• Molecules and Cells
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• 제38권3호
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• pp.202-209
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• 2015

Hepatocellular carcinoma (HCC), a highly malignant disease and the third leading cause of all cancer mortalities worldwide, often responses poorly to current treatments and results in dismal outcomes due to frequent chemoresistance and tumor relapse. The heterogeneity of HCC is an important attribute of the disease. It is the outcome of many factors, including the cross-talk between tumor cells within the tumor microenvironment and the acquisition and accumulation of genetic and epigenetic alterations in tumor cells. In addition, there is accumulating evidence in recent years to show that the malignancy of HCC can be attributed partly to the presence of cancer stem cell (CSC). CSCs are capable to self-renew, differentiate and initiate tumor formation. The regulation of the stem cell-like properties by several important signaling pathways have been found to endow the tumor cells with an increased level of tumorigenicity, chemoresistance, and metastatic ability. In this review, we will discuss the recent findings on hepatic CSCs, with special emphasis on their putative origins, relationship with hepatitis viruses, regulatory signaling networks, tumor microenvironment, and how these factors control the stemness of hepatic CSCs. We will also discuss some novel therapeutic strategies targeted at hepatic CSCs for combating HCC and perspectives of future investigation.

• 한국발생생물학회지:발생과생식
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• 제14권4호
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• pp.233-241
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• 2010

사람의지방줄기세포는지방조직내에존재하는 줄기세포로 얻기 쉽고, 골수줄기세포와 유사한 특징을 가지고 있다. 그러나 지방을 추출하는 과정, 공여자의 나이, 체질량, 추출 부위에 따라 세포의 특성이 달라지며, 이질적인 세포군을 얻게 된다. 따라서 본 연구에서는 허벅지 지방에서 유래한 줄기세포 특성 분석 및 중배엽, 내배엽성 세포로의 분화능을 알아보았다. 허벅지 유래 줄기세포는 골수줄기세포와 유사한 섬유아세포와 유사한 모양을 보였으며, 체외에서 56.5번의 분열을 하였고, 약 $5{\times}10^{22}$개의 세포를 얻을 수 있었다. 이들은 SCF, Oct4, nanog, vimentin, CK18, FGF5, NCAM, Pax6, BMP4, HNF4a, nestin, GATA4, HLA-ABC, HLA-DR과 같은 유전자를 발현하였으며, Oct4, Thy-1, FSP, vWF, vimentin, desmin, CK18, CD54, CD4, CD106, CD31, a-SMA, HLA-ABC 등과 같은 단백질을 발현하였다. 또한 이들은 지방, 골, 연골 세포와 같은 중배엽성 세포로 분화하였고, 더욱이 인슐린 분비세포와 같은 내배엽성 세포로도 분화하였다. 결론적으로, 사람의 허벅지 유래 줄기세포는 골수 줄기세포와 유사하게 체외에서 증식이 가능하였으며, 유전자 및 단백질 발현 패턴을 가지고 있었으며, 다양한 세포로 분화 가능하였다. 이러한 결과로 미루어 보아 허벅지 지방유래 줄기세포는 골수 줄기세포를 대체할 수 있는 세포치료제의 재료가 될 수 있을 것으로 사료된다.

• Biomolecules & Therapeutics
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• 제32권3호
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• pp.368-378
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• 2024

