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Homozygous deficiency of the transcription factor Gata4 in mice causes lethality due to defects in ventral morphogenesis and heart tube formation. There is increasing evidence demonstrating that GATA4 function is also relevant for normal developed organ systems, including the heart and endocrinum. To analyze the implication of Gata4 beyond development, we generated transgenic mice expressing inducible small interfering RNA against Gata4. In longitudinal analysis, efficient suppression of Gata4 mRNA (down to 80% of wild-type levels) and protein expression in the heart was detected 38 days after induction of Gata4 short hairpin RNA. Decreased Gata4 expression was associated with reduction in the expression of known cardiac target genes, but the function of the heart remained unperturbed at 20-30% of normal Gata4 levels. Interestingly, Gata4 expression was almost abolished in the ovary and testis. This was accompanied in the testis by a significant reduction of GATA4 downstream target genes, such as the genes encoding Mullerian inhibiting substance (MIS) and steroidogenic acute regulatory (StAR) protein. By contrast, expression levels of Mis and Star were only slightly modified in the ovary, and concentrations of circulating FSH and LH were normal in female transgenic mice after induction of Gata4 short hairpin RNA. However, inhibition of Gata4 expression led to the formation of ovarian teratoma in 10% of females. Histology of the teratomas showed predominantly ectodermal and mesodermal structures. Our data demonstrate that Gata4 is critically involved in the function and integrity of the gonads in vivo.
J Mol Endocrinol 2009 Oct
PMID:Transgenic mice expressing small interfering RNA against Gata4 point to a crucial role of Gata4 in the heart and gonads. 1949 Nov 95

The discovery of human embryonic stem cells (hESCs) has dramatically increased the tools available to medical scientists interested in regenerative medicine. However, direct injection of hESCs, and cells differentiated from hESCs, into living organisms has thus far been hampered by significant cell death, teratoma formation, and host immune rejection. Understanding the in vivo hESC behavior after transplantation requires novel imaging techniques to longitudinally monitor hESC localization, proliferation, and viability. Molecular imaging, and specifically bioluminescent reporter gene imaging, has given investigators a high-throughput, inexpensive, and sensitive means for tracking in vivo cell proliferation over days, weeks, and even months. This advancement has significantly increased the understanding of the spatiotemporal kinetics of hESC engraftment and proliferation in living subjects. In this chapter, the specific materials and methods needed for tracking stem cell proliferation with bioluminescence imaging will be described.
Methods Mol Biol 2009
PMID:Bioluminescence reporter gene imaging of human embryonic stem cell survival, proliferation, and fate. 1968 2

Human artificial chromosome (HAC) has several advantages as a gene therapy vector, including stable episomal maintenance that avoids insertional mutations and the ability to carry large gene inserts including the regulatory elements. Induced pluripotent stem (iPS) cells have great potential for gene therapy, as such cells can be generated from the individual's own tissues, and when reintroduced can contribute to the specialized function of any tissue. As a proof of concept, we show herein the complete correction of a genetic deficiency in iPS cells derived from Duchenne muscular dystrophy (DMD) model (mdx) mice and a human DMD patient using a HAC with a complete genomic dystrophin sequence (DYS-HAC). Deletion or mutation of dystrophin in iPS cells was corrected by transferring the DYS-HAC via microcell-mediated chromosome transfer (MMCT). DMD patient- and mdx-specific iPS cells with the DYS-HAC gave rise to differentiation of three germ layers in the teratoma, and human dystrophin expression was detected in muscle-like tissues. Furthermore, chimeric mice from mdx-iPS (DYS-HAC) cells were produced and DYS-HAC was detected in all tissues examined, with tissue-specific expression of dystrophin. Therefore, the combination of patient-specific iPS cells and HAC-containing defective genes represents a powerful tool for gene and cell therapies.
Mol Ther 2010 Feb
PMID:Complete genetic correction of ips cells from Duchenne muscular dystrophy. 2012 63

Pluripotent very small embryonic/epiblast derived stem cells (VSELs) as we hypothesize are deposited at begin of gastrulation in developing tissues and play an important role as backup population of pluripotent stem cells (PSCs) for tissue committed stem cells (TCSCs). We envision that during steady state conditions these cells may be involved in tissue rejuvenation and in processes of regeneration/repair after organ injuries. Molecular analysis of adult bone marrow (BM)-derived purified VSELs revealed that they i) express pluripotent stem cells markers e.g., Oct4, Nanog, Klf-4, SSEA-1 ii) share several markers characteristic for epiblast as well as migratory primordial germ cells (PGCs), and iii) possess a unique pattern of genomic imprinting (e.g., erasure of differently methylated regions at Igf2-H19 and Rasgrf1 loci and hypermethylation at KCNQ1 and Igf2R loci). This supports that VSELs are related to epiblast-derived migrating PGC-like cells and, despite their pluripotent stem cell character, changes in the epigenetic signature of imprinted genes keep these cells quiescent in adult tissues and prevent them from teratoma formation. In contrast epigenetic changes/mutations that lead to activation of imprinted genes could potentially lead to tumor formation by these cells. Mounting evidence accumulates that perturbation of expression of imprinted genes is a common phenomenon observed in developing tumors.
Mol Cells 2010 Jun
PMID:Molecular characterization of isolated from murine adult tissues very small embryonic/epiblast like stem cells (VSELs). 2052 17

