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Research Newsletter - October 2006

Spotlighted Research

In a paper published in the scientific journal Nature, a multi-institutional team of Harvard researchers, lead by David Scadden, Scientific-Co Director of HSCI, has advanced our understanding of physiological aging with a new study in which the impact of aging on blood stem cells was greatly reduced.

HSCI Researchers Identify Gene Product Involved In Stem Cell Aging And Death

A Harvard team, lead by Dr. David Scadden, has demonstrated that reducing the accumulation of the cyclin-dependent kinase inhibitor p16INK4a, a gene product previously noted to increase in aging cells, may reduce the physiological impact of aging on adult stem cells, and may improve the ability of aged tissues to better repair themselves. A report on their findings appeared in the journal, Nature, along with similar but independent findings from research teams at the Universities of North Carolina and Michigan.

The researchers found that reducing the accumulation of p16INK4a in haematopoietic stem cells (blood stem cells), reduces cell death and defects in the ability of the cells to repopulate.

"There are two things about this that are important," Scadden said. "It shows that specific properties of aging stem cells directly contribute to the reduced healing that occurs with aging; and it indicates that one might be able to modify a single gene product and improve the function of aging stem cells and repair of aging tissue, and that is very encouraging. This may mean that there are opportunities to target this gene product with medication and potentially decrease the impact of aging."

"However," Scadden noted, "p16INK4a is also known to suppress tumor formation, so a judicious balance must be struck between reduced p16INK4a when needed for repair and sufficient p16INK4a to prevent emergence of malignant stem cells."

The findings by the teams at Harvard, Michigan, and UNC indicate that they may have discovered a generalized mechanism by which various types of tissues have altered healing with age. Thus, discovering ways to suppress p16INK4a could potentially have an ameliorating effect on age-related cell-death and repair of tissue damage throughout the body.

The Scadden team includes Viktor Janzen, Randolf Forkert, Heather E. Fleming, and Yoriko Saito, of HSCI and MGH; Michael T. Waring, and David M. Dombkowski, of MGH; Ronald A. DePinho, of the Dana-Farber Cancer Institute and Harvard Medical School; and Norman E. Sharpless, of the Lineberger Comprehensive Cancer Center, at the University of North Carolina School of Medicine.

Janzen V, Forkert R, Fleming HE, Saito Y, Waring MT, Dombkowski DM, Cheng T, Depinho RA, Sharpless NE, Scadden DT. Stem-cell aging modified by the cyclin-dependent kinase inhibitor p16(INK4a). Nature. 2006 Sep 6; Read abstract.

Scientific Papers

Review and Commentary

  • Jaffer FA, Sosnovik DE, Nahrendorf M, Weissleder R. Molecular imaging of myocardial infarction. J Mol Cell Cardiol. 2006 Oct 23. Read Abstract.
  • Mikkola HK, Orkin SH. The journey of developing hematopoietic stem cells. Development. 2006 Oct;133(19):3733-44. Read Abstract.
  • Vaidya VS, Bonventre JV. Mechanistic biomarkers for cytotoxic acute kidney injury. Expert Opin Drug Metab Toxicol. 2006 Oct;2(5):697-713. Read Abstract.
  • Yates F, Daley GQ. Progress and prospects: gene transfer into embryonic stem cells. Gene Ther. 2006 Oct;13(20):1431-9. Read Abstract.

Blood

  • Bansal D, Scholl C, Frohling S, McDowell E, Lee BH, Dohner K, Ernst P, Davidson AJ, Daley GQ, Zon LI, Gilliland DG, Huntly BJ. Cdx4 dysregulates Hox gene expression and generates acute myeloid leukemia alone and in cooperation with Meis1a in a murine model. Proc Natl Acad Sci USA. 2006 Oct 26. Read Abstract.
  • Bellucci R, Oertelt S, Gallagher M, Li S, Zorn E, Weller E, Porcheray F, Alyea EP, Soiffer RJ, Munshi NC, Gershwin ME, Ritz J. Differential epitope mapping of antibodies to PDC-E2 in patients with hematologic malignancies after allogeneic hematopoietic stem cell transplantation and primary biliary cirrhosis. Blood. 2006 Oct 26. Read Abstract.
  • Ghinassi B, Sanchez M, Martelli F, Amabile G, Vannucchi AM, Migliaccio G, Orkin SH, Migliaccio AR. The hypomorphic Gata1low mutation alters the proliferation/differentiation potential of the common megakaryocytic-erythroid progenitor. Blood. 2006 Oct 12. Read Abstract.
  • Steidl U, Rosenbauer F, Verhaak RG, Gu X, Ebralidze A, Otu HH, Klippel S, Steidl C, Bruns I, Costa DB, Wagner K, Aivado M, Kobbe G, Valk PJ, Passegue E, Libermann TA, Delwel R, Tenen DG. Essential role of Jun family transcription factors in PU.1 knockdown-induced leukemic stem cells. Nat Genet. 2006 Nov;38(11):1269-77. Read Abstract.

Cancer

  • Mao J, Ligon KL, Rakhlin EY, Thayer SP, Bronson RT, Rowitch D, McMahon AP. A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway. Cancer Res. 2006 Oct 15;66(20):10171-8. Read Abstract.
  • Wei G, Twomey D, Lamb J, Schlis K, Agarwal J, Stam RW, Opferman JT, Sallan SE, den Boer ML, Pieters R, Golub TR, Armstrong SA. Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance. Cancer Cell. 2006 Oct;10(4):331-42. Read Abstract.

