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Find video protocols related to scientific articles indexed in Pubmed.
Ca(2+) and EGF induce the differentiation of human embryo mesenchymal stem cells into epithelial-like cells.
Cell Biol. Int.
PUBLISHED: 08-01-2014
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The mesenchymal to epithelial transition (MET) occurs in organ development and anti-tumorigenesis. We have investigated the effects of calcium (Ca(2+) ) and epidermal growth factor (EGF) on human mesenchymal stem cell (hMSCs) differentiation into epithelial-like cells. hMSCs lost their biological characteristics after EGF transfection, and MET was achieved by adding 0.4?mmol Ca(2+) . Western blotting and immunofluorescence showed expression of EGF, keratin, keratin 19 (K19), ?1-integrin, E-cadherin and phosphorylated focal adhesion kinase (p-FAK, Ser-910) increased in hMSCs infected with EGF and exposed to Ca(2+) , although Smad3 activation was downregulated. hMSCs co-stimulated with EGF transfection and Ca(2+) can therefore differentiate into epithelial-like cells in vitro.
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Mir-218 contributes to the transformation of 5-Aza/GF induced umbilical cord mesenchymal stem cells into hematopoietic cells through the MITF pathway.
Mol. Biol. Rep.
PUBLISHED: 03-25-2014
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Experiments with 5'-azacytidine and hematopoietic growth factor approved for the transformation of human mesenchymal cells into hematopoietic cells have demonstrated that cell fate can be dramatically altered by changing the epigenetic state of cells. Here, we demonstrate that umbilical cord-derived human mesenchymal stem cells (uMSC) are easily accessible and could be induced into cells with hematopoietic function. Furthermore, we focused on the crucial miRNAs and relative transcription factors (TFs) in our study. We show that combined Aza/GF incubation can increase expression of miR-218, miR-150, and miR-451. Accordingly, miR-218 overexpression achieved an increase in expression of CD34 (3-13%), CD45 (50-65%), CD133 and c-Kit in uMSCs that cultured with Aza/GF. The expression of the relevant transcriptional factors, such as HoxB4 and NF-Ya, was higher than in the negative control group or miR-218 inhibitor transfected group, and microphthalmia-associated transcription factor (MITF) is regarded to be a direct target of miR-218, as demonstrated by luciferase assays. Overexpression of miR-218 might, in conjunction with the MITF, upregulate the expression of NF-Ya and HoxB4, which induce a hematopoietic state. We concluded that miR-218 might have a role in the transformation of hematopoietic cells through the MITF pathway.
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Occurrence, Sources, and Potential Toxicity of Polycyclic Aromatic Hydrocarbons in Surface Soils from the Yellow River Delta Natural Reserve, China.
Arch. Environ. Contam. Toxicol.
PUBLISHED: 03-13-2014
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A total of 46 surface soil samples collected from the experimental area, buffer area, and core area of the Yellow River Delta Natural Reserve (YRDNR), China, and an adjacent area outside the reserve were analyzed for 23 PAHs including highly carcinogenic dibenzopyrene isomers. The total concentrations ranged from 87.2 to 319 ng/g for ?23PAHs and 79.2 to 311 ng/g for ?16PAHs with average concentrations of 133 and 119 ng/g, respectively. Pearson correlation analysis implied that the total polycyclic aromatic compound (PAH) concentrations had a significant positive correlation with the total organic carbon content on the condition that four sites with abnormal values were removed. Low molecular-weight 2- to 3-ring PAHs predominated in the present study. Source diagnostics based on PAHs isomer ratios, principal component analysis, and multiple linear regression suggested that petroleum contributed most to the PAH contamination in the YRDNR, whereas a potential toxicity assessment using BaPeq indicated that the four dibenzopyrenes were the major carcinogenic PAH contributors in the area under investigation, although their concentrations only represented a small proportion of the total PAH concentrations.
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Mesenchymal stem cells with modification of junctional adhesion molecule a induce hair formation.
