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HSCI Science Update: November 2008

November 27, 2008

  • Two oncogenes replaced by chemicals to create iPS cells

    Induced pluripotent stem cells (iPS cells) can be created when a number of factors are introduced into somatic cells to "reprogram" them into cells that closely resemble embryonic stem cells in terms of their ability to differentiate into almost any cell type. The mix of factors that have been used thus far in the approximately two years since iPS cell reprogramming was first published has included two cancer-causing genes. The presence of these factors has clearly limited the potential therapeutic usefulness of this approach. HSCI Scientific Co-Director Doug Melton and colleagues describe a method, published recently in the journal Nature Biotechnology, for creating iPS cells without these two oncogenes by instead using a chemical, valproic acid, that affects the proteins that associate with DNA in the cell nucleus. This advance brings us one step closer to creating patient specific stem cells, derived by creating iPS cells from patients that may one day be used for therapeutic applications.

    Huangfu, D., Osafune, K., Maehr, R., Guo, W., Eijkelenboom, A., Chen, S., Muhlestein, W., Melton, D.A. (2008). Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol. 26, 1269-75.

  • Growth factor environment defines distinct pluripotent ground states

    Embryonic stem cell (ESC) lines are created by isolating ESCs from blastocyst-stage embryos, at days 4-5 of development. Pluripotent stem cells, cells that can develop into any of the three major tissue types endoderm, mesoderm, or ectoderm; can be derived at a slightly later stage of development from the post-implantation epiblast, a tissue type derived from the inner cell mass. These pluripotent epiblast stem cells (EpiSCs) are very similar to ESCs in many ways including the shape of their cell colonies and patterns of gene expression. Despite these similarities, EpiSCs fail to differentiate similarly to ESCs, suggesting that EpiSC pluripotency is dependent on specific developmental and environmental signals. HSCI Principal Faculty member Niels Geijsen and colleagues investigated the role of different growth factors in the state of pluripotent stem cells. Their findings, published recently in the journal Cell, elaborate the role of growth factors in defining the pluripotent state and contribute to our understanding of how the pluripotent state can be altered. This increased understanding, may in turn have tremendous implications for our ability to coax pluripotent cells to stay pluripotent, or become a number of different cell types.

    Chou, Y.F., Chen, H.H., Eijpe, M., Yabuuchi, A., Chenoweth, J.G., Tesar, P., Lu, J., McKay, R.D., Geijsen, N. (2008). The growth factor environment defines distinct pluripotent ground states in novel blastocyst-derived stem cells. Cell 135, 449-61.

  • Improving treatment for glioblastoma multiforme brain tumors

    Glioblastoma multiforme brain tumors are among the most common type of brain tumor diagnosed in adults and have an associated life expectancy of only 9-12 months. These types of tumors do not respond well to traditional therapies including radiation and chemotherapy. One approach to increase the efficacy of treating these tumors uses tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which selectively kills tumor cells. Neural stem cells target tumor masses such as gliomas and have been found to be a useful drug delivery mechanism when engineered to secrete antitumor therapies such as TRAIL. While TRAIL offers many advantages over current approaches, TRAIL-based treatments have some challenges because some tumor cells are resistant to it, drug delivery can be insufficient, and the half-life of the delivery method may be too short. To improve upon these deficiencies, HSCI faculty and affiliate members Ralph Weissleder, Khalid Shah, and colleagues, who had studied the use of neural stem cells with TRAIL as well, have been experimenting with a new delivery mechanism and adjuvant therapy to enhance TRAIL's effectiveness. In a study recently published in Molecular Cancer Therapeutics, the researchers found that using adeno-associated virus vectors to deliver a secretable form of TRAIL and co-treating with a chemotherapeutic agent enhanced tumor cell death. This combined approach may represent a efficacious way to treat glioblastomas, adding a degree of optimism to a difficult prognosis.

    Hingtgen S, Ren X, Terwilliger E, Classon M, Weissleder R, Shah K. (2008). Targeting multiple pathways in gliomas with stem cell and viral delivered S-TRAIL and Temozolomide. Mol Cancer Ther. (2008) 7, 3575-85.