Cardiovascular System

  • Nahrendorf M, Jaffer FA, Kelly KA, Sosnovik DE, Aikawa E, Libby P, Weissleder R. Noninvasive vascular cell adhesion molecule-1 imaging identifies inflammatory activation of cells in atherosclerosis. Circulation. 2006 Oct 3;114(14):1504-11. Read Abstract.

Developmental Biology

  • Chen T, Bai H, Shao Y, Arzigian M, Janzen V, Attar E, Xie Y, Scadden DT, Wang ZZ. SDF-1/CXCR4 signaling modifies the capillary-like organization of human embryonic stem cell-derived endothelium in vitro. Stem Cells. 2006 Oct 12. Read Abstract.
  • van de Weyer PS, Muehlfeit M, Klose C, Bonventre JV, Walz G, Kuehn EW. A highly conserved tyrosine of Tim-3 is phosphorylated upon stimulation by its ligand galectin-9. Biochem Biophys Res Commun. 2006 Oct 23. Read Abstract.

Diabetes

  • Chen Z, Stockton J, Mathis D, Benoist C. Modeling CTLA4-linked autoimmunity with RNA interference in mice. Proc Natl Acad Sci USA. 2006 Oct 23. Read Abstract.

Imaging

  • Funovics MA, Alencar H, Montet X, Weissleder R, Mahmood U. Simultaneous fluorescence imaging of protease expression and vascularity during murine colonoscopy for colonic lesion characterization. Gastrointest Endosc. 2006 Oct;64(4):589-97. Read Abstract.

Immunology

  • Hirahara K, Liu L, Clark RA, Yamanaka K, Fuhlbrigge RC, Kupper TS. The majority of human peripheral blood CD4+CD25highFoxp3+ regulatory T cells bear functional skin-homing receptors. J Immunol. 2006 Oct 1;177(7):4488-94. Read Abstract.
  • Mostoslavsky G, Fabian AJ, Rooney S, Alt FW, Mulligan RC. Complete correction of murine Artemis immunodeficiency by lentiviral vector-mediated gene transfer. Proc Natl Acad Sci USA. 2006 Oct 24. Read Abstract.
  • Rennert PD, Ichimura T, Sizing ID, Bailly V, Li Z, Rennard R, McCoon P, Pablo L, Miklasz S, Tarilonte L, Bonventre JV. T cell, Ig domain, mucin domain-2 gene-deficient mice reveal a novel mechanism for the regulation of Th2 immune responses and airway inflammation. J Immunol. 2006 Oct 1;177(7):4311-21. Read Abstract.

Nervous System

  • Baker KL, Daniels SB, Lennington JB, Lardaro T, Czap A, Notti RQ, Cooper O, Isacson O, Frasca S Jr, Conover JC. Neuroblast protuberances in the subventricular zone of the regenerative MRL/MpJ mouse. J Comp Neurol. 2006 Oct 20;498(6):747-61. Read Abstract.
  • Ferrari D, Sanchez-Pernaute R, Lee H, Studer L, Isacson O. Transplanted dopamine neurons derived from primate ES cells preferentially innervate DARPP-32 striatal progenitors within the graft. Eur J Neurosci. 2006 Oct;24(7):1885-96. Read Abstract.
  • Kelly BB, Hedlund E, Kim C, Ishiguro H, Isacson O, Chikaraishi DM, Kim KS, Feng G. A tyrosine hydroxylase-yellow fluorescent protein knock-in reporter system labeling dopaminergic neurons reveals potential regulatory role for the first intron of the rodent tyrosine hydroxylase gene. Neuroscience. 2006 Oct 13;142(2):343-54. Read Abstract.
  • Ozdinler PH, Macklis JD. IGF-I specifically enhances axon outgrowth of corticospinal motor neurons. Nat Neurosci. 2006 Nov;9(11):1371-1381. Read Abstract.
  • Sonntag KC, Pruszak J, Yoshizaki T, van Arensbergen J, Sanchez-Pernaute R, Isacson O. Enhanced Yield of Neuroepithelial Precursors and Midbrain-Like Dopaminergic Neurons from Human Embryonic Stem Cells Using the BMP Antagonist Noggin. Stem Cells. 2006 Oct 12. Read Abstract.

Skeletal System

  • Long F, Joeng KS, Xuan S, Efstratiadis A, McMahon AP. Independent regulation of skeletal growth by Ihh and IGF signaling. Dev Biol. 2006 Oct 1;298(1):327-33. Read Abstract.

Technology

  • Montet X, Funovics M, Montet-Abou K, Weissleder R, Josephson L. Multivalent effects of RGD peptides obtained by nanoparticle display. J Med Chem. 2006 Oct 5;49(20):6087-93. Read Abstract.

Translational Medicine

  • Alyea EP, Kim HT, Ho V, Cutler C, Deangelo DJ, Stone R, Ritz J, Antin JH, Soiffer RJ. Impact of Conditioning Regimen Intensity on Outcome of Allogeneic Hematopoietic Cell Transplantation for Advanced Acute Myelogenous Leukemia and Myelodysplastic Syndrome. Biol Blood Marrow Transplant. 2006 Oct;12(10):1047-1055. Read Abstract.