The concept of regenerating diseased myocardium by implanting engineered heart tissue (EHT) is intriguing. Yet it was limited by immune rejection and difficulties to be generated at a size with contractile properties. Somatic cell nuclear transfer is proposed as a practical strategy for generating autologous histocompatible stem (nuclear transferred embryonic stem [NT-ES]) cells to treat diseases. Nevertheless, it is controversial as NT-ES cells may pose risks in their therapeutic application. EHT from NT-ES cell-derived cardiomyocytes was generated through a series of improved techniques in a self-made mould to keep the EHTs from contraction and provide static stretch simultaneously. After 7 days of static and mechanical stretching, respectively, the EHTs were implanted to the infarcted rat heart. Four weeks after transplantation, the suitability of EHT in heart muscle repair after myocardial infarction was evaluated by histological examination, echocardiography and multielectrode array measurement. The results showed that large (thickness/diameter, 2-4 mm/10 mm) spontaneously contracting EHTs was generated successfully. The EHTs, which were derived from NT-ES cells, inte grated and electrically coupled to host myocardium and exerted beneficial effects on the left ventricular function of infarcted rat heart. No teratoma formation was observed in the rat heart implanted with EHTs for 4 weeks. NT-ES cells can be used as a source of seeding cells for cardiac tissue engineering. Large contractile EHT grafts can be constructed in vitro with the ability to survive after implantation and improve myocardial performance of infarcted rat hearts.
J Cell Mol Med 2010 Dec
PMID:Engineered heart tissue graft derived from somatic cell nuclear transferred embryonic stem cells improve myocardial performance in infarcted rat heart. 2058 30

The testis-derived male germ-line stem (GS) cell, the in vitro counterpart of spermatogonial stem cell (SSC), can initiate donor-derived spermatogenesis in recipient testes and therefore, has been viewed as a future therapeutic modality for treatment of male infertility in azoospermic patients and in cancer patients who are expecting chemotherapy. Upon extended in vitro culture, GS cells also generate a second cell type called multipotent adult germ-line stem (maGS) cell which, upon testicular transplantation, produces teratoma instead of initiating spermatogenesis. Here, we show that expressions of both Let-7a and Let-7d were consistently higher while that of miR-294 (embryonic stem cell-cycle-regulating miRNA; ESCC) was lower in GS cells than in maGS cells. Furthermore, among several putative targets of Let-7 identified by in silico bioinformatics, expressions of Igf2 and H19 mRNA targets significantly differed between GS and maGS cells. However, although the CTCF binding factor (a component of DNA methylation machinery at Igf2-H19 cluster) was also a putative target for Let-7, the difference in expressions of Igf2 and H19 between GS and maGS cells was not mediated through a change in DNA methylation. Both GS and maGS cells maintained androgenetic imprinting at the Igf2-H19 imprinting control region and Peg1 differentially methylated region. In conclusion, our study suggests that high Let-7 expression may be a unique property of GS cells and expressions of Let-7 and ESCC miRNAs may serve as miRNA signatures to distinguish them from maGS cells during clinical transplantation, to avoid the likelihood of teratoma formation due to maGS cells generated during extended in vitro culture of GS cells.
Mol Hum Reprod 2010 Nov
PMID:MicroRNA signature in testes-derived male germ-line stem cells. 2061 Jun 16

Human amniotic epithelial cells (hAECs) are a recently identified type of stem cell. Thanks to their ready availability and the lower risk of teratoma formation, hAECs have been studied and tested for a variety of human disease treatments and tissue reconstruction efforts. This aim of this study was to establish a stable tracking system to further monitor hAECs in vivo after transplantation. hAECs were isolated from the placentas of patients who visited the Hunan Province Maternity and Child Care Hospitals between Jan 2008 and Jan 2009. Using the classic transfection/infection technique, we successfully introduced green fluorescent protein (GFP) into cultured hAECs with an adeno-associated virus (AAV) vector. The initial preparation of the AAV-GFP virus stock was titrated using HT1081 cells, and further used for the infection of hAECs. GFP(+) hAECs preserve the capacity of differentiation into hepatocyte-like cells with the expression of cytokeratin-18 (CK18) and albumin (ALB). AAV-GFP virus-infected hAECs were transplanted through the spleen into severe combined immune deficiency (SCID) mice via hepatectomy. Four weeks later, the GFP and human albumin expressions were examined in multiple organs through immunofluorescence staining. In culture, over 50% of the hAECs were GFP-positive 3 days after infection. Following transplantation, AAV-GFP-infected hAECs survived and continued to express GFP in the host for up to 4 weeks. These cells were primarily found in the spleen and liver, expressing human albumin. This study provides a feasible and stable system to track hAECs. It may prove useful to further identify their biological characteristics after transplantation and to elucidate their beneficial roles for therapeutic purposes.
Cell Mol Biol Lett 2011 Jun
PMID:Labeling and tracking human amniotic epithelial cells with green fluorescent protein in an adeno-associated virus vector. 2122 67