Cordycepin, a valuable bioactive component isolated from Cordyceps militaris, has been reported to possess anti-cancer potential and the property to enhance the effects of chemotherapeutic agents in various types of cancers. However, the ability of cordycepin to chemosensitize cholangiocarcinoma (CCA) cells to gemcitabine has not yet been evaluated. The current study was performed to evaluate the above, and the mechanisms associated with it. The study analyzed the effects of cordycepin in combination with gemcitabine on the cancer stem-like properties of the CCA SNU478 cell line, including its anti-apoptotic, migratory, and antioxidant effects. In addition, the combination of cordycepin and gemcitabine was evaluated in the CCA xenograft model. The cordycepin treatment significantly decreased SNU478 cell viability and, in combination with gemcitabine, additively reduced cell viability. The cordycepin and gemcitabine co-treatment significantly increased the Annexin V+ population and downregulated B-cell lymphoma 2 (Bcl-2) expression, suggesting that the decreased cell viability in the cordycepin+gemcitabine group may result from an increase in apoptotic death. In addition, the cordycepin and gemcitabine co-treatment significantly reduced the migratory ability of SNU478 cells in the wound healing and trans-well migration assays. It was observed that the cordycepin and gemcitabine cotreatment reduced the CD44^highCD133^high population in SNU478 cells and the expression level of sex determining region Y-box 2 (Sox-2), indicating the downregulation of the cancer stem-like population. Cordycepin also enhanced oxidative damage mediated by gemcitabine in MitoSOX staining associated with the upregulated Kelch like ECH Associated Protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) expression ratio. In the SNU478 xenograft model, co-administration of cordycepin and gemcitabine additively delayed tumor growth. These results indicate that cordycepin potentiates the chemotherapeutic property of gemcitabine against CCA, which results from the downregulation of its cancer-stem-like properties. Hence, the combination therapy of cordycepin and gemcitabine may be a promising therapeutic strategy in the treatment of CCA.

• Journal of Korean Neurosurgical Society
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• 제42권2호
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• pp.118-124
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• 2007

Objective : Adipose tissue is derived from the embryonic mesoderm and contains a heterogenous stromal cell population. Authors have tried to verify the characteristics of stem cell of adipose derived stromal cells (ADSCs) and to investigate immunohistochemical findings after transplantation of ADSC into rat brain to evaluate survival, migration and differentiation of transplanted stromal cells. Methods : First ADSCs were isolated from human adipose tissue and induced adipose, osseous and neuronal differentiation under appropriate culture condition in vitro and examined phenotypes profile of human ADSCs in undifferentiated states using flow cytometry and immunohistochemical study. Human ADSCs were transplanted into the healthy rat brain to investigate survival, migration and differentiation after 4 weeks. Results : From human adipose tissue, adipose stem cells were harvested and subcultured for several times. The cultured ADSCs were differentiated into adipocytes, osteoctye and neuron-like cell under conditioned media. Flow cytometric analysis of undifferentiated ADSCs revealed that ADSCs were positive for CD29, CD44 and negative for CD34, CD45, CD117 and HLA-DR. Transplanted human ADSCs were found mainly in cortex adjacent to injection site and migrated from injection site at a distance of at least 1 mm along the cortex and corpus callosum. A few transplanted cells have differentiated into neuron and astrocyte. Conclusion : ADSCs were differentiated into multilineage cell lines through transdifferentiation. ADSCs were survived and migrated in xenograft without immunosuppression. Based on this data, ADSCs may be potential source of stem cells for many human disease including neurologic disorder.

• 한국발생생물학회:학술대회논문집
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• 한국발생생물학회 2005년도 제5회 발생공학 국제심포지엄 및 학술대회
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• pp.147-148
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• 2005

• 한국수정란이식학회:학술대회논문집
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• 한국수정란이식학회 2005년도 제5회 발생공학 국제심포지엄 및 학술대회
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• pp.147-148
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• 2005

• 대한생식의학회:학술대회논문집
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• 대한불임학회 2004년도 제46차 춘계학술대회
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• pp.73-74
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• 2004

• International Journal of Stem Cells
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• 제16권3호
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• pp.293-303
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• 2023

