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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 instructs neural progenitor cells to commit to an oligodendroglial lineage and increases the proliferation of committed oligodendrocytes. (A) Adult neural progenitor cell states in culture: α, proliferation rate of progenitors (RIP−); β, differentiation rate of progenitors (RIP−) to oligodendrocytes (RIP+); δ, cell death rate for progenitors (RIP−); γ, proliferation rate for oligodendrocytes (RIP+); ɛ, cell death rate for oligodendrocytes (RIP+). (B and C) Comparison between direct measurements (columns) and modeling analyses (lines) of the total cell numbers (B) and of the percentage of RIP+ cells (C). Black columns are insulin-free (no IGF-I) conditions, and blue columns are 500 ng/ml IGF-I conditions. No significant differences were found between the direct measurements and the values predicted by the model in each case. All data were normalized to values at the 12-h time point within each condition due to variability in cell behavior at time 0 (4 h after plating). (D) The proliferation rates for RIP− (α) and RIP+ (γ) cells in insulin-free (no IGF-I) conditions (black line) and treated with 500 ng/ml IGF-I (blue and red lines). (E) The differentiation rate for RIP− (β) cells treated with 500 ng/ml IGF-I. These data are representative of at least three independent experiments. Error bars (except in D and E) represent SDs. The error bars in D and E represent the upper and lower bounds for proliferation (α, γ) and differentiation (β) rates.
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fig4: IGF-I instructs neural progenitor cells to commit to an oligodendroglial lineage and increases the proliferation of committed oligodendrocytes. (A) Adult neural progenitor cell states in culture: α, proliferation rate of progenitors (RIP−); β, differentiation rate of progenitors (RIP−) to oligodendrocytes (RIP+); δ, cell death rate for progenitors (RIP−); γ, proliferation rate for oligodendrocytes (RIP+); ɛ, cell death rate for oligodendrocytes (RIP+). (B and C) Comparison between direct measurements (columns) and modeling analyses (lines) of the total cell numbers (B) and of the percentage of RIP+ cells (C). Black columns are insulin-free (no IGF-I) conditions, and blue columns are 500 ng/ml IGF-I conditions. No significant differences were found between the direct measurements and the values predicted by the model in each case. All data were normalized to values at the 12-h time point within each condition due to variability in cell behavior at time 0 (4 h after plating). (D) The proliferation rates for RIP− (α) and RIP+ (γ) cells in insulin-free (no IGF-I) conditions (black line) and treated with 500 ng/ml IGF-I (blue and red lines). (E) The differentiation rate for RIP− (β) cells treated with 500 ng/ml IGF-I. These data are representative of at least three independent experiments. Error bars (except in D and E) represent SDs. The error bars in D and E represent the upper and lower bounds for proliferation (α, γ) and differentiation (β) rates.

Mentions: Next, we determined whether proliferation of progenitors might contribute to the observed increase in oligodendrocyte differentiation. 2.5 μM BrdU was added to parallel cultures for 12 h at 0, 12, 24, and 36 h after plating, followed by fixation and quantification of total cell numbers and BrdU+ cells. We counted the progenitor cells (evidenced by a lack of RIP staining) that were labeled with BrdU at each time point. For cells grown in the absence of IGF-I, we observed a progressive decrease in the percentage of cells that were proliferating (BrdU+) during the 48-h experiments (Fig. 3 B). There was a marked decrease in proliferation during the 36- and 48-h periods, probably due to limited cell survival in the absence of IGF-I. In cultures treated with IGF-I, the percentage of RIP− cells that incorporated BrdU also exhibited a decreasing trend in the first three time periods, but to a lesser extent compared with the cells grown without IGF-I (Fig. 3 B, blue columns). This initial decrease in proliferation is most likely due to FGF-2 mitogen withdrawal. The fact that we could already observe the generation of RIP+ oligodendrocytes at the 24-h time point (Fig. 4 C), coupled with the observation that there was a decrease in BrdU uptake of RIP− cells, suggests that IGF-I did not have a major proliferative effect on progenitor cells.


