposition toward hematopoietic specification.
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