Hypoxia inducible factor 2α/insulin-like growth factor receptor signal loop supports the proliferation and Oct-4 maintenance of mouse germline stem cells

Yen-Hua Huang, Mei-Hsiang Lin, P. C. Wang, Yu Chih Wu, H. L. Chiang, Y. L. Wang, Jui Hung Chang, Y. K. Huang, S. Y. Gu, Hong Nerng Ho, Thai Y. Ling

研究成果: 雜誌貢獻文章

10 引文 (Scopus)

摘要

Hypoxia inducible factor 2α (HIF-2α) is critical for primordial germ cell (PGC) survival as knockout of HIF-2α (HIF-2α-/-) decreases both expression of Oct-4 and PGC number in genital ridge. Hypoxia is known to stabilize HIF-2α protein from proteasomal degradation. However, little is known about the hypoxia-associated endocrinal signaling in HIF-2α expression. The current work demonstrates a role for an endocrine insulin-like growth factor-I receptor (IGF-IR)-PI3K/Akt-mTOR-HIF-2α regulatory loop in the proliferation and Oct-4 maintenance of PGC-like alkaline phosphatase positive mouse germline stem cells (AP+GSCs).We found that hypoxia greatly increased the cell proliferation and the levels of nuclear Oct-4/HIF-2α protein of AP+ GSCs. The hypoxic-AP+ GSCs presented stronger stemness ability for germ cell differentiation than normoxic, with expressions of c-KIT (differentiation germ cell marker), VASA (differentiation germ cell marker) and SCP3 (meiotic marker) using a renal capsule transplantation assay. Meanwhile, hypoxia significantly increased the expression levels of secreted-IGF-I and IGF-IR. The IGF-I dose dependently increased the HIF-2α expression levels in AP+GSCs; and, the inhibition of IGF-IR byRNAinterference (shIGF-IR) or LY294002 (PI3K inhibitor)/Rapamycin (mTOR inhibitor) effectively suppressed the IGF-I- and/or hypoxia-induced HIF-2α and Oct-4 expression, suggesting that the IGF-IR and its downstream Akt/mTOR signaling are involved in the IGF-I/hypoxia effects. Additionally, knockdown of HIF-2αdramatically suppressed Oct-4 and IGF-IR protein levels inAP+GSCcells. In conclusion, the present study demonstrates a regulatory loop of IGF-IR-PI3K/Akt-mTOR-HIF-2α in proliferation and Oct-4 maintenance of PGC-like AP+GSCs under hypoxia. This finding provides insights into the niche endocrinology underlying early germ cell development.
原文英語
文章編號gau016
頁(從 - 到)526-537
頁數12
期刊Molecular Human Reproduction
20
發行號6
DOIs
出版狀態已發佈 - 2014

指紋

Somatomedin Receptors
Stem Cells
Germ Cells
IGF Type 1 Receptor
Maintenance
Insulin-Like Growth Factor I
Phosphatidylinositol 3-Kinases
endothelial PAS domain-containing protein 1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Endocrinology
Differentiation Antigens
Sirolimus
Hypoxia
Kidney Transplantation
Proteolysis
Capsules
Alkaline Phosphatase
Cell Differentiation
Cell Survival
Proteins

ASJC Scopus subject areas

  • Obstetrics and Gynaecology
  • Reproductive Medicine
  • Developmental Biology
  • Genetics
  • Cell Biology
  • Embryology
  • Molecular Biology
  • Medicine(all)

引用此文

Hypoxia inducible factor 2α/insulin-like growth factor receptor signal loop supports the proliferation and Oct-4 maintenance of mouse germline stem cells. / Huang, Yen-Hua; Lin, Mei-Hsiang; Wang, P. C.; Wu, Yu Chih; Chiang, H. L.; Wang, Y. L.; Chang, Jui Hung; Huang, Y. K.; Gu, S. Y.; Ho, Hong Nerng; Ling, Thai Y.

於: Molecular Human Reproduction, 卷 20, 編號 6, gau016, 2014, p. 526-537.

