STEM CELL SIGNALING · Signalling mechanisms in human embryonic stem cells
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2005-12-01 → 2007-11-30
- EU contribution
- €80,000
- Participants
- 1
- Scheme
- IRG
Lines connect the coordinator with its partners. CORDIS does not always give exact coordinates for projects before 2014. These points are placed at city or country level.
Results in brief
Final Activity Report Summary - STEM CELL SIGNALING (Signalling mechanisms in human embryonic stem cells)
Human embryonic stem cells (hESCs) can be maintained undifferentiated (pluripotent) or differentiated to basically all functional cell types, depending on the culture conditions used. Culture of hESCs in the presence of medium conditioned by mouse embryonic fibroblasts (MEFs) can be used to keep hESCs undifferentiated. This observation suggests that MEFs produce factors required for the pluripo tency of hESCs. The data presented here shows that fibroblast growth factor 2 (FGF2) treatment of MEFs is crucial for the production of these factors. To identify the potential factors that are expressed in the presence of FGF2 in MEFs, a global expression profile analysis using microarrays was performed. This analysis indicated that 17 secreted factors are down-regulated in the absence of FGF2. These factors include several ligands for known signalling receptors, extracellular proteases and components of the extracellular matrix that may all be involved in signalling events. Surprisingly, we found that selective blocking of extracellular signal-regulated kinase (ERK) signalling by the MAPK/ERK kinase (MEK) inhibitor U0126 affected the expression of only some of the FGF2-regulated genes, suggesting FGF2-induced pathways that are independent of ERK signalling. It has been shown recently that activation of Activin/Nodal signalling and inhibition of bone morphogenetic protein signalling are required for the maintenance of pluripotency. Accordingly, among the 17 FGF2-regulated genes we found inhibin beta B that can lead to the assembly of Activin B and gremlin 1 that codes for an antagonist of bone morphogenetic proteins. This study identifies potentially important factors involved in the maintenance of pluripotency in hESCs and may allow the development of defined culture conditions without contaminating material from animal cells.
Data: CORDIS, © European Union
Project objective
Human embryonic stem cells (hESCs) have the potential to proliferate indefinitely when maintained undifferentiated in culture, and to differentiate to basically all functional cell types. The molecular mechanisms underlying these biological processes in hE SCs are not well characterized. To maintain these cells undifferentiated in culture they can be cultured on an extra-cellular matrix in the presence of conditioned medium from mouse embryo fibroblasts (MEFs) and fibroblast growth factor-2 (FGF-2). This sugg ests that MEFs produce a factor/s that is/are required for the maintenance of undifferentiated state of hESCs. Further analysis has revealed that treatment of the MEFs with FGF-2 is involved in the production of these factors. A global expression profile analysis using micro-arrays between MEFs treated without or with FGF-2 indicated that around 20 secreted factors are down regulated in the absence of FGF-2. These factors included several ligands for known signaling pathways as well as extra-celluar proteases, which in turn can be involved in the processing of ligands, and components of the extra-cellular matrix, which in turn can be involved in cells matrix interaction and subsequent signalling events. The identification of these factors and the availability of ESTs harbouring their genes will allow us to identify factors required for the undifferentiated state of hESCs and their downstream signalling events. Moreover we have recently shown, that activation of the Activin/Nodal signalling pathway and subsequent activation of the transcription factors Smad2/3 are important for the maintenance of the undifferentiated state. The interaction of the regulation of the Activin/Nodal pathway and the factors secreted by the MEFs upon FGF-2 treatment will reveal important mechanisms that underlie the maintenance of the undifferentiated state of hESCs and will have a major impact in the knowledge of the biology of these cells.
Original text from CORDIS.
Participants
- MAX-DELBRUCK-CENTRUM FUR MOLEKULARE MEDIZIN · BERLINCoordinatorCity levelGermany
Links
Data: CORDIS, © European Union