SPOTLIGHTED RESEARCH REVIEW and COMMENTARY ARTICLES SCIENTIFIC PAPERS blood disease cancer cardiovascular disease development diabetes imaging immunology kidney disease lung disease nervous system diseases skeletal tissue engineering translational medicine

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. Spotlight In a research paper published in Nature, HSCI Scientific Co-Director, Douglas Melton and collaborators at the Harvard Stem Cell Institute and Massachusetts General Hospital, describe how organ size is limited by the number of embryonic progenitor cells in the pancreas but not the liver.

Organ size is limited by the number of embryonic progenitor cells in the pancreas but not the liver

The determinants of vertebrate organ size are poorly understood, but the process is thought to depend heavily on growth factors and other environmental cues. In the blood and central nervous system, for example, organ mass is determined primarily by growth-factor-regulated cell proliferation and apoptosis to achieve a final target size. Here, we report that the size of the mouse pancreas is constrained by an intrinsic programme established early in development, one that is essentially not subject to growth compensation. Specifically, final pancreas size is limited by the size of the progenitor cell pool that is set aside in the developing pancreatic bud. By contrast, the size of the liver is not constrained by reductions in the progenitor cell pool. These findings show that progenitor cell number, independently of regulation by growth factors, can be a key determinant of organ size.

Figure 1

Figure 1 | Pancreatic progenitor cell ablation. a, Experimental design. Two classes of embryos are generated by crossing Pdx1tTA/1 and tetODTA/DTA mice: Pdx11/1; tetODTA/1 (Control; 1/DTA) and Pdx1tTA/1; tetODTA/1 (Experimental; tTA/DTA). In untreated tTA/DTA embryos (2Tet), Pdx11 progenitors are killed after tTA-mediated expression of DTA. Treatment with tetracycline (1Tet) represses tTA-mediated transcription, allowing survival of Pdx11 progenitors. b, Pregnant females were given plain water or water containing tetracycline throughout gestation; embryos were examined at E18.5. The midgut of a control (1/DTA) embryo is shown (right panel) to illustrate normal structures. d, duodenum; dp, dorsal pancreas; Li, liver; s, stomach; spl, spleen; vp, ventral pancreas.

Figure 2

Figure 2 | Lack of compensatory growth during pancreas development. aŠe, Pregnant mice carrying tTA/DTA embryos were given tetracycline either throughout embryogenesis (a) or at various time points during early pancreas organogenesis (b, E9.5; c, E10.5; d, E11.5; e, no tetracycline) and embryos were examined at E18.5. Black arrows denote the period of tetracycline administration (DTA repressed); red arrows denote the period during which tetracycline was omitted, resulting in ablation. Weights were calculated as a percentage of non-ablated control (a) and are displayed along with 95% confidence intervals (CI) and the number of tTA/DTA embryos examined. Asterisk, P , 0.001.

Stanger BZ, Tanaka AJ, Melton DA. Organ size is limited by the number of embryonic progenitor cells in the pancreas but not the liver. Nature. 2007 Jan 28; Read Abstract.

Review and Commentary Articles

• Ihle JN, Gilliland DG. Jak2: normal function and role in hematopoietic disorders. Curr Opin Genet Dev. 2007 Feb;17(1):8-14. Read Abstract.
• Sears C, Armstrong SA. Microarrays to identify new therapeutic strategies for cancer. Adv Cancer Res. 2007;96:51-74. Review. Read Abstract.
• Levine RL, Gilliland DG. JAK-2 mutations and their relevance to myeloproliferative disease. Curr Opin Hematol. 2007 Jan;14(1):43-7. Review. Read Abstract.
• Grimm J, Kircher MF, Weissleder R. Cell tracking : Principles and applications. Radiologe. 2007 Jan;47(1):25-33. German. Read Abstract.
• Nahrendorf M, Weissleder R. Advances in cardiovascular medicine through molecular imaging. Radiologe. 2007 Jan;47(1):18-24. German. Read Abstract.