Stem Cells Transl Med
PUBLISHED: 02-20-2014
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The junctional adhesion molecule A (JAM-A) has been shown to serve a crucial role in the proliferation, differentiation, and tube-like formation of epithelial cells during angiogenesis. The role of JAM-A in hair follicle (HF) regeneration has not yet been reported. In this study, we used human JAM-A-modified human mesenchymal stem cells (MSCs) to repair HF abnormalities in BALB/c nu/nu mice. The JAM-A gene and JAM-A short hairpin RNA were transfected into cultured human MSCs to generate the JAM-A overexpression MSCs (JAM-A(ov) MSCs) and JAM-A knockdown MSCs (JAM-A(kd) MSCs), respectively. These cells were injected intradermally into the skin of nude mice during the first telogen phase of the HF that occurs 21 days postnatally. We found that JAM-A(ov) MSCs migrated into the HF sheath and remodeled HF structure effectively. The HF abnormalities such as HF curve and HF zigzag were remodeled, and hair formation was improved 7 days following injection in both the JAM-A(ov) MSC and MSC groups, compared with the JAM-A(kd) MSC group or negative control group. Furthermore, the JAM-A(ov) MSC group showed enhanced hair formation in contrast to the MSC group, and the number of curved and zigzagged HFs was reduced by 80% (p < .05). These results indicated that JAM-A(ov) MSCs improved hair formation in nude mice through HF structure remodeling.
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LIFR?-CT3 induces differentiation of a human acute myelogenous leukemia cell line HL-60 by suppressing miR-155 expression through the JAK/STAT pathway.
Leuk. Res.
PUBLISHED: 01-22-2014
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The distal cytoplasmic motifs of the leukemia inhibitory factor receptor ?-chain (LIFR?-CT3) and its TAT fusion protein (TAT-CT3) can independently suppress cell viability and induce myeloid differentiation in human leukemia HL-60 cells in our previous studies. But its underlying mechanism remains undefined. Herein, we show that a prokaryotic expressed TAT-CT3 induced a rapid elevation of STAT3 phosphorylation (pSTAT3), and then suppress the transcription of miR-155 and induce the elevation of SOCS-1, which further inhibited STAT3 phosphorylation for a long-term period. Our result indicated a novel mechanism of TAT-CT3 to promote HL60 cells differentiation, which provides some potential therapeutic targets for future acute myelogenous leukemia therapy.
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Distinct roles of sAPP-? and sAPP-? in regulating U251 cell differentiation.
Curr Alzheimer Res
PUBLISHED: 07-21-2013
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Sequential cleavages of APP by ?-secretase and ?-secretase release ?-amyloid (A?) and one secreted form of APP (sAPP-?) in Alzheimer s disease (AD). Alternatively, in non-pathological situations, APP is predominantly cleaved by ?-secretase within the amyloid sequence, to release the other soluble form of APP, sAPP-?. However, the functions of the two types of sAPP are still unclear. We performed this study to compare the function of sAPP-? and sAPP-? in differentiation of the glioma cell line U251. We found that sAPP-? suppressed astrocytic differentiation and promoted neuronal differentiation in U251 cells. Additionally, sAPP-? enhanced U251 terminal differentiation into a cholinergic-like neuronal phenotype. In contrast, sAPP-? suppressed neuronal differentiation and promoted the astrocytic differentiation of U251 cells. These findings could not only enrich the knowledge of the potential physiological function of sAPP-? and sAPP-?, but also indicate that they may be connected to the pathological mechanism of AD. Furthermore, these findings suggest that new strategies, such as increasing the level of sAPP-? and/or decreasing the level of sAPP-? in brain, or transplanting stem cells with increased sAPP-? and/or decreased sAPP-?, may have potential value for AD treatment.
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Directed differentiation of aged human bone marrow multipotent stem cells effectively generates dopamine neurons.
In Vitro Cell. Dev. Biol. Anim.
PUBLISHED: 04-18-2013
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This study aimed to isolate aged human bone marrow multipotent stem cells (hAMSCs) with the potential for multilineage differentiation and to directly induce the cells to generate dopamine neurons, which could be used for Parkinsons disease therapy. We compared different culture methods for stem cells from aged human bone marrow and identified hAMSCs that could proliferate in vitro for at least 60 doubling times. Using RT-PCR and IHC, we found that these hAMSCs expressed pluripotent genes, such as Oct4, Sox2, and Nanog. In vitro studies also proved that hAMSCs could differentiate into three germ layer-derived cell types, such as osteogenic, chondrogenic, adipogenic, and hepatocyte-liked cells. After induction for more than 20 d in vitro with retinoic acid, basic fibroblast growth factor, and sonic hedgehog using a two-step method and withdrawal of serum, hAMSCs could differentiate into dopamine neurons at the positive ratio of 70%, which showed DA secretion function upon depolarization. In conclusion, we suggest that hAMSCs can be used as cell sources to develop medical treatments to prevent the progression of Parkinsons disease, especially in aged persons.
