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IGF-I instructs multipotent adult neural progenitor cells to become oligodendrocytes.

Hsieh J, Aimone JB, Kaspar BK, Kuwabara T, Nakashima K, Gage FH - J. Cell Biol. (2004)

Bottom Line: Oligodendrocyte differentiation by IGF-I appears to be mediated through an inhibition of bone morphogenetic protein signaling.Furthermore, overexpression of IGF-I in the hippocampus leads to an increase in oligodendrocyte markers.These data demonstrate the existence of a single molecule, IGF-I, that can influence the fate choice of multipotent adult neural progenitor cells to an oligodendroglial lineage.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Genetics, The Salk Institute, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.

ABSTRACT
Adult multipotent neural progenitor cells can differentiate into neurons, astrocytes, and oligodendrocytes in the mammalian central nervous system, but the molecular mechanisms that control their differentiation are not yet well understood. Insulin-like growth factor I (IGF-I) can promote the differentiation of cells already committed to an oligodendroglial lineage during development. However, it is unclear whether IGF-I affects multipotent neural progenitor cells. Here, we show that IGF-I stimulates the differentiation of multipotent adult rat hippocampus-derived neural progenitor cells into oligodendrocytes. Modeling analysis indicates that the actions of IGF-I are instructive. Oligodendrocyte differentiation by IGF-I appears to be mediated through an inhibition of bone morphogenetic protein signaling. Furthermore, overexpression of IGF-I in the hippocampus leads to an increase in oligodendrocyte markers. These data demonstrate the existence of a single molecule, IGF-I, that can influence the fate choice of multipotent adult neural progenitor cells to an oligodendroglial lineage.

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IGF-I–mediated increase in oligodendrocyte differentiation is independent of effects on neural progenitor cell survival in 2-d cultures. (A) Treatment of cells with 2 μM Q-VD-OPh resulted in a general absence of apoptosis in short-term cultures. The maintenance of cell survival is shown by a general persistence of cells and a lack of fragmented DAPI-stained nuclei, without obvious effects on cell proliferation or differentiation. Addition of 500 ng/ml IGF-I to the Q-VD-OPh–treated cultures mediated an increase in oligodendrocyte differentiation, as evidenced by O4 staining and morphological criteria. (B) Similar results were seen with RIP. (C) Quantification of O4 and RIP+ oligodendrocytes. Bar, 25 μm.
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fig2: IGF-I–mediated increase in oligodendrocyte differentiation is independent of effects on neural progenitor cell survival in 2-d cultures. (A) Treatment of cells with 2 μM Q-VD-OPh resulted in a general absence of apoptosis in short-term cultures. The maintenance of cell survival is shown by a general persistence of cells and a lack of fragmented DAPI-stained nuclei, without obvious effects on cell proliferation or differentiation. Addition of 500 ng/ml IGF-I to the Q-VD-OPh–treated cultures mediated an increase in oligodendrocyte differentiation, as evidenced by O4 staining and morphological criteria. (B) Similar results were seen with RIP. (C) Quantification of O4 and RIP+ oligodendrocytes. Bar, 25 μm.

Mentions: The severe and rapid death of neural progenitor cells cultured in the absence of IGF-I left open the possibility that FGF-2 withdrawal alone could be promoting oligodendrocyte differentiation and that the addition of IGF-I merely promoted oligodendrocyte survival. To address this issue, we kept neural progenitor cells alive with the broad caspase inhibitor Q-VD-OPh (Caserta et al., 2003), and assessed neural progenitor differentiation with and without IGF-I in 2-d cultures (Fig. 2, A–C). Neural progenitors that differentiated into definitive oligodendrocytes were scored on the basis of morphological criteria (elaboration of weblike processes), as well as immunoreactivity with various oligodendrocyte markers (O4, NG2, RIP, and MBP). In the absence of Q-VD-OPh in insulin-free N2 medium, there was decreased cell survival, evidenced by the presence of fragmented DAPI-stained nuclei and a general disappearance of cells. Addition of 2 μM Q-VD-OPh to the cells promoted the majority of the cells to survive, as seen by smooth DAPI-stained nuclei and a general persistence of cells in 2-d cultures, without obvious effects on proliferation or differentiation (Fig. 2, A and B). The absolute number of cells does not significantly change in Q-VD-OPh-treated cultures compared with cells just after plating (unpublished data). Although the cells exhibited some degree of O4 and RIP staining in the soma, only a small number of cells (∼2–4%) exhibited both staining and morphological criteria indicative of a differentiated oligodendrocyte in Q-VD-OPh–treated cultures. This finding is presumably due to spontaneous differentiation upon FGF-2 withdrawal. In addition, we did not detect MBP staining in Q-VD-OPH–treated cultures, further confirming that FGF-2 withdrawal alone could not promote the robust differentiation and maturation of a multipotent neural progenitor cell into a definitive oligodendrocyte. Only when neural progenitors were cultured with 500 ng/ml IGF-1 did we observe a large increase in O4 and RIP+ cells with the characteristic weblike morphology in 2-d cultures (Fig. 2, A and B). The quantification of oligodendrocyte differentiation is also shown (Fig. 2 C). The presence of NG2+ cells was not observed in Q-VD-OPh–treated cultures, with or without IGF-I, suggesting that adult multipotent neural progenitor cells do not transition through an NG2+ cell upon IGF-I stimulation. These data suggest that IGF-1 can directly induce multipotent neural progenitor cells to differentiate into oligodendrocytes, instead of merely promoting the survival of differentiated oligodendrocytes.