Scientific Papers

Blood Disease

• Tissing WJ, Den Boer ML, Meijerink JP, Menezes RX, Swagemakers S, van der Spek PJ, Sallan SE, Armstrong SA, Pieters R. Genome-wide identification of prednisolone-responsive genes in acute lymphoblastic leukemia cells. Blood. 2007 Jan 11; Read Abstract.

Cancer

• Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH, Cullen DE, McDowell EP, Lazo-Kallanian S, Williams IR, Sears C, Armstrong SA, Passegue E, Depinho RA, Gilliland DG. FoxOs Are Critical Mediators of Hematopoietic Stem Cell Resistance to Physiologic Oxidative Stress. Cell. 2007 Jan 26;128(2):325-339. Read Abstract.
• Costa DB, Li S, Kocher O, Feins RH, Keller SM, Schiller JH, Johnson DH, Tenen DG, Halmos B. Immunohistochemical analysis of C/EBPalpha in non-small cell lung cancer reveals frequent down-regulation in stage II and IIIA tumors: A correlative study of E3590. Lung Cancer. 2007 Jan 17; Read Abstract.
• Shepard JL, Amatruda JF, Finkelstein D, Ziai J, Finley KR, Stern HM, Chiang K, Hersey C, Barut B, Freeman JL, Lee C, Glickman JN, Kutok JL, Aster JC, Zon LI. A mutation in separase causes genome instability and increased susceptibility to epithelial cancer. Genes Dev. 2007 Jan 1;21(1):55-9. Read Abstract.
• Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell. 2007 Jan;11(1):83-95. Read Abstract.
• Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, Newman J, Reczek EE, Weissleder R, Jacks T. Restoration of p53 function leads to tumour regression in vivo. Nature. 2007 Jan 24; Read Abstract.
• Nakazawa Y, Suzuki M, Manabe N, Yamada T, Kihara-Negishi F, Sakurai T, Tenen DG, Iwama A, Mochizuki M, Oikawa T. Cooperative interaction between ETS1 and GFI1 transcription factors in the repression of Bax gene expression. Oncogene. 2007 Jan 8; Read Abstract.

Cardiovascular Disease

• Aikawa E, Nahrendorf M, Sosnovik D, Lok VM, Jaffer FA, Aikawa M, Weissleder R. Multimodality molecular imaging identifies proteolytic and osteogenic activities in early aortic valve disease. Circulation. 2007 Jan 23;115(3):377-86. Read Abstract.
• Swirski FK, Libby P, Aikawa E, Alcaide P, Luscinskas FW, Weissleder R, Pittet MJ. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest. 2007 Jan;117(1):195-205. Read Abstract.

Development

• Matsuda T, Cepko CL. Controlled expression of transgenes introduced by in vivo electroporation. Proc Natl Acad Sci USA. 2007 Jan 16;104(3):1027-32. Read Abstract.
• Stanger BZ, Tanaka AJ, Melton DA. Organ size is limited by the number of embryonic progenitor cells in the pancreas but not the liver. Nature. 2007 Jan 28; Read Abstract.
• Hultman KA, Bahary N, Zon LI, Johnson SL. Gene Duplication of the zebrafish kit ligand and partitioning of melanocyte development functions to kit ligand a. PLoS Genet. 2007 Jan 26;3(1):e17. Read Abstract.
• Neal J, Takahashi M, Silva M, Tiao G, Walsh CA, Sheen VL. Insights into the gyrification of developing ferret brain by magnetic resonance imaging. J Anat. 2007 Jan;210(1):66-77. Read Abstract.
• Gritli-Linde A, Hallberg K, Harfe BD, Reyahi A, Kannius-Janson M, Nilsson J, Cobourne MT, Sharpe PT, McMahon AP, Linde A. Abnormal hair development and apparent follicular transformation to mammary gland in the absence of hedgehog signaling. Dev Cell. 2007 Jan;12(1):99-112. Read Abstract.
• Cheng HT, Kim M, Valerius MT, Surendran K, Schuster-Gossler K, Gossler A, McMahon AP, Kopan R. Notch2, but not Notch1, is required for proximal fate acquisition in the mammalian nephron. Development. 2007 Feb;134(4):801-11. Read Abstract.