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Epidermal growth factor promotes transforming growth factor-?1-induced epithelial-mesenchymal transition in HK-2 cells through a synergistic effect on Snail.
Mol. Biol. Rep.
PUBLISHED: 03-24-2013
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Epithelial-mesenchymal transition (EMT) is a central mechanism for wound healing, tissue repair, organ fibrosis and carcinoma progression in adults. Evidence shows that both epidermal growth factor (EGF) and transforming growth factor-?1 (TGF-?1) are upregulated during renal interstitial fibrosis, and that co-stimulation of EGF and TGF-?1 could induce renal tubular epithelial cells to undergo EMT more effectively than EGF or TGF-?1 alone. This study was intended to explore the molecular mechanism underlying this effect. HK-2 cells underwent apparent EMT with increased cell motility after co-stimulation of EGF and TGF-?1 as compared with TGF-?1 or EGF alone. Co-stimulation of EGF and TGF-?1 resulted in rapid and robust ERK1/2 activation and induced persistent high expression of Snail protein. Treatment with the MEK inhibitor U0126 followed by co-stimulation with EGF and TGF-?1 prevented the upregulation of Snail protein, EMT and motility, without impairing Snail mRNA. TGF-?1 induced Snail at the transcriptional level, which was not influenced by EGF. Inhibition of Snail expression by siRNA interference also prevented EMT caused by co-stimulation of EGF and TGF-?1. These data suggest that EGF promotes TGF-?1-induced EMT through a synergistic effect on Snail at the post-transcriptional level in HK-2 cells.
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Critical regulation of miR-200/ZEB2 pathway in Oct4/Sox2-induced mesenchymal-to-epithelial transition and induced pluripotent stem cell generation.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 02-05-2013
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Fibroblasts can be reprogrammed to induced pluripotent stem cells (iPSCs) by application of transcription factors octamer-binding protein 4 (Oct4), SRY-box containing gene 2 (Sox2), Kruppel-like factor 4 (Klf4), and c-Myelocytomatosis oncogene (c-Myc) (OSKM), but the underlying mechanisms remain unclear. Here, we report that exogenous Oct4 and Sox2 can bind at the promoter regions of mir-141/200c and mir-200a/b/429 cluster, respectively, and induce the transcription activation of miR-200 family during the OSKM-induced reprogramming. Functional suppression of miR-200s with specific inhibitors significantly represses the OSKM-caused mesenchymal-to-epithelial transition (MET, an early event in reprogramming of fibroblasts to iPSCs) and iPSC generation, whereas overexpression of miR-200s promotes the MET and iPSC generation. Mechanistic studies showed that miR-200s significantly repress the expression of zinc finger E-box binding homeobox 2 (ZEB2) through directly targeting its 3 UTR and direct inhibition of ZEB2 can mimic the effects of miR-200s on iPSC generation and MET process. Moreover, the effects of miR-200s during iPSC generation can be blocked by ZEB2 overexpression. Collectively, our findings not only reveal that members of the miR-200 family are unique mediators of the reprogramming factors Oct4/Sox2, but also demonstrate that the miR-200/ZEB2 pathway as one critical mechanism of Oct4/Sox2 to induce somatic cell reprogramming at the early stage.
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Endogenous miRNA sponge lincRNA-RoR regulates Oct4, Nanog, and Sox2 in human embryonic stem cell self-renewal.
