SPOTLIGHTED RESEARCH REVIEW and COMMENTARY ARTICLES SCIENTIFIC PAPERS blood disease cancer cardiovascular disease development diabetes gastrointestinal imaging immunology nervous system diseases technology

This HSCI Research Update synthesizes the scientific work published by HSCI Principal Faculty each month. To continue receiving this newsletter, please register as an HSCI Affiliate or Friend by clicking here. If you are having problems viewing this newletter, click here to view it in your web browser. 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.

Review and Commentary Articles

• Shivraj Sohur U, Emsley JG, Mitchell BD, Macklis JD. Adult neurogenesis and cellular brain repair with neural progenitors, precursors and stem cells. Philos Trans R Soc Lond B Biol Sci. 2006 Sep;361(1473):1477-1497. Read abstract.
• Zorn E, Ritz J. Studying Human Regulatory T Cells In vivo. Clin Cancer Res. 2006 Sep 15;12(18):5265-7. Read abstract.
• Rosenzweig A. Cardiac cell therapy--mixed results from mixed cells. N Engl J Med. 2006 Sep 21;355(12):1274-7. Read abstract.
• Amadio JP, Walsh CA. Brain Evolution and Uniqueness in the Human Genome. Cell. 2006 Sep 22;126(6):1033-1035. Read abstract.
• Isacson O. What are the long-term effects of neural grafting in patients with Huntington's disease? Nat Clin Pract Neurol. 2006 Sep;2(9):470-1. Read abstract.
• Mullally A, Ritz J. Beyond HLA: the significance of genomic variation for allogeneic hematopoietic stem cell transplantation. Blood. 2006 Sep 28. Read abstract.

Scientific Papers

Blood Disease

• Zada AA, Geletu MH, Pulikkan JA, Muller-Tidow C, Reddy VA, Christopeit M, Hiddemann WD, Behre HM, Tenen DG, Behre G. Proteomic analysis of acute promyelocytic leukemia: PML-RARalpha leads to decreased phosphorylation of OP18 at serine 63. Proteomics. 2006 Sep 25. Read abstract.
• Clark RA, Kupper TS. IL-15 and dermal fibroblasts induce proliferation of natural regulatory T cells isolated from human skin. Blood. 2006 Sep 12; Read abstract.
• Tefferi A, Barosi G, Mesa RA, Cervantes F, Deeg HJ, Reilly JT, Verstovsek S, Dupriez B, Silver RT, Odenike O, Cortes J, Wadleigh M, Solberg LA Jr, Camoriano JK, Gisslinger H, Noel P, Thiele J, Vardiman JW, Hoffman R, Cross NC, Gilliland DG, Kantarjian H; IWG for Myelofibrosis Research and Treatment (IWG-MRT). International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT). Blood. 2006 Sep 1;108(5):1497-503. Read abstract.
• Chan IT, Kutok JL, Williams IR, Cohen S, Moore S, Shigematsu H, Ley TJ, Akashi K, Le Beau MM, Gilliland DG. Oncogenic K-ras cooperates with PML-RAR alpha to induce an acute promyelocytic leukemia-like disease. Blood. 2006 Sep 1;108(5):1708-15. Read abstract.

Cancer

• Newton JR, Kelly KA, Mahmood U, Weissleder R, Deutscher SL. In vivo selection of phage for the optical imaging of PC-3 human prostate carcinoma in mice. Neoplasia. 2006 Sep;8(9):772-80. Read abstract.
• Aghi M, Cohen KS, Klein RJ, Scadden DT, Chiocca EA. Tumor Stromal-Derived Factor-1 Recruits Vascular Progenitors to Mitotic Neovasculature, where Microenvironment Influences Their Differentiated Phenotypes. Cancer Res. 2006 Sep 15;66(18):9054-64. Read abstract.
• Mowry SE, Ho A, Lotempio MM, Sadeghi A, Blackwell KE, Wang MB. Quality of life in advanced oropharyngeal carcinoma after chemoradiation versus surgery and radiation. Laryngoscope. 2006 Sep;116(9):1589-93. Read abstract.

Cardiovascular

• 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 Sep 25. Read abstract.
• Prunier F, Pfister O, Hadri L, Liang L, Del Monte F, Liao R, Hajjar RJ. Delayed erythropoietin therapy reduces post-MI cardiac remodeling only at a dose that mobilizes endothelial progenitor cells. Am J Physiol Heart Circ Physiol. 2006 Sep 22. Read abstract.

