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Heo Jinbeom,Lee Jinyoung,Nam Yun Ji,Kim YongHwan,Yun HongDuck,Lee Seungun,Ju Hyein,Ryu Chae-Min,Jeong Seon Min,Lee Jinwon,Lim Jisun,Cho Yong Mee,Jeong Eui Man,Hong Bumsik,Son Jaekyoung,Shin Dong-Myung 생화학분자생물학회 2022 Experimental and molecular medicine Vol.54 No.-
Aberrant activation of embryogenesis-related molecular programs in urothelial bladder cancer (BC) is associated with stemness features related to oncogenic dedifferentiation and tumor metastasis. Recently, we reported that overexpression of transcription factor CP2-like protein-1 (TFCP2L1) and its phosphorylation at Thr177 by cyclin-dependent kinase-1 (CDK1) play key roles in regulating bladder carcinogenesis. However, the clinical relevance and therapeutic potential of this novel CDK1-TFCP2L1 molecular network remain elusive. Here, we demonstrated that inhibitor of DNA binding-2 (ID2) functions as a crucial mediator by acting as a direct repressive target of TFCP2L1 to modulate the stemness features and survival of BC cells. Low ID2 and high CDK1 expression were significantly associated with unfavorable clinical characteristics. TFCP2L1 downregulated ID2 by directly binding to its promoter region. Consistent with these findings, ectopic expression of ID2 or treatment with apigenin, a chemical activator of ID2, triggered apoptosis and impaired the proliferation, suppressed the stemness features, and reduced the invasive capacity of BC cells. Combination treatment with the specific CDK1 inhibitor RO-3306 and apigenin significantly suppressed tumor growth in an orthotopic BC xenograft animal model. This study demonstrates the biological role and clinical utility of ID2 as a direct target of the CDK1-TFCP2L1 pathway for modulating the stemness features of BC cells.
Jisun Lim,Hwan Yeul Yul,Jinbeom Heo,Eui Man Jeong,In-Gyu Kim,Kihang Choi,Myung-Soo Choo,Dong-Myung Shin 한국수정란이식학회 2018 한국수정란이식학회 학술대회 Vol.2018 No.11
Transplantation of stem cells, such as mesenchymal stem cells (MSCs), is a promising strategy for treating several types of intractable disorders. Mechanistically, it could not only replace damaged cells by direct contribution, but also establish an anti-inflammatory or immunomodulatory microenvironment. However, the cellular mechanisms underlying molecular and biological properties of stem cells during ex vivo expansion and also after transplantation in pathological environments remain largely elusive. We recently developed the cyanoacrylamide-based coumarin derivatives (Fluorescent real-time thiol tracer; FreSHtracer*) reversibly react with glutathione for monitoring of glutathione levels in living stem cells. These probes revealed that glutathione levels are heterogeneous among subcellular organelles and among individual cells and show dynamic changes and heterogeneity in repopulating stem cells depending on oxidative-stress or culture conditions. Importantly, a subpopulation of stem cells with high-glutathione levels exhibited increased self-renewal and migration activities in vitro and showed improved therapeutic efficiency in treating asthma. Furthermore, employing a novel combination of longitudinal intravital confocal fluorescence imaging and microcystoscopy in living animals, we investigated the distributions and properties of transplanted multipotent MSCs derived from human embryonic stem cells at single-cell resolution in real-time by performing confocal imaging of bladder tissues in a rat model of IC/BPS for up to 6 months post-transplantation. These novel real-time monitoring strategies demonstrate the novel molecular insight for maintaining stem cell functions and also enhance understanding of the in vivo behaviors of the engrafted stem cells, which is crucial to determine the efficacy and safety of stem cell-based therapies. This strategy may facilitate the translation of various stem cell-based approaches into clinical practice.