Background and Objectives: The physiological oxygen tension in fetal brains (~3%, physioxia) is beneficial for the maintenance of neural stem cells (NSCs). Sensitivity to oxygen varies between NSCs from different fetal brain regions, with midbrain NSCs showing selective susceptibility. Data on Hif-1𝛼/Notch regulatory interactions as well as our observations that Hif-1𝛼 and oxygen affect midbrain NSCs survival and proliferation prompted our investigations on involvement of Notch signalling in physioxia-dependent midbrain NSCs performance. Methods and Results: Here we found that physioxia (3% O₂) compared to normoxia (21% O₂) increased proliferation, maintained stemness by suppression of spontaneous differentiation and supported cell cycle progression. Microarray and qRT-PCR analyses identified significant changes of Notch related genes in midbrain NSCs after long-term (13 days), but not after short-term physioxia (48 hours). Consistently, inhibition of Notch signalling with DAPT increased, but its stimulation with Dll4 decreased spontaneous differentiation into neurons solely under normoxic but not under physioxic conditions. Conclusions: Notch signalling does not influence the fate decision of midbrain NSCs cultured in vitro in physioxia, where other factors like Hif-1𝛼 might be involved. Our findings on how physioxia effects in midbrain NSCs are transduced by alternative signalling might, at least in part, explain their selective susceptibility to oxygen.

• BMB Reports
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• 제55권2호
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• pp.98-103
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• 2022

Increased mRNA levels of cancer upregulated gene (CUG)2 have been detected in many different tumor tissues using Affymetrix microarray. Oncogenic capability of the CUG2 gene has been further reported. However, the mechanism by which CUG2 overexpression promotes cancer stem cell (CSC)-like phenotypes remains unknown. With recent studies showing that pyruvate kinase muscle 2 (PKM2) is overexpressed in clinical tissues from gastric, lung, and cervical cancer patients, we hypothesized that PKM2 might play an important role in CSC-like phenotypes caused by CUG2 overexpression. The present study revealed that PKM2 protein levels and translocation of PKM2 into the nucleus were enhanced in CUG2-overexpressing lung carcinoma A549 and immortalized bronchial BEAS-2B cells than in control cells. Expression levels of c-Myc, CyclinD1, and PKM2 were increased in CUG2-overexpressing cells than in control cells. Furthermore, EGFR and ERK inhibitors as well as suppression of Yap1 and NEK2 expression reduced PKM2 protein levels. Interestingly, knockdown of β-catenin expression failed to reduce PKM2 protein levels. Furthermore, reduction of PKM2 expression with its siRNA hindered CSC-like phenotypes such as faster wound healing, aggressive transwell migration, and increased size/number of sphere formation. The introduction of mutant S37A PKM2-green fluorescence protein (GFP) into cells without ability to move to the nucleus did not confer CSC-like phenotypes, whereas forced expression of wild-type PKM2 promoted such phenotypes. Overall, CUG2-induced increase in the expression of nuclear PKM2 contributes to CSC-like phenotypes by upregulating c-Myc and CyclinD1 as a co-activator.

• 한국수정란이식학회지
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• 제31권1호
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• pp.81-88
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• 2016

There are various factors i.e. donor cell type, culture system as well as technical procedures which influence the pre-implantation embryonic development; however, may attempts have been made and still it is under investigation to improve the cloning efficiency using somatic cell nuclear transfer technique. It is has been investigated that stem cells like mesenchymal stem cell are able to more efficiently reprogram and reactivate the expression of early embryonic genes to promote nuclear transfer efficiency. In addition, Oct4 expression plays a pivotal role in early embryo development. In the present study, we investigated distribution of Oct4 expression and changes of apoptosis and total cell number in nuclear transfer blastocyst after using Oct4 transfected bone marrow stem cell as donor cells. Although Oct4-RFP expression was observed across blastocyst, more concentrated intensity was shown at hatched region in blastocyst on day 7. Reduction of apoptotic bodies was revealed in Oct4 transfected blastocyst by TUNEL staining, however, there was no significant difference in total cell number between Oct4 transfected and non-transfected nuclear transfer embryos. In conclusion, Oct4 transfected donor cells exhibited higher expression in hatching sight in day 7 blastocyst and were able to prevent apoptosis compared to non-transfected donor cells.