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Combined microarray analysis uncovers self-renewal related signaling in mouse embryonic stem cells.

Zhu H, Yang H, Owen MR - Syst Synth Biol (2008)

Bottom Line: Albeit the expression of individual genes in signaling pathways was not noticeably different between cells cultivated with and without LIF, at gene-set level the expression of ERK/MAPK (but not JAK/STAT) and cell cycle related genes was found significantly enriched in cells cultivated with LIF.When data at the first 7 time points were compared with data at the last 4 time points, the expression of several cell cycle related gene sets was apparently enriched in all three cell lines, indicating the active cell proliferation in the first 2 days.When that mechanism weakens, cell differentiation begins.

View Article: PubMed Central - PubMed

Affiliation: Center for Mathematical Medicine and Biology, School of Mathematical Sciences, University of Nottingham, Nottingham, NG7 2RD, UK, Hao.Zhu@nottingham.ac.uk.

ABSTRACT
Due to the limited understanding of self-renewal and pluripotency related signaling in stem cells, extracting information from genome-wide expression data is not only important but also challenging. With the combined use of two methods, we analyzed a set of microarray data at 11 time points from three mouse embryonic stem cell lines cultivated with and without leukemia inhibitory factor (LIF) for 14 days. Albeit the expression of individual genes in signaling pathways was not noticeably different between cells cultivated with and without LIF, at gene-set level the expression of ERK/MAPK (but not JAK/STAT) and cell cycle related genes was found significantly enriched in cells cultivated with LIF. This indicates that the Ras/Raf/ERK pathway, in addition to JAK/STAT, may also be a key player to carry on external LIF signal into mouse embryonic stem cells to promote self-renewal. When data at the first 7 time points were compared with data at the last 4 time points, the expression of several cell cycle related gene sets was apparently enriched in all three cell lines, indicating the active cell proliferation in the first 2 days. Compared with the slight decay of Oct4/Nanog/Sox2 during the 14 days, the expression of cell differentiation genes such as Gata4/6 underwent a drastic increase, which indicates that the upregulated expression of cell differentiation genes may better reflect the loss of self renewal than the down regulated expression of the stemness indicators Oct4, Sox2 and Nanog. Apart from differential expression and gene set enrichment analyses, a clustering algorithm was also used to classify genes into co-expression clusters. The possible regulation of two clusters, whose expression was most changed during cell culture from very low to very high, was explored. The drastic changes of these genes, including Slc39a8 which was a potential indicator of cell differentiation, in contrast the slight changes of self-renewal genes, imply that differentiation may be the default fate of stem cells and self-renewal may rely on a maintenance mechanism. When that mechanism weakens, cell differentiation begins.

No MeSH data available.


Related in: MedlinePlus

Two pathways, JAK/STAT and Ras/Raf/ERK, both carry the external LIF signal into mES stem cells to promote cell proliferation and self-renewal
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Fig4: Two pathways, JAK/STAT and Ras/Raf/ERK, both carry the external LIF signal into mES stem cells to promote cell proliferation and self-renewal

Mentions: Persistent self-renewal is a common feature of both stem cells and cancer cells, although whether they employ common mechanisms to implement self-renewal is not clear. There exist extrinsic and intrinsic mechanisms that work in parallel to promote stem cell self-renewal. In mouse embryonic stem (mES) cells leukemia inhibitory factor (LIF), through the LIF receptor (LIFR) and gp130, activates the JAK/STAT pathway (Smith et al. 1988; Williams et al. 1988; Yoshida et al. 1994; Niwa et al. 1998) (Fig. 4). Afterwards the phosphorylated and dimerized STAT3 is translocated to the nucleus to stimulate self-renewal gene expression. In human embryonic stem (hES) cells, however, LIF appears not to function but ligands of the fibroblast growth factor (FGF) family are required (Thomson et al. 1998; Amit et al. 2000; Daheron et al. 2004). On the other hand, the intrinsic mechanisms, centered at Nanog and Oct4, are more conserved in species and independent of STAT3 (Chambers et al. 2003; Mitsui et al. 2003; Catena et al. 2004; Okumura-Nakanishi et al. 2005). Apart from these extra- and intra-cellular factors, their downstream targets and signaling processes are important. Recent studies reveal that the JAK/STAT pathway may not be the sole player in self-renewal signaling in mES. In the complete absence of LIF, self-renewal is not abolished and undifferentiated mES cell colonies are still obtained (Dani et al. 1998). The possible mechanism is that a co-cultivated, differentiated, and LIF-deficient cell line provides a paracrine factor supporting mES self-renewal. Moreover, intrinsic self-renewal factors like Nanog and Oct4 may play a more fundamental role than extrinsic factors such as LIF and FGF. To reveal how these and other possible genes and pathways, collaborative with or independent of JAK/STAT, contribute to self-renewal of stem cells under different conditions is important for the understanding of stem cell self-renewal mechanisms.


