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설치류 유리체 혈관의 퇴화과정에서 Ninjurin1 단백질의 기능 연구 (Role of Ninjurin1 in macrophage-induced hyaloids regression during early rodent ocular development)
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Project Number E00022
Year(selected) 2005 Year
the present condition of Project 종료
State of proposition 재단승인
Completion Date 2009년 09월 03일
Year type 결과보고
Year(final report) 2009년
Research result report
  • Abstract
  • Part I. Role of Ninjurin1 in macrophage-induced hyaloids regression during early ocular development

    Developmental tissues go through regression, remodeling and apoptosis. In these processes, macrophages phagocytize dead cells and induce apoptosis directly. In hyaloid vessels (HVs), macrophages induce apoptosis of vascular endothelial cells (VECs) by cooperation between the Wnt and Angiopoietin (Ang) pathways. We hypothesized that some factors might exist to regulate the cell-cell interaction leading to regression of HVs. Here we show that macrophages express Ninjurin1 (Nerve injury-induced protein, Ninj1) to mediate direct interactions between macrophages and VECs, followed by activation of the Wnt?Ang pathway.
    Initially, we found that Ninj1 was temporally increased in macrophages during regression of hyaloid vascular system (HVS) and that these Ninj1-expressing macrophages closely interacted with hyaloid VECs. Systemic neutralization using an anti-Ninj1 antibody resulted in the delay of hyaloids regression in vivo. We also found that Ninj1 increased cell-to-matrix and cell-to-cell adhesion of macrophages in vitro. Furthermore, Ninj1 stimulated the expression of Wnt7b in macrophages and the conditioned media from Ninj1-overexpressing macrophages (Ninj1-CM) decreased Ang1 and increased Ang2 in pericytes, which consequently switched hyaloid VEC fate from survival to death. Collectively, these findings suggest that macrophages express Ninj1 to increase death signal through cell-cell interaction and raise the possibility that Ninj1 may act similarly in other developmental regression mediated by macrophages.


    Part II. Investigation of the ES (embryonic stem) cell differentiation by protein modificational regulation
    - Suppression of HIF-1? by HDAC and/or PKC inhibitors sustains self-renewal of mouse embryonic stem cells under hypoxia in vitro.

    The developing embryo naturally undergoes relatively hypoxic conditions in vivo. Under in vitro hypoxia, mouse embryonic stem cells (mESCs) lose their self-renewal activity and display an early differentiated morphology mediated by the hypoxia-inducible factor-1? (HIF-1?). Here, we examined the effects of histone deacetylase (HDAC) and protein kinase C (PKC) inhibitors on the self-renewal properties of mESCs under hypoxia. Inhibition of HDAC and PKC activity under hypoxia effectively decreased HIF-1? protein levels and substantially recovered the expression of LIF-specific receptor (LIFR) and phosphorylated-STAT3 in mESCs. Moreover, our RT-PCR data indicate that these inhibitors aid to sustain the self-renewal activity of mESCs under hypoxia. Taken together, these results suggest that HDAC and PKC inhibitors block the early differentiation of mESCs via destabilization of HIF-1? under hypoxia.
  • Research result and Utilization method
  • Part I.
    In summary, major findings presented in my thesis are as follows:
    1. Ninj1 was temporally increased in macrophages during regression of HVs and that these Ninj1-expressing macrophages closely interacted with hyaloid VECs.
    2. Systemic neutralization using an anti-Ninj1 antibody resulted in the delay of hyaloids regression in vivo.
    3. Ninj1 increased cell-to-matrix and cell-to-cell adhesion of macrophages in vitro.
    4. Ninj1 stimulated the expression of Wnt7b in macrophages and the conditioned media from Ninj1-overexpressing macrophages decreased Ang1 and increased Ang2 in pericytes, which consequently switched hyaloid VEC fate from survival to death.

    These findings suggest that macrophages transiently expressed Ninj1 to migrate, adhere to their target cells and activate Wnt7b-Ang pathway, resulting in programmed-cell death of VECs during HVS regression.It will be of great interest to determine the role of Ninj1 in macrophages of any other tissues, which will provide important clues for macrophage-related diseases, such as inflammation, cancer, HIV-associated dementia, multiple sclerosis, atherosclerosis, age-related macular degeneration and diabetic neuropathy.

    Part II.
    In summary, major findings presented in my thesis are as follows:
    1. HDAC inhibitors downregulated HIF-1? protein levels and suppressed the decrease of LIF-STAT3 pathway under hypoxia.
    2. PKC inhibitors decreased the HIF-1? stability and prevented the attenuation of LIF-STAT3 pathway under hypoxia.
    3. HDAC inhibitors and PKC inhibitors maintained the AP activity and self-renewal marker genes under hypoxia, which consequently kept mESCs fate as self-renewal.
    4. DEG screening of mESCs under different oxygen states revealed the novel and potent molecules which may have an important role in hypoxia-induced differentiation of mESCs.

    These findings suggest that inhibitors of HDAC and/or PKC block the hypoxia-induced early differentiation of mESCs and may be important for the understanding of the molecular mechanisms underlying physiologic events during mammalian embryogenesis.
  • Index terms
  • Part I : Ninjurin1; Wnt7b; Angiopoietin 1; Angiopoietin2; hyaloids vessel; macrophage; pericyte; endothelail cell; apoptosis; developmental regression Part II : mouse embryonic stem cell; leukemia inhibitory factor (LIF); LIF receptor (LIFR); histone deacetylase (HDAC); protein kinase (PKC); differentiation; self-renewal; hypoxia; hypoxia-inducible factor-1? (HIIF-1?); signal transducer and activator of transcription-3 (STAT3)
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