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 instructs neural progenitor cells to commit to an oligodendroglial lineage and increases the proliferation of committed oligodendrocytes. (A) Adult neural progenitor cell states in culture: α, proliferation rate of progenitors (RIP−); β, differentiation rate of progenitors (RIP−) to oligodendrocytes (RIP+); δ, cell death rate for progenitors (RIP−); γ, proliferation rate for oligodendrocytes (RIP+); ɛ, cell death rate for oligodendrocytes (RIP+). (B and C) Comparison between direct measurements (columns) and modeling analyses (lines) of the total cell numbers (B) and of the percentage of RIP+ cells (C). Black columns are insulin-free (no IGF-I) conditions, and blue columns are 500 ng/ml IGF-I conditions. No significant differences were found between the direct measurements and the values predicted by the model in each case. All data were normalized to values at the 12-h time point within each condition due to variability in cell behavior at time 0 (4 h after plating). (D) The proliferation rates for RIP− (α) and RIP+ (γ) cells in insulin-free (no IGF-I) conditions (black line) and treated with 500 ng/ml IGF-I (blue and red lines). (E) The differentiation rate for RIP− (β) cells treated with 500 ng/ml IGF-I. These data are representative of at least three independent experiments. Error bars (except in D and E) represent SDs. The error bars in D and E represent the upper and lower bounds for proliferation (α, γ) and differentiation (β) rates.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171962&req=5

fig4: IGF-I instructs neural progenitor cells to commit to an oligodendroglial lineage and increases the proliferation of committed oligodendrocytes. (A) Adult neural progenitor cell states in culture: α, proliferation rate of progenitors (RIP−); β, differentiation rate of progenitors (RIP−) to oligodendrocytes (RIP+); δ, cell death rate for progenitors (RIP−); γ, proliferation rate for oligodendrocytes (RIP+); ɛ, cell death rate for oligodendrocytes (RIP+). (B and C) Comparison between direct measurements (columns) and modeling analyses (lines) of the total cell numbers (B) and of the percentage of RIP+ cells (C). Black columns are insulin-free (no IGF-I) conditions, and blue columns are 500 ng/ml IGF-I conditions. No significant differences were found between the direct measurements and the values predicted by the model in each case. All data were normalized to values at the 12-h time point within each condition due to variability in cell behavior at time 0 (4 h after plating). (D) The proliferation rates for RIP− (α) and RIP+ (γ) cells in insulin-free (no IGF-I) conditions (black line) and treated with 500 ng/ml IGF-I (blue and red lines). (E) The differentiation rate for RIP− (β) cells treated with 500 ng/ml IGF-I. These data are representative of at least three independent experiments. Error bars (except in D and E) represent SDs. The error bars in D and E represent the upper and lower bounds for proliferation (α, γ) and differentiation (β) rates.
Mentions: Next, we determined whether proliferation of progenitors might contribute to the observed increase in oligodendrocyte differentiation. 2.5 μM BrdU was added to parallel cultures for 12 h at 0, 12, 24, and 36 h after plating, followed by fixation and quantification of total cell numbers and BrdU+ cells. We counted the progenitor cells (evidenced by a lack of RIP staining) that were labeled with BrdU at each time point. For cells grown in the absence of IGF-I, we observed a progressive decrease in the percentage of cells that were proliferating (BrdU+) during the 48-h experiments (Fig. 3 B). There was a marked decrease in proliferation during the 36- and 48-h periods, probably due to limited cell survival in the absence of IGF-I. In cultures treated with IGF-I, the percentage of RIP− cells that incorporated BrdU also exhibited a decreasing trend in the first three time periods, but to a lesser extent compared with the cells grown without IGF-I (Fig. 3 B, blue columns). This initial decrease in proliferation is most likely due to FGF-2 mitogen withdrawal. The fact that we could already observe the generation of RIP+ oligodendrocytes at the 24-h time point (Fig. 4 C), coupled with the observation that there was a decrease in BrdU uptake of RIP− cells, suggests that IGF-I did not have a major proliferative effect on progenitor cells.

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