IGF-I instructs multipotent adult neural progenitor cells to become oligodendrocytes.

Hsieh J, Aimone JB, Kaspar BK, Kuwabara T, Nakashima K, Gage FH - J. Cell Biol. (2004)

IGF-I–mediated increase in oligodendrocyte differentiation is independent of effects on neural progenitor cell survival in 2-d cultures. (A) Treatment of cells with 2 μM Q-VD-OPh resulted in a general absence of apoptosis in short-term cultures. The maintenance of cell survival is shown by a general persistence of cells and a lack of fragmented DAPI-stained nuclei, without obvious effects on cell proliferation or differentiation. Addition of 500 ng/ml IGF-I to the Q-VD-OPh–treated cultures mediated an increase in oligodendrocyte differentiation, as evidenced by O4 staining and morphological criteria. (B) Similar results were seen with RIP. (C) Quantification of O4 and RIP+ oligodendrocytes. Bar, 25 μm.
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Related In: Results  -  Collection

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fig2: IGF-I–mediated increase in oligodendrocyte differentiation is independent of effects on neural progenitor cell survival in 2-d cultures. (A) Treatment of cells with 2 μM Q-VD-OPh resulted in a general absence of apoptosis in short-term cultures. The maintenance of cell survival is shown by a general persistence of cells and a lack of fragmented DAPI-stained nuclei, without obvious effects on cell proliferation or differentiation. Addition of 500 ng/ml IGF-I to the Q-VD-OPh–treated cultures mediated an increase in oligodendrocyte differentiation, as evidenced by O4 staining and morphological criteria. (B) Similar results were seen with RIP. (C) Quantification of O4 and RIP+ oligodendrocytes. Bar, 25 μm.
Mentions: The severe and rapid death of neural progenitor cells cultured in the absence of IGF-I left open the possibility that FGF-2 withdrawal alone could be promoting oligodendrocyte differentiation and that the addition of IGF-I merely promoted oligodendrocyte survival. To address this issue, we kept neural progenitor cells alive with the broad caspase inhibitor Q-VD-OPh (Caserta et al., 2003), and assessed neural progenitor differentiation with and without IGF-I in 2-d cultures (Fig. 2, A–C). Neural progenitors that differentiated into definitive oligodendrocytes were scored on the basis of morphological criteria (elaboration of weblike processes), as well as immunoreactivity with various oligodendrocyte markers (O4, NG2, RIP, and MBP). In the absence of Q-VD-OPh in insulin-free N2 medium, there was decreased cell survival, evidenced by the presence of fragmented DAPI-stained nuclei and a general disappearance of cells. Addition of 2 μM Q-VD-OPh to the cells promoted the majority of the cells to survive, as seen by smooth DAPI-stained nuclei and a general persistence of cells in 2-d cultures, without obvious effects on proliferation or differentiation (Fig. 2, A and B). The absolute number of cells does not significantly change in Q-VD-OPh-treated cultures compared with cells just after plating (unpublished data). Although the cells exhibited some degree of O4 and RIP staining in the soma, only a small number of cells (∼2–4%) exhibited both staining and morphological criteria indicative of a differentiated oligodendrocyte in Q-VD-OPh–treated cultures. This finding is presumably due to spontaneous differentiation upon FGF-2 withdrawal. In addition, we did not detect MBP staining in Q-VD-OPH–treated cultures, further confirming that FGF-2 withdrawal alone could not promote the robust differentiation and maturation of a multipotent neural progenitor cell into a definitive oligodendrocyte. Only when neural progenitors were cultured with 500 ng/ml IGF-1 did we observe a large increase in O4 and RIP+ cells with the characteristic weblike morphology in 2-d cultures (Fig. 2, A and B). The quantification of oligodendrocyte differentiation is also shown (Fig. 2 C). The presence of NG2+ cells was not observed in Q-VD-OPh–treated cultures, with or without IGF-I, suggesting that adult multipotent neural progenitor cells do not transition through an NG2+ cell upon IGF-I stimulation. These data suggest that IGF-1 can directly induce multipotent neural progenitor cells to differentiate into oligodendrocytes, instead of merely promoting the survival of differentiated oligodendrocytes.

Bottom Line: Oligodendrocyte differentiation by IGF-I appears to be mediated through an inhibition of bone morphogenetic protein signaling.Furthermore, overexpression of IGF-I in the hippocampus leads to an increase in oligodendrocyte markers.These data demonstrate the existence of a single molecule, IGF-I, that can influence the fate choice of multipotent adult neural progenitor cells to an oligodendroglial lineage.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Genetics, The Salk Institute, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.

ABSTRACT
Adult multipotent neural progenitor cells can differentiate into neurons, astrocytes, and oligodendrocytes in the mammalian central nervous system, but the molecular mechanisms that control their differentiation are not yet well understood. Insulin-like growth factor I (IGF-I) can promote the differentiation of cells already committed to an oligodendroglial lineage during development. However, it is unclear whether IGF-I affects multipotent neural progenitor cells. Here, we show that IGF-I stimulates the differentiation of multipotent adult rat hippocampus-derived neural progenitor cells into oligodendrocytes. Modeling analysis indicates that the actions of IGF-I are instructive. Oligodendrocyte differentiation by IGF-I appears to be mediated through an inhibition of bone morphogenetic protein signaling. Furthermore, overexpression of IGF-I in the hippocampus leads to an increase in oligodendrocyte markers. These data demonstrate the existence of a single molecule, IGF-I, that can influence the fate choice of multipotent adult neural progenitor cells to an oligodendroglial lineage.

Show MeSH
Related in: MedlinePlus