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Research Newsletter - October 2007

Spotlight

In an article paper published in The Journal of Clinical Investigation, HSCI Co-Scientific Director Douglas Melton, and collaborators Yuval Dor and Tomer Nir from the Hebrew University-Hadassah Medical School, report results that suggest that regenerative therapy for type 1 diabetes may be achieved if autoimmunity is halted using regeneration-compatible drugs.

Recovery from diabetes in mice by β cell regeneration

The mechanisms that regulate pancreatic β cell mass are poorly understood. While autoimmune and pharmacological destruction of insulin-producing β cells is often irreversible, adult β cell mass does fluctuate in response to physiological cues including pregnancy and insulin resistance. This plasticity points to the possibility of harnessing the regenerative capacity of the β cell to treat diabetes. We developed a transgenic mouse model to study the dynamics of β cell regeneration from a diabetic state. Following doxycycline administration, transgenic mice expressed diphtheria toxin in β cells, resulting in apoptosis of 70%–80% of β cells, destruction of islet architecture, and diabetes. Withdrawal of doxycycline resulted in a spontaneous normalization of blood glucose levels and islet architecture and a significant regeneration of β cell mass with no apparent toxicity of transient hyperglycemia. Lineage tracing analysis indicated that enhanced proliferation of surviving β cells played the major role in regeneration. Surprisingly, treatment with Sirolimus and Tacrolimus, immunosuppressants used in the Edmonton protocol for human islet transplantation, inhibited β cell regeneration and prevented the normalization of glucose homeostasis. These results suggest that regenerative therapy for type 1 diabetes may be achieved if autoimmunity is halted using regeneration-compatible drugs.

Nir T, Melton DA, Dor Y. Recovery from diabetes in mice by beta cell regeneration. J Clin Invest. 2007 Sep;117(9):2553-61. Full Text.

Scientific Papers

Review and Commentary

  • Arnaout MA, Goodman SL, Xiong JP. Structure and mechanics of integrin-based cell adhesion. Curr Opin Cell Biol. 2007 Oct;19(5):495-507. Read Abstract.
  • Hedlund E, Hefferan MP, Marsala M, Isacson O. Cell therapy and stem cells in animal models of motor neuron disorders. Eur J Neurosci. 2007 Oct;26(7):1721-37. Read Abstract.
  • Humphreys BD, Bonventre JV. Mesenchymal Stem Cells in Acute Kidney Injury. Annu Rev Med. 2007 Oct 3 - Epub ahead of print. Read Abstract.
  • Hyun I, Hochedlinger K, Jaenisch R, Yamanaka S. New Advances in iPS Cell Research Do Not Obviate the Need for Human Embryonic Stem Cells. Cell Stem Cell. 2007 Oct 11;1(4):367-368. Read Abstract.
  • Mathis D, Benoist C. Yes, it does. Nat Rev Immunol. 2007 Oct 12;7(10):1 - Epub ahead of print. Read Abstract.
  • Morgan KJ, Gilliland DG. A Role for JAK2 Mutations in Myeloproliferative Diseases. Annu Rev Med. 2007 Oct 5 - Epub ahead of print. Read Abstract.
  • Vaidya VS, Ferguson MA, Bonventre JV. Biomarkers of Acute Kidney Injury. Annu Rev Pharmacol Toxicol. 2007 Oct 15 - Epub ahead of print. Read Abstract.

Cancer

  • Costa DB, Halmos B, Kumar A, Schumer ST, Huberman MS, Boggon TJ, Tenen DG, Kobayashi S. BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS Med. 2007 Oct 30;4(10):1669-79. Read Abstract.
  • Lee BH, Tothova Z, Levine RL, Anderson K, Buza-Vidas N, Cullen DE, McDowell EP, Adelsperger J, Frohling S, Huntly BJ, Beran M, Jacobsen SE, Gilliland DG. FLT3 mutations confer enhanced proliferation and survival properties to multipotent progenitors in a murine model of chronic myelomonocytic leukemia. Cancer Cell. 2007 Oct;12(4):367-80. Read Abstract.
  • Renlund N, Pieretti-Vanmarcke R, O'Neill FH, Zhang L, Donahoe PK, Teixeira J. JNK inhibitor II (SP600125) activates Mullerian Inhibiting Substance type II receptor-mediated signal transduction. Endocrinology. 2007 Oct 18 - Epub ahead of print. Read Abstract.

