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Research Newsletter - May 2008

Spotlight

This month's spotlighted article, published online in the journal Nature, is by new HSCI Principal Faculty member Alexander Meissner, PhD, Assistant Professor in Harvard's new inter-school Department of Stem Cell and Regenerative Biology and Associate Member of the Broad Institute.

Dissecting direct reprogramming through integrative genomic analysis

Abstract:

Somatic cells can be reprogrammed to a pluripotent state through the ectopic expression of defined transcription factors. Understanding the mechanism and kinetics of this transformation may shed light on the nature of developmental potency and suggest strategies with improved efficiency or safety. Here we report an integrative genomic analysis of reprogramming of mouse fibroblasts and B lymphocytes. Lineage-committed cells show a complex response to the ectopic expression involving induction of genes downstream of individual reprogramming factors. Fully reprogrammed cells show gene expression and epigenetic states that are highly similar to embryonic stem cells. In contrast, stable partially reprogrammed cell lines show reactivation of a distinctive subset of stem-cell-related genes, incomplete repression of lineage-specifying transcription factors, and DNA hypermethylation at pluripotency-related loci. These observations suggest that some cells may become trapped in partially reprogrammed states owing to incomplete repression of transcription factors, and that DNA de-methylation is an inefficient step in the transition to pluripotency. We demonstrate that RNA inhibition of transcription factors can facilitate reprogramming, and that treatment with DNA methyltransferase inhibitors can improve the overall efficiency of the reprogramming process.

Mikkelsen TS, Hanna J, Zhang X, Ku M, Wernig M, Schorderet P, Bernstein BE, Jaenisch R, Lander ES, Meissner A. Dissecting direct reprogramming through integrative genomic analysis. Nature. 2008 May 28. Read Paper.

Scientific Papers

Review and Commentary

  • Koh I, Hong R, Weissleder R, Josephson L. Sensitive NMR Sensors Detect Antibodies to Influenza. Angew Chem Int Ed Eng. 2008 Apr 21;47(22):4119-4121. No abstract available. Read Abstract. Read Abstract.
  • Martin-Puig S, Wang Z, Chien KR. Lives of a heart cell: tracing the origins of cardiac progenitors. Cell Stem Cell. 2008 Apr 10;2(4):320-31. Read Abstract. Read Abstract.
  • Papayannopoulou T, Scadden DT. Stem-cell ecology and stem cells in motion. Blood. 2008 Apr 15;111(8):3923-30. Read Abstract. Read Abstract.
  • Punzo C, Cepko CL. Ultrasound-guided in utero injections allow studies of the development and function of the eye. Dev Dyn. 2008 Apr;237(4):1034-42. Read Abstract. Read Abstract.
  • Wang Y, Armstrong SA. Cancer: inappropriate expression of stem cell programs? Cell Stem Cell. 2008 Apr 10;2(4):297-9. Read Abstract. Read Abstract.
  • Weissleder R, Pittet MJ. Imaging in the era of molecular oncology. Nature. 2008 Apr 3;452(7187):580-9. Review. Read Abstract. Read Abstract.
  • Williams DA. Foamy virus vectors come of age. Mol Ther. 2008 Apr;16(4):635-6. No abstract available. Read Abstract. Read Abstract.

Blood

  • Min IM, Pietramaggiori G, Kim FS, Passegue E, Stevenson KE, Wagers AJ. The transcription factor EGR1 controls both the proliferation and localization of hematopoietic stem cells. Cell Stem Cell. 2008 Apr 10;2(4):380-91. Read Abstract. Read Abstract.
  • Muller LU, Milsom MD, Kim MO, Schambach A, Schuesler T, Williams DA. Rapid Lentiviral Transduction Preserves the Engraftment Potential of Fanca(-/-) Hematopoietic Stem Cells. Mol Ther. 2008 Apr 8. Read Abstract. Read Abstract.

