Browsing by Subject "Hematopoietic Stem Cell"
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Item Development of a Human Immune System from Hematopoietic Stem Cells in a Human/Mouse Xenogeneic Model(2006-12-20) Melkus, Michael W.; Garcia-Martinez, J. VictorT cells play a central role in the development of immune responses. Patients lacking T cells due to genetic defects such as DiGeorge or Nezelof's syndrome and individuals infected with the human immunodeficiency virus are highly susceptible to infections and cancers. The lack of adequate in vivo models of T cell neogenesis has hindered the development and clinical implementation of effective therapeutic modalities aimed at treating these and other clinically important maladies. Transplantation of severe combined immunodeficient (SCID) mice with human hematopoietic stem cells results in long-term engraftment and systemic reconstitution with human progenitor, B and myeloid cells but curiously, human T cells are rarely present in any tissue. While the implantation of SCID mice with human fetal thymus and liver (SCID-hu thy/liv mice) allows for the development of abundant thymocytes that are localized to the human organoid implant, there is minimal systemic repopulation with human T cells. Here I present evidence that transplantation of autologous human hematopoietic fetal liver CD34+ cells into NOD/SCID mice previously implanted with fetal thymic and liver tissues results in long-term, systemic human T cell homeostasis. In addition to human T cells, these mice have systemic repopulation with human B cells, monocytes/macrophages and dendritic cells (DC). This mouse model of the human immune system has been designated as BLT for a Bone marrow transplant in fetal Liver and Thymus implanted mice. T cells in these mice generate human MHC Class I and Class II restricted adaptive immune responses to Epstein Barr virus infection and are activated by human DCs to mount potent T cell immune response to super antigens. Administration of the super-antigen toxic shock syndrome toxin-1 (TSST-1) resulted in the specific systemic expansion of human Vbeta 2+ T cells, release of human pro-inflammatory cytokines and localized specific activation and maturation of human CD11c+ dendritic cells. These results represent the first demonstration of long-term systemic human T cell reconstitution in vivo allowing for the manifestation of the differential response by human DCs to TSST-1.Item Understanding the Role of SCL in Early Mammalian Development Using Mouse Embryonic Stem Cell Differentiation as a Model(2010-05-14) Ismailoglu, Ismail; Kyba, MichaelHow a complete organism develops from a single cell is among the most complicated questions in life sciences. Early experimental studies on the development of animals were performed on amphibians and birds due to the size and accessibility of their embryos, while studies in placental mammals have been limited by the difficulty posed by in utero development. In vitro differentiation of ES cells provides a convenient model for the study of the mammalian development. Since ES cells can be grown and maintained in a pluripotent state virtually forever, ample amount of research material for molecularbiological studies can be produced; differentiating ES cells are easily accessible and they can also be manipulated genetically. I have used the ES cell differentiation model to study the bHLH factor SCL, a critical regulator of the formation of the hematopoietic lineage in the early embryo and the maturation of erythrocytes and megakaryocytes later on. The latter function of the protein has been studied extensively, but a complete molecular analysis of the former function has been lacking. My work shows that SCL can skew the patterning of the mesoderm towards the hematopoietic lineage. This function required the interaction of SCL with LMO2. Transcriptional profiling revealed organizer genes FoxA2 and Chordin as novel downregulated targets of SCL during this time. Differentiation of human pluripotent cells to be used in cellular therapy or to generate replacement tissues; is considered to be one of the most promising branches of medical research. Considering the importance of SCL in hematopoiesis, we hypothesized that SCL can direct differentiation of pluripotent cells to this lineage in a simple culture system. Ectopic expression of SCL induced hematopoiesis at low levels. Co-expression of LMO2 and GATA2 increased efficiency of the programming significantly.