Dev. Cell
PUBLISHED: 01-23-2013
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The embryonic stem cell (ESC) transcriptional and epigenetic networks are controlled by a multilayer regulatory circuitry, including core transcription factors (TFs), posttranscriptional modifier microRNAs (miRNAs), and some other regulators. However, the role of large intergenic noncoding RNAs (lincRNAs) in this regulatory circuitry and their underlying mechanism remains undefined. Here, we demonstrate that a lincRNA, linc-RoR, may function as a key competing endogenous RNA to link the network of miRNAs and core TFs, e.g., Oct4, Sox2, and Nanog. We show that linc-RoR shares miRNA-response elements with these core TFs and that linc-RoR prevents these core TFs from miRNA-mediated suppression in self-renewing human ESC. We suggest that linc-RoR forms a feedback loop with core TFs and miRNAs to regulate ESC maintenance and differentiation. These results may provide insights into the functional interactions of the components of genetic networks during development and may lead to new therapies for many diseases.
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Neural stem cell-like cells derived from autologous bone mesenchymal stem cells for the treatment of patients with cerebral palsy.
J Transl Med
PUBLISHED: 01-21-2013
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Stem cell therapy is a promising treatment for cerebral palsy, which refers to a category of brain diseases that are associated with chronic motor disability in children. Autologous MSCs may be a better cell source and have been studied for the treatment of cerebral palsy because of their functions in tissue repair and the regulation of immunological processes.
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MicroRNA-181 regulates CARM1 and histone arginine methylation to promote differentiation of human embryonic stem cells.
PLoS ONE
PUBLISHED: 01-03-2013
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As a novel epigenetic mechanism, histone H3 methylation at R17 and R26, which is mainly catalyzed by coactivator-associated protein arginine methyltransferase 1 (CARM1), has been reported to modulate the transcription of key pluripotency factors and to regulate pluripotency in mouse embryos and mouse embryonic stem cells (mESCs) in previous studies. However, the role of CARM1 in human embryonic stem cells (hESCs) and the regulatory mechanism that controls CARM1 expression during ESCs differentiation are presently unknown. Here, we demonstrate that CARM1 plays an active role in the resistance to differentiation in hESCs by regulating pluripotency genes in response to BMP4. In a functional screen, we identified the miR-181 family as a regulator of CARM1 that is induced during ESC differentiation and show that endogenous miR-181c represses the expression of CARM1. Depletion of CARM1 or enforced expression of miR-181c inhibits the expression of pluripotency genes and induces differentiation independent of BMP4, whereas overexpression of CARM1 or miR-181c inhibitor elevates Nanog and impedes differentiation. Furthermore, expression of CARM1 rescue constructs inhibits the effect of miR-181c overexpression in promoting differentiation. Taken together, our findings demonstrate the importance of a miR-181c-CARM1 pathway in regulating the differentiation of hESCs.
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Contact by melanoma cells causes malignant transformation of human epithelial-like stem cells via alpha V integrin activation of transforming growth factor ?1 signaling.
Exp. Biol. Med. (Maywood)
PUBLISHED: 03-24-2011
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The embryonic microenvironment is known to suppress the tumorigenic phenotype of aggressive cancer cells; however, the effects of tumorigenic microenvironments on stem cells have not been sufficiently explored due to the lack of suitable model systems. In order to study the tumorigenic microenviornment, we developed a novel in vitro model system for induction of malignant transformation of human epithelial-like stem cells (hEpSCs), involving co-cultivation and close contact of hEpSCs with the A375 melanoma cell line, together with mutagen treatment of hEpSCs with dimethylbenzanthracene (DMBA). Both factors (close contact and mutagen treatment) were required to transform hEpSCs in vitro and cause phenotypic changes characteristic of epithelial to mesenchymal transition (EMT), including colony formation, decreased E-cadherin and increased N-cadherin and vimentin expression. Direct contact between tumor cells and hEpSCs treated with DMBA increased integrin alpha V (ITGAV gene) expression and caused local activation of the transforming growth factor (TGF)-?1/Smad signaling pathways in hEpSCs. The novel model system described here is being used to elucidate the microenvironmental factors and biological mechanisms involved in the induction of neoplastic progression in hEpSCs in vitro by A375 melanoma cells. A better understanding of the molecular mechanisms by which melanoma cells exert these effects on hEpSCs may open up new avenues for therapeutic and preventive cancer interventions.
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Free LIF receptor ?-chain distal cytoplasmic motifs enhance Jak2-independent STAT3 phosphorylation and induce differentiation in HL-60 cells.