Development

• Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, Sharpless NE. p16(INK4a) induces an age-dependent decline in islet regenerative potential. Nature. 2006 Sep 6; Read abstract.
• Juriloff DM, Harris MJ, McMahon AP, Carroll TJ, Lidral AC. Wnt9b is the mutated gene involved in multifactorial nonsyndromic cleft lip with or without cleft palate in A/WySn mice, as confirmed by a genetic complementation test. Birth Defects Res A Clin Mol Teratol. 2006 Sep 22;76(8):574-579. Read abstract.
• Hu G, Tang J, Zhang B, Lin Y, Hanai J, Galloway J, Bedell V, Bahary N, Han Z, Ramchandran R, Thisse B, Thisse C, Zon LI, Sukhatme VP. A novel endothelial-specific heat shock protein HspA12B is required in both zebrafish development and endothelial functions in vitro. J Cell Sci. 2006 Oct 1;119(Pt 19):4117-26. Read abstract.
• Arango NA, Huang TT, Fujino A, Pieretti-Vanmarcke R, Donahoe PK. Expression analysis and evolutionary conservation of the mouse germ cell-specific D6Mm5e gene. Dev Dyn. 2006 Sep;235(9):2613-9. Read abstract.
• Janzen V, Forkert R, Fleming HE, Saito Y, Waring MT, Dombkowski DM, Cheng T, Depinho RA, Sharpless NE, Scadden DT. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16(INK4a). Nature. 2006 Sep 6; Read abstract.

Diabetes

• Evgenov NV, Medarova Z, Pratt J, Pantazopoulos P, Leyting S, Bonner-Weir S, Moore A. In vivo imaging of immune rejection in transplanted pancreatic islets. Diabetes. 2006 Sep;55(9):2419-28. Read abstract.

Gastrointestinal

• Yamamoto-Furusho JK, Barnich N, Xavier R, Hisamatsu T, Podolsky DK. Centaurin Beta 1 down-regulates NOD1 and NOD2-dependent NF-kB activation. J Biol Chem. 2006 Sep 27. Read abstract.

Imaging

• Lamfers ML, Fulci G, Gianni D, Tang Y, Kurozumi K, Kaur B, Moeniralm S, Saeki Y, Carette JE, Weissleder R, Vandertop WP, van Beusechem VW, Dirven CM, Chiocca EA. Cyclophosphamide Increases Transgene Expression Mediated by an Oncolytic Adenovirus in Glioma-Bearing Mice Monitored by Bioluminescence Imaging. Mol Ther. 2006 Sep 20. Read abstract.
• Kubo S, Levantini E, Kobayashi S, Kocher O, Halmos B, Tenen DG, Takahashi M. Three-dimensional magnetic resonance microscopy of pulmonary solitary tumors in transgenic mice. Magn Reson Med. 2006 Sep;56(3):698-703. Read abstract.

Immunology

• Liu L, Fuhlbrigge RC, Karibian K, Tian T, Kupper TS. Dynamic programing of CD8(+) T cell trafficking after live viral immunization. Immunity. 2006 Sep;25(3):511-20. Read abstract.
• Scheller M, Huelsken J, Rosenbauer F, Taketo MM, Birchmeier W, Tenen DG, Leutz A. Hematopoietic stem cell and multilineage defects generated by constitutive beta-catenin activation. Nat Immunol. 2006 Oct;7(10):1037-47. Read abstract.

Nervous System Diseases

• Chang BS, Duzcan F, Kim S, Cinbis M, Aggarwal A, Apse KA, Ozdel O, Atmaca M, Zencir S, Bagci H, Walsh CA. The role of RELN in lissencephaly and neuropsychiatric disease. Am J Med Genet B Neuropsychiatr Genet. 2006 Sep 6; Read abstract.

Technology

• Lamb J, Crawford ED, Peck D, Modell JW, Blat IC, Wrobel MJ, Lerner J, Brunet JP, Subramanian A, Ross KN, Reich M, Hieronymus H, Wei G, Armstrong SA, Haggarty SJ, Clemons PA, Wei R, Carr SA, Lander ES, Golub TR. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science. 2006 Sep 29;313(5795):1929-35. Read abstract.
• Yang M, Lim CC, Liao R, Zhang X. A novel microfluidic impedance assay for monitoring endothelin-induced cardiomyocyte hypertrophy. Biosens Bioelectron. 2006 Sep 6; Read abstract.
• Hynynen K, McDannold N, Vykhodtseva N, Raymond S, Weissleder R, Jolesz FA, Sheikov N. Focal disruption of the blood-brain barrier due to 260-kHz ultrasound bursts: a method for molecular imaging and targeted drug delivery. J Neurosurg. 2006 Sep;105(3):445-54. Read abstract.

The Harvard Stem Cell Institute is a scientific collaborative established to fulfill the promise of stem cell biology as the basis for cures and treatments for a wide range of chronic medical conditions.

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