If induced pluripotent stem (iPS) cells are to be used to treat damaged tissues or repair organs in elderly patients, it will be necessary to establish iPS cells from their tissues. To determine the feasibility of using this technology with elderly patients, we asked if it was indeed possible to establish iPS cells from the bone marrow (BM) of aged mice. BM cells from aged C57BL/6 mice carrying the green fluorescence protein (GFP) gene were cultured with granulocyte macrophage-colony stimulating factor (GM-CSF) for 4 days. Four factors (Oct3/4, Sox2, Klf4 and c-Myc) were introduced into the BM-derived myeloid (BM-M) cells. The efficiency of generating iPS cells from aged BM cultured in GM-CSF was low. However, we succeeded in obtaining BM-M-iPS cells from aged C57BL/6 mice, which carried GFP. Our BM-M-iPS cells expressed SSEA-1 and Pou5f1 and were positive for alkaline phosphatase staining. The iPS cells did make teratoma with three germ layers following injection into syngeneic C57BL/6 mice, and can be differentiated to three germ layers in vitro. By co-culturing with OP9, the BM-M-iPS cells can be differentiated to the myeloid lineage. The differentiated BM-M-iPS cells proliferated well in the presence of GM-CSF, and lost expression of Nanog and Pou5f1, at least in part, due to methylation of their promoters. On the contrary, Tnf and Il1b gene expression was upregulated and their promoters were hypomethylated.
J Mol Cell Biol 2011 Apr
PMID:Establishment of induced pluripotent stem cells from aged mice using bone marrow-derived myeloid cells. 2122 11

Testicular cancer is a rare tumor, subdivided into seminomatous and nonseminomatous tumors. Whereas there are no serum tumor markers in the first group, they are present in nonseminomatous tumors, and are also important prognostic factors. Overall, the prognosis for testicular cancers is good, which makes the choice of accurate treatment intensity between under- and overtreatment often difficult. Residual masses in advanced clinical stages occur frequently but are nonvital tissue. PET with F-18 FDG has no defined role in imaging of primary tumors where CT is the first-choice imaging modality. For assessing the success of chemotherapy in the presence of residual masses, especially in pure seminoma, F-18 FDG PET is an important tool. In nonseminomatous tumors, it is hampered by the false-negative results in mature teratoma, for which reason false-negative results are a common problem. F-18 FDG PET performs best in predicting relapse in seminoma residuals larger than 3 cm. So far, no alternative to F-18 FDG for PET imaging of testicular cancer has been found. PET-CT has not yet been proven to be superior to PET alone in testicular cancer.
Methods Mol Biol 2011
PMID:PET in testicular cancer. 2133 37

Embryonic stem (ES) cells with the capacity for germ line transmission have only been verified in mouse and rat. Methods for derivation, propagation, and differentiation of ES cells from domestic animals have not been fully established. Here, we describe derivation of ES cells from goat embryos. In vivo-derived embryos were cultured on goat fetal fibroblast feeders. Embryos either attached to the feeder layer or remained floating and expanded in culture. Embryos that attached showed a prominent inner cell mass (ICM) and those that remained floating formed structures resembling ICM disks surrounded by trophectodermal cells. ICM cells and embryonic disks were isolated mechanically, cultured on feeder cells in the presence of hLIF, and outgrown into ES-like colonies. Two cell lines were cultured for 25 passages and stained positive for alkaline phosphatase, POU5F1, NANOG, SOX2, SSEA-1, and SSEA-4. Embryoid bodies formed in suspension culture without hLIF. One cell line was cultured for 2 years (over 120 passages). This cell line differentiated in vitro into epithelia and neuronal cells, and could be stably transfected and selected for expression of a fluorescent marker. When cells were injected into SCID mice, teratomas were identified 5-6 weeks after transplantation. Expression of known ES cell markers, maintenance in vitro for 2 years in an undifferentiated state, differentiation in vitro, and formation of teratomas in immunodeficient mice provide evidence that the established cell line represents goat ES cells. This also is the first report of teratoma formation from large animal ES cells.
Mol Reprod Dev 2011 Mar
PMID:Establishment of goat embryonic stem cells from in vivo produced blastocyst-stage embryos. 2138 53


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