Oncol. Rep.
PUBLISHED: 02-22-2011
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The leukemia inhibitory factor (LIF) affects multiple types of leukemia cells in vitro through the functional LIF receptor (LIFR), which comprises a complex of the LIFR ?-chain (LIFR ?) and gp130. As Jak2/STAT3 has been proven to be a significant mediator in the LIF-induced differentiation of promyeloid leukemia cells, we constructed a recombinant vector, pcDNA3.0-CT3 (containing the structurally conserved triple YXXQ motifs of LIFR ?, termed LIFR ?-CT3), and its specific tyrosine-mutated counterpart, pcDNA3.0-MUT, to determine the sites and examine the corresponding mechanisms involved in STAT3 phosphorylation. We found that the triple YXXQ motifs of LIFR ?-CT3 are capable of up-regulating phosphorylated levels of STAT3 in a Jak2-independent manner prior to the induction of myeloid differentiation by LIFR ?-CT3 in the human promyeloid cell line HL-60. By specifically blocking Jak2 using the AG-490 inhibitor, we observed that the LIFR ?-CT3 group of HL-60 cells still demonstrated up-regulation of phosphorylated STAT3 and this up-regulation could result in the myeloid differentiation of HL-60 cells. These results may shed light on acute promyeloid leukemia therapy in future clinical practice.
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microRNA-29b is a novel mediator of Sox2 function in the regulation of somatic cell reprogramming.
Cell Res.
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Fibroblasts can be reprogrammed into induced pluripotent stem cells (iPSCs) by the application of Yamanaka factors (OSKM), but the mechanisms underlying this reprogramming remain poorly understood. Here, we report that Sox2 directly regulates endogenous microRNA-29b (miR-29b) expression during iPSC generation and that miR-29b expression is required for OSKM- and OSK-mediated reprogramming. Mechanistic studies show that Dnmt3a and Dnmt3b are in vivo targets of miR-29b and that Dnmt3a and Dnmt3b expression is inversely correlated with miR-29b expression during reprogramming. Moreover, the effect of miR-29b on reprogramming can be blocked by Dnmt3a or Dnmt3b overexpression. Further experiments indicate that miR-29b-DNMT signaling is significantly involved in the regulation of DNA methylation-related reprogramming events, such as mesenchymal-to-epithelial transition (MET) and Dlk1-Dio3 region transcription. Thus, our studies not only reveal that miR-29b is a novel mediator of reprogramming factor Sox2 but also provide evidence for a multistep mechanism in which Sox2 drives a miR-29b-DNMT signaling axis that regulates DNA methylation-related events during reprogramming.
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hMSCs possess the potential to differentiate into DP cells in vivo and in vitro.
Cell Biol Int Rep (2010)
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DP (dermal papilla) is a mesenchyme-derived structure situated at the base of the HF (hair follicle) that plays an important role in embryonic hair morphogenesis and maintenance of the hair growth cycle. hMSCs (human mesenchymal stem cells) have gained widespread attention in the field of tissue engineering, but not much is known about the differentiation of hMSCs into DP cells. hMSCs involved in HF formation were examined in our previous study. Here, we have explored the differentiation potential of hMSCs into DP cells by co-culturing hMSCs with DP cells, which proved to be the case. During the differentiation process, the expression of versican, CD133, SCF (stem cell factor), ET-1 (endothelin-1) and bFGF (basic fibroblast growth factor) increased. Compared with hMSCs alone, the aggregate number clearly increased when co-cultured with DP cells. The expression in vivo of HLA-I (human leucocyte antigen class I) was confined to DP of the newly formed HF. The data suggest that hMSCs possess the potential to differentiate into DP cells in vivo and in vitro.
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Accelerated expansion of epidermal keratinocyte and improved dermal reconstruction achieved by engineered amniotic membrane.
