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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–induced differentiation of multipotent neural progenitor cells. (A) Adult hippocampus-derived neural progenitor cells cultured in insulin-containing N2 media with 20 ng/ml FGF-2 (undifferentiated), 1 μM RA, and 1% FBS for 4 d (mixed), 1 μM RA and 5 μM forskolin for 4 d (neuronal), or 50 ng/ml leukemia inhibitory factor and 50 ng/ml BMP2 for 6 d (astrocytic). Cells were stained for markers for neurons (Tuj1), astrocytes (GFAP), or oligodendrocytes (RIP), and also with DAPI. Bar, 50 μm. (B) Differentiation of neural progenitor cells in insulin-free N2 media without IGF-I (control) or with IGF-I for 4 d. Insets show cells of typical oligodendrocyte morphology stained with RIP or MBP. Bar, 25 μm. (C) Quantification of cells in either proliferating or differentiating conditions. (D) Quantification of cultures grown in insulin-free N2 media (control) or treated with 500 ng/ml IGF-I, IGF-II, or insulin after 4 d. (E) Quantification of cells in response to different doses of IGF-I (20–500 ng/ml) in 4-d cultures. All data shown are from at least three experiments in parallel cultures with error bars representing SDs. Significant differences are indicated with an asterisk (P < 0.005).
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fig1: IGF-I–induced differentiation of multipotent neural progenitor cells. (A) Adult hippocampus-derived neural progenitor cells cultured in insulin-containing N2 media with 20 ng/ml FGF-2 (undifferentiated), 1 μM RA, and 1% FBS for 4 d (mixed), 1 μM RA and 5 μM forskolin for 4 d (neuronal), or 50 ng/ml leukemia inhibitory factor and 50 ng/ml BMP2 for 6 d (astrocytic). Cells were stained for markers for neurons (Tuj1), astrocytes (GFAP), or oligodendrocytes (RIP), and also with DAPI. Bar, 50 μm. (B) Differentiation of neural progenitor cells in insulin-free N2 media without IGF-I (control) or with IGF-I for 4 d. Insets show cells of typical oligodendrocyte morphology stained with RIP or MBP. Bar, 25 μm. (C) Quantification of cells in either proliferating or differentiating conditions. (D) Quantification of cultures grown in insulin-free N2 media (control) or treated with 500 ng/ml IGF-I, IGF-II, or insulin after 4 d. (E) Quantification of cells in response to different doses of IGF-I (20–500 ng/ml) in 4-d cultures. All data shown are from at least three experiments in parallel cultures with error bars representing SDs. Significant differences are indicated with an asterisk (P < 0.005).

Mentions: First, we tested the action of exogenous IGF-I on the differentiation of hippocampus-derived adult neural progenitor cells. These neural progenitor cells have stem cell properties in vitro: (1) they self-renew in the presence of basic FGF-2; (2) single genetically marked clones can differentiate into all three main CNS cell types in vitro (neurons, oligodendrocytes, and astrocytes) and when grafted back to adult hippocampus in vivo; and (3) they express progenitor cell markers such as nestin, but lack markers of lineage-specific differentiation (Fig. 1 A; Gage et al., 1995; Palmer et al., 1997). To confirm that the adult neural progenitor cell population in our model system is indeed multipotent, we first used various standard differentiation paradigms and evaluated the expression of lineage markers. Differentiation with 1 μM retinoic acid (RA) and 1% FBS resulted in mixed numbers of Tuj1+ neurons, GFAP+ astrocytes, and RIP+ oligodendrocytes (Fig. 1 A). Neuron-enriched differentiation can be achieved with 1 μM RA and 5 μM forskolin (Chu, V., personal communication), and astrocyte-enriched differentiation with 50 ng/ml leukemia inhibitory factor and 50 ng/ml BMP2 (Fig. 1 A; Nakashima et al., 1999). The quantification of lineage-specific differentiation is also shown (Fig. 1 C). These results are in agreement with previous reports (Palmer et al., 1997), and indicate that the majority of the adult neural progenitor cells within the bulk population are multipotent progenitors, and not restricted neuronal or glial progenitors.


