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

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
Article numbergau016
Pages (from-to)526-537
Number of pages12
JournalMolecular Human Reproduction
Volume20
Issue number6
DOIs
Publication statusPublished - 2014

Fingerprint

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

Keywords

  • Germline
  • Niche growth factor
  • Oxygen tension
  • Self-renewal
  • Tissue-specific stem cells

ASJC Scopus subject areas

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

Cite this

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.

In: Molecular Human Reproduction, Vol. 20, No. 6, gau016, 2014, p. 526-537.

Research output: Contribution to journalArticle

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. In: Molecular Human Reproduction. 2014 ; Vol. 20, No. 6. pp. 526-537.
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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.

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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.

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