Cancer

  • Austin KM, Gupta ML, Coats SA, Tulpule A, Mostoslavsky G, Balazs AB, Mulligan RC, Daley G, Pellman D, Shimamura A. Mitotic spindle destabilization and genomic instability in Shwachman-Diamond syndrome. J Clin Invest. 2008 Apr;118(4):1511-8. Read Abstract. Read Abstract.
  • Kirstetter P, Schuster MB, Bereshchenko O, Moore S, Dvinge H, Kurz E, Theilgaard-Monch K, Mansson R, Pedersen TA, Pabst T, Schrock E, Porse BT, Jacobsen SE, Bertone P, Tenen DG, Nerlov C. Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells. Cancer Cell. 2008 Apr;13(4):299-310. Read Abstract. Read Abstract.
  • Quintas-Cardama A, Tong W, Manshouri T, Vega F, Lennon PA, Cools J, Gilliland DG, Lee F, Cortes J, Kantarjian H, Garcia-Manero G. Activity of tyrosine kinase inhibitors against human NUP214-ABL1-positive T cell malignancies. Leukemia. 2008 Apr 10. Read Abstract. Read Abstract.
  • Wernig G, Kharas MG, Okabe R, Moore SA, Leeman DS, Cullen DE, Gozo M, McDowell EP, Levine RL, Doukas J, Mak CC, Noronha G, Martin M, Ko YD, Lee BH, Soll RM, Tefferi A, Hood JD, Gilliland DG. Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer Cell. 2008 Apr;13(4):311-20. Read Abstract. Read Abstract.

Cell Biology

  • Saharinen P, Eklund L, Miettinen J, Wirkkala R, Anisimov A, Winderlich M, Nottebaum A, Vestweber D, Deutsch U, Koh GY, Olsen BR, Alitalo K. Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts. Nat Cell Biol. 2008 May;10(5):527-37. Epub 2008 Apr 20. Read Abstract. Read Abstract.

Developmental Biology

  • Kim DS, Ross SE, Trimarchi JM, Aach J, Greenberg ME, Cepko CL. Identification of molecular markers of bipolar cells in the murine retina. J Comp Neurol. 2008 Apr 10;507(5):1795-810. Read Abstract. Read Abstract.
  • Sue N, Jack BH, Eaton SA, Pearson RC, Funnell AP, Turner J, Czolij R, Denyer G, Bao S, Molero-Navajas JC, Perkins A, Fujiwara Y, Orkin SH, Bell-Anderson K, Crossley M. Targeted disruption of the Basic Kruppel-like Factor (Klf3) gene reveals a role in adipogenesis. Mol Cell Biol. 2008 Apr 7. Read Abstract. Read Abstract.
  • Wang J, Levasseur DN, Orkin SH. Requirement of Nanog dimerization for stem cell self-renewal and pluripotency. Proc Natl Acad Sci USA. 2008 Apr 29;105(17):6326-31. Epub 2008 Apr 24. Read Abstract. Read Abstract.
  • Wu X, Tu X, Joeng KS, Hilton MJ, Williams DA, Long F. Rac1 activation controls nuclear localization of beta-catenin during canonical Wnt signaling. Cell. 2008 Apr 18;133(2):340-53. Read Abstract. Read Abstract.

Diabetes

  • Cha HC, Oak NR, Kang S, Tran TA, Kobayashi S, Chiang SH, Tenen DG, Macdougald OA. Phosphorylation of C/EBPalpha regulates GLUT4 expression and glucose transport in adipocytes. J Biol Chem. 2008 Apr 11. Read Abstract. Read Abstract.

Imaging

  • Kelly KA, Bardeesy N, Anbazhagan R, Gurumurthy S, Berger J, Alencar H, Depinho RA, Mahmood U, Weissleder R. Targeted nanoparticles for imaging incipient pancreatic ductal adenocarcinoma. PLoS Med. 2008 Apr 15;5(4):e85. Read Abstract. Read Abstract.
  • Kelly KA, Setlur SR, Ross R, Anbazhagan R, Waterman P, Rubin MA, Weissleder R. Detection of early prostate cancer using a hepsin-targeted imaging agent. Cancer Res. 2008 Apr 1;68(7):2286-91. Read Abstract. Read Abstract.
  • Shah K, Hingtgen S, Kasmieh R, Figueiredo JL, Garcia-Garcia E, Martinez-Serrano A, Breakefield X, Weissleder R. Bimodal viral vectors and in vivo imaging reveal the fate of human neural stem cells in experimental glioma model. J Neurosci. 2008 Apr 23;28(17):4406-13. Read Abstract. Read Abstract.