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–induced differentiation of multipotent neural progenitor cells. (A) Adult hippocampus-derived neural progenitor cells cultured in insulin-containing N2 media with 20 ng/ml FGF-2 (undifferentiated), 1 μM RA, and 1% FBS for 4 d (mixed), 1 μM RA and 5 μM forskolin for 4 d (neuronal), or 50 ng/ml leukemia inhibitory factor and 50 ng/ml BMP2 for 6 d (astrocytic). Cells were stained for markers for neurons (Tuj1), astrocytes (GFAP), or oligodendrocytes (RIP), and also with DAPI. Bar, 50 μm. (B) Differentiation of neural progenitor cells in insulin-free N2 media without IGF-I (control) or with IGF-I for 4 d. Insets show cells of typical oligodendrocyte morphology stained with RIP or MBP. Bar, 25 μm. (C) Quantification of cells in either proliferating or differentiating conditions. (D) Quantification of cultures grown in insulin-free N2 media (control) or treated with 500 ng/ml IGF-I, IGF-II, or insulin after 4 d. (E) Quantification of cells in response to different doses of IGF-I (20–500 ng/ml) in 4-d cultures. All data shown are from at least three experiments in parallel cultures with error bars representing SDs. Significant differences are indicated with an asterisk (P < 0.005).
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Related In: Results  -  Collection

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fig1: IGF-I–induced differentiation of multipotent neural progenitor cells. (A) Adult hippocampus-derived neural progenitor cells cultured in insulin-containing N2 media with 20 ng/ml FGF-2 (undifferentiated), 1 μM RA, and 1% FBS for 4 d (mixed), 1 μM RA and 5 μM forskolin for 4 d (neuronal), or 50 ng/ml leukemia inhibitory factor and 50 ng/ml BMP2 for 6 d (astrocytic). Cells were stained for markers for neurons (Tuj1), astrocytes (GFAP), or oligodendrocytes (RIP), and also with DAPI. Bar, 50 μm. (B) Differentiation of neural progenitor cells in insulin-free N2 media without IGF-I (control) or with IGF-I for 4 d. Insets show cells of typical oligodendrocyte morphology stained with RIP or MBP. Bar, 25 μm. (C) Quantification of cells in either proliferating or differentiating conditions. (D) Quantification of cultures grown in insulin-free N2 media (control) or treated with 500 ng/ml IGF-I, IGF-II, or insulin after 4 d. (E) Quantification of cells in response to different doses of IGF-I (20–500 ng/ml) in 4-d cultures. All data shown are from at least three experiments in parallel cultures with error bars representing SDs. Significant differences are indicated with an asterisk (P < 0.005).
Mentions: First, we tested the action of exogenous IGF-I on the differentiation of hippocampus-derived adult neural progenitor cells. These neural progenitor cells have stem cell properties in vitro: (1) they self-renew in the presence of basic FGF-2; (2) single genetically marked clones can differentiate into all three main CNS cell types in vitro (neurons, oligodendrocytes, and astrocytes) and when grafted back to adult hippocampus in vivo; and (3) they express progenitor cell markers such as nestin, but lack markers of lineage-specific differentiation (Fig. 1 A; Gage et al., 1995; Palmer et al., 1997). To confirm that the adult neural progenitor cell population in our model system is indeed multipotent, we first used various standard differentiation paradigms and evaluated the expression of lineage markers. Differentiation with 1 μM retinoic acid (RA) and 1% FBS resulted in mixed numbers of Tuj1+ neurons, GFAP+ astrocytes, and RIP+ oligodendrocytes (Fig. 1 A). Neuron-enriched differentiation can be achieved with 1 μM RA and 5 μM forskolin (Chu, V., personal communication), and astrocyte-enriched differentiation with 50 ng/ml leukemia inhibitory factor and 50 ng/ml BMP2 (Fig. 1 A; Nakashima et al., 1999). The quantification of lineage-specific differentiation is also shown (Fig. 1 C). These results are in agreement with previous reports (Palmer et al., 1997), and indicate that the majority of the adult neural progenitor cells within the bulk population are multipotent progenitors, and not restricted neuronal or glial progenitors.

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