研究成果: 雜誌貢獻文章

Huang, Yen-Hua ; Lin, Mei-Hsiang ; Wang, P. C. ; Wu, Yu Chih ; Chiang, H. L. ; Wang, Y. L. ; Chang, Jui Hung ; Huang, Y. K. ; Gu, S. Y. ; Ho, Hong Nerng ; Ling, Thai Y. / Hypoxia inducible factor 2α/insulin-like growth factor receptor signal loop supports the proliferation and Oct-4 maintenance of mouse germline stem cells. 於: Molecular Human Reproduction. 2014 ; 卷 20, 編號 6. 頁 526-537.
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abstract = "Hypoxia inducible factor 2α (HIF-2α) is critical for primordial germ cell (PGC) survival as knockout of HIF-2α (HIF-2α-/-) decreases both expression of Oct-4 and PGC number in genital ridge. Hypoxia is known to stabilize HIF-2α protein from proteasomal degradation. However, little is known about the hypoxia-associated endocrinal signaling in HIF-2α expression. The current work demonstrates a role for an endocrine insulin-like growth factor-I receptor (IGF-IR)-PI3K/Akt-mTOR-HIF-2α regulatory loop in the proliferation and Oct-4 maintenance of PGC-like alkaline phosphatase positive mouse germline stem cells (AP+GSCs).We found that hypoxia greatly increased the cell proliferation and the levels of nuclear Oct-4/HIF-2α protein of AP+ GSCs. The hypoxic-AP+ GSCs presented stronger stemness ability for germ cell differentiation than normoxic, with expressions of c-KIT (differentiation germ cell marker), VASA (differentiation germ cell marker) and SCP3 (meiotic marker) using a renal capsule transplantation assay. Meanwhile, hypoxia significantly increased the expression levels of secreted-IGF-I and IGF-IR. The IGF-I dose dependently increased the HIF-2α expression levels in AP+GSCs; and, the inhibition of IGF-IR byRNAinterference (shIGF-IR) or LY294002 (PI3K inhibitor)/Rapamycin (mTOR inhibitor) effectively suppressed the IGF-I- and/or hypoxia-induced HIF-2α and Oct-4 expression, suggesting that the IGF-IR and its downstream Akt/mTOR signaling are involved in the IGF-I/hypoxia effects. Additionally, knockdown of HIF-2αdramatically suppressed Oct-4 and IGF-IR protein levels inAP+GSCcells. In conclusion, the present study demonstrates a regulatory loop of IGF-IR-PI3K/Akt-mTOR-HIF-2α in proliferation and Oct-4 maintenance of PGC-like AP+GSCs under hypoxia. This finding provides insights into the niche endocrinology underlying early germ cell development.",
keywords = "Germline, Niche growth factor, Oxygen tension, Self-renewal, Tissue-specific stem cells",
author = "Yen-Hua Huang and Mei-Hsiang Lin and Wang, {P. C.} and Wu, {Yu Chih} and Chiang, {H. L.} and Wang, {Y. L.} and Chang, {Jui Hung} and Huang, {Y. K.} and Gu, {S. Y.} and Ho, {Hong Nerng} and Ling, {Thai Y.}",
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T1 - Hypoxia inducible factor 2α/insulin-like growth factor receptor signal loop supports the proliferation and Oct-4 maintenance of mouse germline stem cells

AU - Huang, Yen-Hua

AU - Lin, Mei-Hsiang

AU - Wang, P. C.

AU - Wu, Yu Chih

AU - Chiang, H. L.

AU - Wang, Y. L.

AU - Chang, Jui Hung

AU - Huang, Y. K.

AU - Gu, S. Y.

AU - Ho, Hong Nerng

AU - Ling, Thai Y.