Combined microarray analysis uncovers self-renewal related signaling in mouse embryonic stem cells.

Zhu H, Yang H, Owen MR - Syst Synth Biol (2008)

Two pathways, JAK/STAT and Ras/Raf/ERK, both carry the external LIF signal into mES stem cells to promote cell proliferation and self-renewal
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2553326&req=5

Fig4: Two pathways, JAK/STAT and Ras/Raf/ERK, both carry the external LIF signal into mES stem cells to promote cell proliferation and self-renewal
Mentions: Persistent self-renewal is a common feature of both stem cells and cancer cells, although whether they employ common mechanisms to implement self-renewal is not clear. There exist extrinsic and intrinsic mechanisms that work in parallel to promote stem cell self-renewal. In mouse embryonic stem (mES) cells leukemia inhibitory factor (LIF), through the LIF receptor (LIFR) and gp130, activates the JAK/STAT pathway (Smith et al. 1988; Williams et al. 1988; Yoshida et al. 1994; Niwa et al. 1998) (Fig. 4). Afterwards the phosphorylated and dimerized STAT3 is translocated to the nucleus to stimulate self-renewal gene expression. In human embryonic stem (hES) cells, however, LIF appears not to function but ligands of the fibroblast growth factor (FGF) family are required (Thomson et al. 1998; Amit et al. 2000; Daheron et al. 2004). On the other hand, the intrinsic mechanisms, centered at Nanog and Oct4, are more conserved in species and independent of STAT3 (Chambers et al. 2003; Mitsui et al. 2003; Catena et al. 2004; Okumura-Nakanishi et al. 2005). Apart from these extra- and intra-cellular factors, their downstream targets and signaling processes are important. Recent studies reveal that the JAK/STAT pathway may not be the sole player in self-renewal signaling in mES. In the complete absence of LIF, self-renewal is not abolished and undifferentiated mES cell colonies are still obtained (Dani et al. 1998). The possible mechanism is that a co-cultivated, differentiated, and LIF-deficient cell line provides a paracrine factor supporting mES self-renewal. Moreover, intrinsic self-renewal factors like Nanog and Oct4 may play a more fundamental role than extrinsic factors such as LIF and FGF. To reveal how these and other possible genes and pathways, collaborative with or independent of JAK/STAT, contribute to self-renewal of stem cells under different conditions is important for the understanding of stem cell self-renewal mechanisms.

Bottom Line: Albeit the expression of individual genes in signaling pathways was not noticeably different between cells cultivated with and without LIF, at gene-set level the expression of ERK/MAPK (but not JAK/STAT) and cell cycle related genes was found significantly enriched in cells cultivated with LIF.When data at the first 7 time points were compared with data at the last 4 time points, the expression of several cell cycle related gene sets was apparently enriched in all three cell lines, indicating the active cell proliferation in the first 2 days.When that mechanism weakens, cell differentiation begins.

View Article: PubMed Central - PubMed

Affiliation: Center for Mathematical Medicine and Biology, School of Mathematical Sciences, University of Nottingham, Nottingham, NG7 2RD, UK, Hao.Zhu@nottingham.ac.uk.

ABSTRACT
Due to the limited understanding of self-renewal and pluripotency related signaling in stem cells, extracting information from genome-wide expression data is not only important but also challenging. With the combined use of two methods, we analyzed a set of microarray data at 11 time points from three mouse embryonic stem cell lines cultivated with and without leukemia inhibitory factor (LIF) for 14 days. Albeit the expression of individual genes in signaling pathways was not noticeably different between cells cultivated with and without LIF, at gene-set level the expression of ERK/MAPK (but not JAK/STAT) and cell cycle related genes was found significantly enriched in cells cultivated with LIF. This indicates that the Ras/Raf/ERK pathway, in addition to JAK/STAT, may also be a key player to carry on external LIF signal into mouse embryonic stem cells to promote self-renewal. When data at the first 7 time points were compared with data at the last 4 time points, the expression of several cell cycle related gene sets was apparently enriched in all three cell lines, indicating the active cell proliferation in the first 2 days. Compared with the slight decay of Oct4/Nanog/Sox2 during the 14 days, the expression of cell differentiation genes such as Gata4/6 underwent a drastic increase, which indicates that the upregulated expression of cell differentiation genes may better reflect the loss of self renewal than the down regulated expression of the stemness indicators Oct4, Sox2 and Nanog. Apart from differential expression and gene set enrichment analyses, a clustering algorithm was also used to classify genes into co-expression clusters. The possible regulation of two clusters, whose expression was most changed during cell culture from very low to very high, was explored. The drastic changes of these genes, including Slc39a8 which was a potential indicator of cell differentiation, in contrast the slight changes of self-renewal genes, imply that differentiation may be the default fate of stem cells and self-renewal may rely on a maintenance mechanism. When that mechanism weakens, cell differentiation begins.

No MeSH data available.


Related in: MedlinePlus