Developmental Biology

  • Aidlen JT, Nazarey PP, Kinane TB, Donahoe PK, Schnitzer JJ, Kling DE. Retinoic acid-mediated differentiation protects against nitrofen-induced apoptosis. Birth Defects Res B Dev Reprod Toxicol. 2007 Oct;80(5):406-16. Read Abstract.
  • Burket CT, Montgomery JE, Thummel R, Kassen SC, Lafave MC, Langenau DM, Zon LI, Hyde DR. Generation and characterization of transgenic zebrafish lines using different ubiquitous promoters. Transgenic Res. 2007 Oct 30 - Epub ahead of print. Read Abstract.
  • Zhou Q, Chipperfield H, Melton DA, Wong WH. A gene regulatory network in mouse embryonic stem cells. Proc Natl Acad Sci USA. 2007 Oct 16;104(42):16438-43. Read Abstract.

Imaging

  • Farrar CT, Dai G, Novikov M, Rosenzweig A, Weissleder R, Rosen BR, Sosnovik DE. Impact of field strength and iron oxide nanoparticle concentration on the linearity and diagnostic accuracy of off-resonance imaging. NMR Biomed. 2007 Oct 8 - Epub ahead of print. Read Abstract.
  • Law B, Weissleder R, Tung CH. Protease-Sensitive Fluorescent Nanofibers. Bioconjug Chem. 2007 Oct 5 - Epub ahead of print. Read Abstract.
  • Swirski FK, Berger CR, Figueiredo JL, Mempel TR, von Andrian UH, Pittet MJ, Weissleder R. A near-infrared cell tracker reagent for multiscopic in vivo imaging and quantification of leukocyte immune responses. PLoS ONE. 2007 Oct 24;2(10):e1075. Read Abstract.
  • Tam JM, Upadhyay R, Pittet MJ, Weissleder R, Mahmood U. Improved in vivo whole-animal detection limits of green fluorescent protein-expressing tumor lines by spectral fluorescence imaging. Mol Imaging. 2007 Oct-Dec;6(4):269-76. Read Abstract.

Immunology

  • Gray D, Abramson J, Benoist C, Mathis D. Proliferative arrest and rapid turnover of thymic epithelial cells expressing Aire. J Exp Med. 2007 Oct 29;204(11):2521-8. Read Abstract.
  • Munoz NM, Meliton AY, Arm JP, Bonventre JV, Cho W, Leff AR. Deletion of secretory group v phospholipase A2 attenuates cell migration and airway hyperresponsiveness in immunosensitized mice. J Immunol. 2007 Oct 1;179(7):4800-7. Read Abstract.
  • Sarantopoulos S, Stevenson KE, Kim HT, Bhuiya NS, Cutler CS, Soiffer RJ, Antin JH, Ritz J. High Levels of B-Cell Activating Factor in Patients with Active Chronic Graft-Versus-Host Disease. Clin Cancer Res. 2007 Oct 15;13(20):6107-6114. Read Abstract.

Muscular System

  • Eisenberg I, Eran A, Nishino I, Moggio M, Lamperti C, Amato AA, Lidov HG, Kang PB, North KN, Mitrani-Rosenbaum S, Flanigan KM, Neely LA, Whitney D, Beggs AH, Kohane IS, Kunkel LM. Distinctive patterns of microRNA expression in primary muscular disorders. Proc Natl Acad Sci USA. 2007 Oct 23;104(43):17016-21. Read Abstract.

Nervous System

  • Hong S, Kang UJ, Isacson O, Kim KS. Neural precursors derived from human embryonic stem cells maintain long-term proliferation without losing the potential to differentiate into all three neural lineages, including dopaminergic neurons. J Neurochem. 2007 Oct 18 - Epub ahead of print. Read Abstract.
  • Mizuno Y, Guyon JR, Okamoto K, Kunkel LM. Synemin expression in brain. Muscle Nerve. 2007 Oct;36(4):497-504. Read Abstract.

Renal System

  • Wingert RA, Selleck R, Yu J, Song HD, Chen Z, Song A, Zhou Y, Thisse B, Thisse C, McMahon AP, Davidson AJ. The cdx genes and retinoic acid control the positioning and segmentation of the zebrafish pronephros. PLoS Genet. 2007 Oct 19;3(10):1922-38. Read Abstract.
  • Zhang Z, Humphreys BD, Bonventre JV. Shedding of the urinary biomarker kidney injury molecule-1 (KIM-1) is regulated by MAP kinases and juxtamembrane region. J Am Soc Nephrol. 2007 Oct;18(10):2704-14. Read Abstract.
  • Zhou Y, Vaidya VS, Brown RP, Zhang J, Rosenzweig BA, Thompson KL, Miller TJ, Bonventre JV, Goering PL. Comparison of Kidney Injury Molecule-1 and Other Nephrotoxicity Biomarkers in Urine and Kidney Following Acute Exposure to Gentamicin, Mercury, and Chromium. Toxicol Sci. 2007 Oct 13 - Epub ahead of print. Read Abstract.