PY - 2014

Y1 - 2014

N2 - Hypoxia inducible factor 2α (HIF-2α) is critical for primordial germ cell (PGC) survival as knockout of HIF-2α (HIF-2α-/-) decreases both expression of Oct-4 and PGC number in genital ridge. Hypoxia is known to stabilize HIF-2α protein from proteasomal degradation. However, little is known about the hypoxia-associated endocrinal signaling in HIF-2α expression. The current work demonstrates a role for an endocrine insulin-like growth factor-I receptor (IGF-IR)-PI3K/Akt-mTOR-HIF-2α regulatory loop in the proliferation and Oct-4 maintenance of PGC-like alkaline phosphatase positive mouse germline stem cells (AP+GSCs).We found that hypoxia greatly increased the cell proliferation and the levels of nuclear Oct-4/HIF-2α protein of AP+ GSCs. The hypoxic-AP+ GSCs presented stronger stemness ability for germ cell differentiation than normoxic, with expressions of c-KIT (differentiation germ cell marker), VASA (differentiation germ cell marker) and SCP3 (meiotic marker) using a renal capsule transplantation assay. Meanwhile, hypoxia significantly increased the expression levels of secreted-IGF-I and IGF-IR. The IGF-I dose dependently increased the HIF-2α expression levels in AP+GSCs; and, the inhibition of IGF-IR byRNAinterference (shIGF-IR) or LY294002 (PI3K inhibitor)/Rapamycin (mTOR inhibitor) effectively suppressed the IGF-I- and/or hypoxia-induced HIF-2α and Oct-4 expression, suggesting that the IGF-IR and its downstream Akt/mTOR signaling are involved in the IGF-I/hypoxia effects. Additionally, knockdown of HIF-2αdramatically suppressed Oct-4 and IGF-IR protein levels inAP+GSCcells. In conclusion, the present study demonstrates a regulatory loop of IGF-IR-PI3K/Akt-mTOR-HIF-2α in proliferation and Oct-4 maintenance of PGC-like AP+GSCs under hypoxia. This finding provides insights into the niche endocrinology underlying early germ cell development.

AB - Hypoxia inducible factor 2α (HIF-2α) is critical for primordial germ cell (PGC) survival as knockout of HIF-2α (HIF-2α-/-) decreases both expression of Oct-4 and PGC number in genital ridge. Hypoxia is known to stabilize HIF-2α protein from proteasomal degradation. However, little is known about the hypoxia-associated endocrinal signaling in HIF-2α expression. The current work demonstrates a role for an endocrine insulin-like growth factor-I receptor (IGF-IR)-PI3K/Akt-mTOR-HIF-2α regulatory loop in the proliferation and Oct-4 maintenance of PGC-like alkaline phosphatase positive mouse germline stem cells (AP+GSCs).We found that hypoxia greatly increased the cell proliferation and the levels of nuclear Oct-4/HIF-2α protein of AP+ GSCs. The hypoxic-AP+ GSCs presented stronger stemness ability for germ cell differentiation than normoxic, with expressions of c-KIT (differentiation germ cell marker), VASA (differentiation germ cell marker) and SCP3 (meiotic marker) using a renal capsule transplantation assay. Meanwhile, hypoxia significantly increased the expression levels of secreted-IGF-I and IGF-IR. The IGF-I dose dependently increased the HIF-2α expression levels in AP+GSCs; and, the inhibition of IGF-IR byRNAinterference (shIGF-IR) or LY294002 (PI3K inhibitor)/Rapamycin (mTOR inhibitor) effectively suppressed the IGF-I- and/or hypoxia-induced HIF-2α and Oct-4 expression, suggesting that the IGF-IR and its downstream Akt/mTOR signaling are involved in the IGF-I/hypoxia effects. Additionally, knockdown of HIF-2αdramatically suppressed Oct-4 and IGF-IR protein levels inAP+GSCcells. In conclusion, the present study demonstrates a regulatory loop of IGF-IR-PI3K/Akt-mTOR-HIF-2α in proliferation and Oct-4 maintenance of PGC-like AP+GSCs under hypoxia. This finding provides insights into the niche endocrinology underlying early germ cell development.

KW - Germline

KW - Niche growth factor

KW - Oxygen tension

KW - Self-renewal

KW - Tissue-specific stem cells

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