Small hypoxia-primed mesenchymal stem cells attenuate graft-versus-host disease
Kim, YongHwan,Jin, Hye Jin,Heo, Jinbeom,Ju, Hyein,Lee, Hye-Yeon,Kim, Sujin,Lee, Seungun,Lim, Jisun,Jeong, Sang Young,Kwon, JiHye,Kim, Miyeon,Choi, Soo Jin,Oh, Wonil,Yang, Yoon Sun,Hwang, Hyun Ho,Yu, H Nature Publishing Group UK 2018 Leukemia Vol.32 No.12
<P>Mesenchymal stem cells (MSCs) are of particular interest for the treatment of immune-related diseases due to their immunosuppressive capacity. Here, we show that Small MSCs primed with Hypoxia and Calcium ions (SHC-MSCs) exhibit enhanced stemness and immunomodulatory functions for treating allogeneic conflicts. Compared with naïve cultured human umbilical cord blood-derived MSCs, SHC-MSCs were resistant to passage-dependent senescence mediated via the monocyte chemoattractant protein-1 and p53/p21 cascade and secreted large amounts of pro-angiogenic and immunomodulatory factors, resulting in suppression of T-cell proliferation. SHC-MSCs showed DNA demethylation in pluripotency, germline, and imprinted genes similarly to very small embryonic-like stem cells, suggesting a potential mutual relationship. Genome-wide DNA methylome and transcriptome analyses indicated that genes related to immune modulation, cell adhesion, and the cell cycle were up-regulated in SHC-MSCs. Particularly, polo-like kinase-1 (<I>PLK1</I>), zinc-finger protein-143, dehydrogenase/reductase-3, and friend-of-GATA2 play a key role in the beneficial effects of SHC-MSCs. Administration of SHC-MSCs or <I>PLK1</I>-overexpressing MSCs significantly ameliorated symptoms of graft-versus-host disease (GVHD) in a humanized mouse model, resulting in significantly improved survival, less weight loss, and reduced histopathologic injuries in GVHD target organs compared with naïve MSC-infused mice. Collectively, our findings suggest that SHC-MSCs can improve the clinical treatment of allogeneic conflicts, including GVHD.</P>
Valproic acid enforces the priming effect of sphingosine-1 phosphate on human mesenchymal stem cells
Lim, Jisun,Lee, Seungun,Ju, Hyein,Kim, Yonghwan,Heo, Jinbeom,Lee, Hye-Yeon,Choi, Kyung-Chul,Son, Jaekyoung,Oh, Yeon-Mok,Kim, In-Gyu,Shin, Dong-Myung UNKNOWN 2017 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE Vol.40 No.3
<P>Engraftment and homing of mesenchymal stem cells (MSCs) are modulated by priming factors including the bioactive lipid sphingosine-1-phosphate (S1P), by stimulating CXCR4 receptor signaling cascades. However, limited <I>in vivo</I> efficacy and the remaining priming molecules prior to administration of MSCs can provoke concerns regarding the efficiency and safety of MSC priming. Here, we showed that valproic acid (VPA), a histone deacetylase inhibitor, enforced the priming effect of S1P at a low dosage for human umbilical cord-derived MSCs (UC-MSCs). A DNA-methylation inhibitor, 5-azacytidine (5-Aza), and VPA increased the expression of <I>CXCR4</I> in UC-MSCs. In particular, UC-MSCs primed with a suboptimal dose (50 nM) of S1P in combination with 0.5 mM VPA (VPA+S1P priming), but not 1 <I>µ</I>M 5-Aza, significantly improved the migration activity in response to stromal cell-derived factor 1 (SDF-1) concomitant with the activation of both MAPK<SUP>p42/44</SUP> and AKT signaling cascades. Both epigenetic regulatory compounds had little influence on cell surface marker phenotypes and the multi-potency of UC-MSCs. In contrast, VPA+S1P priming of UC-MSCs potentiated the proliferation, colony forming unit-fibroblast, and anti-inflammatory activities, which were severely inhibited in the case of 5-Aza treatment. Accordingly, the VPA+S1P-primed UC-MSCs exhibited upregulation of a subset of genes related to stem cell migration and anti-inflammation response. Thus, the present study demonstrated that VPA enables MSC priming with S1P at a low dosage by enhancing their migration and other therapeutic beneficial activities. This priming strategy for MSCs may provide a more efficient and safe application of MSCs for treating a variety of intractable disorders.</P>
Expression of Stem Cell Markers in Primo Vessel of Rat
Park, Eun Seok,Lee, Jeong Hoon,Kim, Won Jin,Heo, Jinbeom,Shin, Dong Myung,Leem, Chae Hun Hindawi Publishing Corporation 2013 Evidence-based Complementary and Alternative Medic Vol.2013 No.-