Muscular System

  • Luth ES, Jun SJ, Wessen MK, Liadaki K, Gussoni E, Kunkel LM. Bone marrow side population cells are enriched for progenitors capable of myogenic differentiation. J Cell Sci. 2008 May 1;121(Pt 9):1426-34. Epub 2008 Apr 8. Read Abstract. Read Abstract.

Nervous System

  • Hedlund EM, Pruszak J, Lardaro T, Ludwig W, Vi√ɬ±uela A, Kim KS, Isacson O. Embryonic Stem (ES) Cell-derived Pitx3-eGFP Midbrain Dopamine Neurons Survive Enrichment by FACS and Function in an Animal Model of Parkinson's Disease. Stem Cells. 2008 Apr 3. Read Abstract. Read Abstract.
  • Kohno T, Wang H, Amaya F, Brenner GJ, Cheng JK, Ji RR, Woolf CJ. Bradykinin enhances AMPA and NMDA receptor activity in spinal cord dorsal horn neurons by activating multiple kinases to produce pain hypersensitivity. J Neurosci. 2008 Apr 23;28(17):4533-40. Read Abstract. Read Abstract.
  • Lagali PS, Balya D, Awatramani GB, Munch TA, Kim DS, Busskamp V, Cepko CL, Roska B. Light-activated channels targeted to ON bipolar cells restore visual function in retinal degeneration. Nat Neurosci. 2008 Apr 27. Read Abstract. Read Abstract.
  • Mendez I, Vinuela A, Astradsson A, Mukhida K, Hallett P, Robertson H, Tierney T, Holness R, Dagher A, Trojanowski JQ, Isacson O. Dopamine neurons implanted into people with Parkinson's disease survive without pathology for 14 years. Nat Med. 2008 May;14(5):507-9. Epub 2008 Apr 6. Read Abstract. Read Abstract.
  • Wang X, Liu J, Zhu H, Tejima E, Tsuji K, Murata Y, Atochin DN, Huang PL, Zhang C, Lo EH. Effects of Neuroglobin Overexpression on Acute Brain Injury and Long-Term Outcomes After Focal Cerebral Ischemia. Stroke. 2008 Apr 10. Read Abstract. Read Abstract.
  • Wernig M, Zhao JP, Pruszak J, Hedlund E, Fu D, Soldner F, Broccoli V, Constantine-Paton M, Isacson O, Jaenisch R. Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson's disease. Proc Natl Acad Sci USA. 2008 Apr 15;105(15):5856-61. Epub 2008 Apr 7. Read Abstract. Read Abstract.

Renal System

  • Zhang J, Brown RP, Shaw M, Vaidya VS, Zhou Y, Espandiari P, Sadrieh N, Stratmeyer M, Keenan J, Kilty CG, Bonventre JV, Goering PL. Immunolocalization of Kim-1, RPA-1, and RPA-2 in Kidney of Gentamicin-, Mercury-, or Chromium-Treated Rats: Relationship to Renal Distributions of iNOS and Nitrotyrosine. Toxicol Pathol. 2008 Apr 25. Read Abstract. Read Abstract.

Tissue Engineering

  • Rocha FG, Sundback CA, Krebs NJ, Leach JK, Mooney DJ, Ashley SW, Vacanti JP, Whang EE. The effect of sustained delivery of vascular endothelial growth factor on angiogenesis in tissue-engineered intestine. Biomaterials. 2008 Jul;29(19):2884-90. Epub 2008 Apr 8. Read Abstract. Read Abstract.