Diabetes

• Weir GC, Bonner-Weir S. A dominant role for glucose in beta cell compensation of insulin resistance. J Clin Invest. 2007 Jan;117(1):81-3. Read Abstract.
• Rodacki M, Svoren B, Butty V, Besse W, Laffel L, Benoist C, Mathis D. Altered natural killer cells in type 1 diabetic patients. Diabetes. 2007 Jan;56(1):177-85. Read Abstract.

Imaging

• McCarthy JR, Weissleder R. Model Systems for Fluorescence and Singlet Oxygen Quenching by Metalloporphyrins. ChemMedChem. 2007 Jan 23; Read Abstract.
• Izmailova ES, Paz N, Alencar H, Chun M, Schopf L, Hepperle M, Lane JH, Harriman G, Xu Y, Ocain T, Weissleder R, Mahmood U, Healy AM, Jaffee B. Use of molecular imaging to quantify response to IKK-2 inhibitor treatment in murine arthritis. Arthritis Rheum. 2007 Jan;56(1):117-28. Read Abstract.

Immunology

• Nguyen LT, Jacobs J, Mathis D, Benoist C. Where FoxP3-dependent regulatory T cells impinge on the development of inflammatory arthritis. Arthritis Rheum. 2007 Jan 30;56(2):509-520 Read Abstract.

Kidney Disease

• Liangos O, Perianayagam MC, Vaidya VS, Han WK, Wald R, Tighiouart H, Mackinnon RW, Li L, Balakrishnan VS, Pereira BJ, Bonventre JV, Jaber BL. Urinary N-Acetyl-{beta}-(D)-Glucosaminidase Activity and Kidney Injury Molecule-1 Level Are Associated with Adverse Outcomes in Acute Renal Failure. J Am Soc Nephrol. 2007 Jan 31; Read Abstract.

Nervous System Diseases

• Hedlund E, Pruszak J, Ferree A, Vinuela A, Hong S, Isacson O, Kim KS. Selection of embryonic stem cell derived eGFP+ dopamine neurons using the tyrosine hydroxylase promoter is confounded by reporter gene expression in immature cell populations. Stem Cells. 2007 Jan 18; Read Abstract.
• 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. 2007 Jan 5;144(1):58-63. Read Abstract.

Skeletal

• Ueki Y, Lin CY, Senoo M, Ebihara T, Agata N, Onji M, Saheki Y, Kawai T, Mukherjee PM, Reichenberger E, Olsen BR. Increased myeloid cell responses to M-CSF and RANKL cause bone loss and inflammation in SH3BP2 "cherubism" mice. Cell. 2007 Jan 12;128(1):71-83. Read Abstract.
• Tu X, Joeng KS, Nakayama KI, Nakayama K, Rajagopal J, Carroll TJ, McMahon AP, Long F. Noncanonical Wnt signaling through G protein-linked PKCdelta activation promotes bone formation. Dev Cell. 2007 Jan;12(1):113-27. Read Abstract.

Tissue Engineering

• Weinand C, Gupta R, Huang AY, Weinberg E, Madisch I, Qudsi RA, Neville CM, Pomerantseva I, Vacanti JP. Comparison of Hydrogels in the In Vivo Formation of Tissue-Engineered Bone Using Mesenchymal Stem Cells and Beta-Tricalcium Phosphate. Tissue Eng. 2007 Jan 1; Read Abstract.

Translational Medicine

• Adams GB, Martin RP, Alley IR, Chabner KT, Cohen KS, Calvi LM, Kronenberg HM, Scadden DT. Therapeutic targeting of a stem cell niche. Nat Biotechnol. 2007 Jan 21; 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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