<P>Accumulating line of evidence support that adult tissues contain a rare population of pluripotent stem cells (PSCs), which differentiate into all types of cells in our body. Bonghan microcell (primo microcells (PMCs)) discovered in 1960s was reported to have a pluripotency like a stem cell <I>in vivo</I> as well as <I>in vitro</I> condition. Here, we describe the detailed morphology and molecular features of PMCs. PMCs reside in Bonghan duct (primo vessel (PV)) reported as a corresponding structure of acupuncture points and meridian system. We found that PMCs were frequently observed in the liver surface of the rat between 300 g and 400 g from April to June, suggesting that the their detection frequency depends on the weight, the season, and the organ of rat. As reported, PMCs freshly isolated from PVs were spherical ~1-2 <I><I>μ</I></I>m microsized cells. In contrast, a unique bithread or budding-shaped PMCs emerged during tissue culture around 8 days. RT-PCR analysis demonstrated that PVs-derived cells express the <I>Oct4</I>, the most important PSCs gene, in addition to several PSCs markers (<I>Sox2</I>, <I>Stella</I>, <I>Rex1</I>, and <I>Klf4</I>). Thus, we for the first time provide the evidence about Oct4-expressing stem-like characteristics for cells resident in PVs, a possible novel stem cell enriched niche.</P>
The Molecular Nature of Very Small Embryonic-Like Stem Cells in Adult Tissues
Kim, YongHwan,Jeong, Jaeho,Kang, Hyunsook,Lim, Jisun,Heo, Jinbeom,Ratajczak, Janina,Ratajczak, Mariusz Z.,Shin, Dong-Myung Korean Society for Stem Cell Research 2014 International journal of stem cells Vol.7 No.2
<P>Pluripotent stem cells (PSCs) have been considered as the most important cells in regenerative medicine as they are able to differentiate into all types of cells in the human body. PSCs have been established from several sources of embryo tissue or by reprogramming of terminally differentiated adult tissue by transduction of so-called Yamanaka factors (<I>Oct4</I>, <I>Sox2</I>, <I>Klf4</I>, and <I>cMyc</I>). Interestingly, accumulating evidence has demonstrated the residence of PSCs in adult tissue and with the ability to differentiate into multiple types of tissue-committed stem cells (TCSCs). We also recently demonstrated that a population of pluripotent Oct4<SUP>+</SUP> SSEA-1<SUP>+</SUP>Sca-1<SUP>+</SUP>Lin<SUP>−</SUP>CD45<SUP>−</SUP> very small embryonic-like stem cells (VSELs) resides in the adult murine bone marrow (BM) and in other murine tissue. These very small (∼3–6 <I>μ</I>m) cells express pluripotent markers such as Oct4, Nanog, and SSEA-1. VSELs could be specified into several tissue-residing TCSCs in response to tissue/organ injury, and thus suggesting that these cells have a physiological role in the rejuvenation of a pool of TCSCs under steady-state conditions. In this review article, we discuss the molecular nature of the rare population of VSELs which have a crucial role in regulating the pluripotency, proliferation, differentiation, and aging of these cells.</P>
Endoplasmic reticulum stress activates transglutaminase 2 leading to protein aggregation
LEE, JIN-HAENG,JEONG, JAEHO,JEONG, EUI MAN,CHO, SUNG-YUP,KANG, JEONG WOOK,LIM, JISUN,HEO, JINBEOM,KANG, HYUNSOOK,KIM, IN-GYU,SHIN, DONG-MYUNG UNKNOWN 2014 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE Vol.33 No.4
<P>Aberrant activation of transglutaminase 2 (TGase2) contributes to a variety of protein conformational disorders such as neurodegenerative diseases and age-related cataracts. The accumulation of improperly folded proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), which promotes either repair or degradation of the damaged proteins. Inadequate UPR results in protein aggregation that may contribute to the development of age-related degenerative diseases. TGase2 is a calcium-dependent enzyme that irreversibly modifies proteins by forming cross-linked protein aggregates. Intracellular TGase2 is activated by oxidative stress which generates large quantities of unfolded proteins. However, the relationship between TGase2 activity and UPR has not yet been established. In the present study, we demonstrated that ER stress activated TGase2 in various cell types. TGase2 activation was dependent on the ER stress-induced increase in the intracellular calcium ion concentration but not on the TGase2 protein expression level. Enzyme substrate analysis revealed that TGase2-mediated protein modification promoted protein aggregation concurrently with decreasing water solubility. Moreover, treatment with KCC009, a TGase2 inhibitor, abrogated ER stress-induced TGase2 activation and subsequent protein aggregation. However, TGase2 activation had no effect on ER stress-induced cell death. These results demonstrate that the accumulation of misfolded proteins activates TGase2, which further accelerates the formation of protein aggregates. Therefore, we suggest that inhibition of TGase2 may be a novel strategy by which to prevent the protein aggregation in age-related degenerative diseases.</P>