Cell Transplant
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In this study, we used human amniotic membrane (AM) to prepare a dermal scaffold with intact basement membrane (BM) and good biostability for quick expansion and transplantation of epidermal keratinocytes (EKs). Fresh AM was treated by repeated freeze-thaw cycles and DNase digestion. This new method was able to cleanse the cell components effectively and retain the BM structure with continuous distributions of laminin, collagen IV, VI, and VII. Subsequently, the acellular amniotic membrane (AAM) was cross-linked with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) for 5 min, 30 min, and 6 h. With the time of cross-linking prolonging, the mechanical strength and biostability of AAM increased gradually, while its cytotoxicity to EKs also increased. The 5-min cross-linked AAM (5min-AAM) had no significant cytotoxicity with good histocompatibility. The relative cell viability of EKs seeded on the 5min-AAM surface was 367 ± 33% and 631 ± 43% at 7 and 14 days of culture, respectively, both higher than 294 ± 30% and 503 ± 41% of the conventional cell culture dish (CCD) group, and the proportion of P63-positive cells was significantly higher than that of the CCD group on day 7 (54.32 ± 4.27% vs. 33.32 ± 3.18%, p < 0.05). When the 5min-AAM loaded with EKs (EK-AAM) was grafted onto full-thickness skin defects in nude mice, the cells survived well and formed an epidermis similar to normal skin. The new epidermis was thicker, and reconstruction of the dermal structure was good with an intact BM. Four weeks after transplantation, the wound contraction rate in the EK-AAM group was 43.09 ± 7.05%, significantly lower than that in the EK sheet group (57.49 ± 5.93%) and control group (69.94 ± 9.47%) (p < 0.05). In conclusion, repeated freeze-thaw treatment with appropriate EDC cross-linking offers AAM an intact BM structure with good operability and biostability. It may prove to be an ideal dermal scaffold to promote expansion of EKs in vitro and be transplanted for reconstruction of the dermal structure.
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Leukemia inhibitory factor receptor ?-chain: a potential method for acute promyeloid leukemia therapy.
Med. Hypotheses
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Leukemia inhibitory factor (LIF) affects multiple types of leukemia cells in vitro through its functional receptor LIFR, which comprises a complex of the LIFR ?-chain (LIFR?) and gp130. Researchers have recently observed that the C-terminus of the LIFR? cytoplasmic domain contains as many conserved YXXQ motifs as gp130 (C-terminal triple YXXQ motifs, LIFR?-CT3), whose free structure has been shown to be capable of activating STAT3 phosphorylation in the cytoplasm and consequently activating STAT3-related downstream molecules in the nucleus. This process can induce pathological acute myeloid leukemia (AML) or acute promyeloid leukemia (APL) cells to differentiate into mature granulocytes, simulating the LIF-related differential cascade. This process reduces or inhibits the side effects caused by toxic all-trans retinoid acid (ATRA), which has long been used as a fundamental medication for treating AML/APL in clinical practice despite its related high relapse rate. Therefore, we believe that it is possible to maximize the beneficial effects of LIF by enriching LIFR?-CT3 in AML/APL cell cytoplasm. The aims of this work were to enrich LIFR?-specific motifs in leukemia cells using molecular biological methods and evaluate the use of membrane-permeable polypeptides as a novel possible AML/APL therapy in combination with or independent of ATRA-based chemotherapy.
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MiR-138 promotes induced pluripotent stem cell generation through the regulation of the p53 signaling.
Stem Cells
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Induced pluripotent stem (iPS) cells, especially those reprogrammed from patient somatic cells, have a great potential usage in regenerative medicine. The expression of p53 has been proven as a key barrier limiting iPS cell generation, but how p53 is regulated during cell reprogramming remains unclear. In this study, we found that the ectopic expression of miR-138 significantly improved the efficiency of iPS cell generation via Oct4, Sox2, and Klf4, with or without c-Myc (named as OSKM or OSK, respectively), without sacrificing the pluripotent characteristics of the generated iPS cells. Exploration of the mechanism showed that miR-138 directly targeted the 3 untranslated region (UTR) of p53, significantly decreasing the expression of p53 and its downstream genes. Furthermore, the ectopic expression of p53 having a mutant 3-UTR, which cannot be bound by miR-138, seriously impaired the effect of miR-138 on p53 signaling and OSKM-initiated somatic cell reprogramming. Combined with the fact that miR-138 is endogenously expressed in fibroblasts, iPS cells, and embryonic stem cells, our study demonstrated that regulation of the p53 signaling pathway and promotion of iPS cell generation represent an unrevealed important function of miR-138.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.