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HSCI Science Update: November 2009

November 12, 2009

  • Fidelity of DNA Methylation Critical for Hematopoietic Stem Cells and Progenitors

    DNA methylation plays an important role in gene regulation and in the control of a range of biological processes. Recently, HSCI Principal Faculty member Stuart Orkin, MD, and colleagues elaborated a very important role for a factor involved in DNA methylation, Dnmt1. In a paper recently published in the journal Cell Stem Cell, the authors describe a role for Dnmt1 in the regulation of quiescent adult hematopoietic stem cells (HSCs) and found that when this factor was disrupted a range of defects were seen in the HSCs, including losing their ability to differentiate normally. DNA methylation represents a not entirely well understood, yet critical component of gene regulation. A better understanding of factors involved in DNA methylation is vital for our understanding of stem cell replication and differentiation and our ability to harness this knowledge toward therapeutic goals.

    Trowbridge, J.J., Snow, J.W., Kim, J., Orkin, S.H. (2009). DNA methyltransferase 1 is essential for and uniquely regulates hematopoietic stem and progenitor cells. Cell Stem Cell 5, 442-9.

  • Lighting Up Our Understanding of Heart Development

    The mammalian heart is generated from two groups of progenitor cells termed first and second heart field cells. These cells give rise to the different cell types that make up the heart. The way in which these more specialized cell types emerge remains not entirely understood. In order to gain a more comprehensive understanding of these two groups of progenitors, HSCI Principal Faculty members Ken Chien, MD, PhD, Kit Parker, PhD, and fellow researchers used a two-colored fluorescent reporter system to identify and isolate the two progenitor cell populations and use genome profiling techniques to define the molecular differences between the two groups. They published these findings recently in the journal Science along with their discovery of a ventricular heart muscle progenitor lineage. These advances represent significant gains in our understanding of heart progenitor cell differentiation and learning how distinct cell types in the heart are formed.

    Domian, I.J., Chiravuri, M., van der Meer, P., Feinberg, A.W., Shi, X., Shao, Y., Wu, S.M., Parker, K.K., Chien, K.R. (2009). Generation of functional ventricular heart muscle from mouse ventricular progenitor cells. Science 326, 426-9

  • Small Molecules Aim to Increase Clinical Utility of iPS cells

    Reprogramming adult cells into induced pluripotent stem cells (iPS cells) has been one of the most lauded discoveries in stem cell science. There is concern, however, with the potential utility of these cells since the protocol by which they are made typically uses multiple factors and a viral delivery method that may be questionable in terms of safety in a clinical setting. In order to identify small molecules that might replace these reprogramming factors, HSCI Principal Faculty member Kevin Eggan, PhD, and HSCI Director of Translational Medicine Lee Rubin, PhD, and colleagues conducted a chemical screen to identify small molecules that could replace the factor Sox 2 in the reprogramming process. Their recently published paper in the journal Cell Stem Cell reports the discovery of a small molecule they identified that takes the place of Sox2 in reprogramming by inhibiting the Tgf-beta signaling pathway and activating the factor Nanog. Such findings may help move iPS cells closer to the clinic by increasing their safety and enabling them to realize their potential therapeutic potential, such as in creating patient-specific cell lines.

    Ichida, J.K., Blanchard, J., Lam, K., Son, E.Y., Chung, J.E., Egli, D., Loh, K.M., Carter, A.C., Di Giorgio, F.P., Koszka, K., Huangfu, D., Akutsu, H., Liu, D.R., Rubin, L.L., Eggan, K. (2009). A Small-Molecule Inhibitor of Tgf-beta Signaling Replaces Sox2 in Reprogramming by Inducing Nanog. Cell Stem Cell. 2009 Oct 7. [Epub ahead of print]