Harvard Stem Cell Institute Research Newsletter
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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.
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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.  Representative confocal image of an islet from a 2-month-old Insulin-rtTA;TET-DTA;Insulin-CreERTM;Z/AP transgenic mouse exposed to doxycycline to ablate β cells, injected with tamoxifen to label surviving β cells, and treated with BrdU for 2 weeks to label new cells as shown in A. Arrows denote HPAP+BrdU+ β cells, the progeny of surviving and proliferating β cells; arrowheads mark HPAP–BrdU+ β cells, derived from either non-β cells or nonlabeled β cells. Because the Insulin-rtTA and Insulin-CreERTM driver strains are distinct transgenes, their efficiency of β cell killing and recombination, respectively, was not expected to be identical.
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. | Review and Commentary Articles - Lensch MW, Schlaeger TM, Zon LI, and Daley GQ. Teratoma Formation Assays with Human Embryonic Stem Cells: A Rationale for One Type of Human-Animal Chimera Cell Stem Cell, Vol 1, 253-258, 13 September 2007. Read Abstract
- Purton LE, and Scadden DT. Limiting Factors in Murine Hematopoietic Stem Cell Assays Cell Stem Cell, Vol 1, 253-258, 13 September 2007. Read Abstract
- Orkin SH, and Pera M. Stem Cells Down Under - ISSCR 2007 Cell Stem Cell, Vol 1, 253-258, 13 September 2007. Read Abstract
- Xie H, Orkin SH. Immunology: changed destiny. Nature. 2007 Sep 27;449(7161):410-1. Read Abstract.
- Hochedlinger K. Konrad Hochedlinger: the new kid of nuclear reprogramming. J Cell Biol. 2007 Sep 24;178(7):1098-9. Read Abstract.
- Agarwal S, Lensch MW, Daley GQ. Current prospects for the generation of patient-specific pluripotent cells from adult tissues. Regen Med. 2007 Sep;2(5):743-52. Read Abstract.
- Levine RL, Pardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer. 2007 Sep;7(9):673-83. Review. Read Abstract.
- Arnaout MA, Goodman SL, Xiong JP. Structure and mechanics of integrin-based cell adhesion. Curr Opin Cell Biol. 2007 Oct 8. Read Abstract.
| Blood - Steidl U, Steidl C, Ebralidze A, Chapuy B, Han HJ, Will B, Rosenbauer F, Becker A, Wagner K, Koschmieder S, Kobayashi S, Costa DB, Schulz T, O'Brien KB, Verhaak RG, Delwel R, Haase D, Trumper L, Krauter J, Kohwi-Shigematsu T, Griesinger F, Tenen DG. A distal single nucleotide polymorphism alters long-range regulation of the PU.1 gene in acute myeloid leukemia. J Clin Invest. 2007 Sep;117(9):2611-20. Read Abstract.
- Stubbs MC, Kim YM, Krivtsov AV, Wright RD, Feng Z, Agarwal J, Kung AL, Armstrong SA. MLL-AF9 and FLT3 cooperation in acute myelogenous leukemia: development of a model for rapid therapeutic assessment. Leukemia. 2007 Sep 13. Read Abstract.
- Barry EV, Clark JJ, Cools J, Roesel J, Gilliland DG. Uniform sensitivity of FLT3 activation loop mutants to the tyrosine kinase inhibitor midostaurin. Blood. 2007 Sep 7. Read Abstract.
- Hoogenkamp M, Krysinska H, Ingram R, Huang G, Barlow R, Clarke D, Ebralidze A, Zhang P, Tagoh H, Cockerill PN, Tenen DG, Bonifer C. The pu.1 locus is differentially regulated at the level of chromatin structure and noncoding transcription by alternate mechanisms at distinct developmental stages of hematopoiesis. Mol Cell Biol. 2007 Nov;27(21):7425-38. Epub 2007 Sep 4. Read Abstract.
| Cancer - Cortes J, Jabbour E, Daley GQ, O'Brien S, Verstovsek S, Ferrajoli A, Koller C, Zhu Y, Statkevich P, Kantarjian H. Phase 1 study of lonafarnib (SCH 66336) and imatinib mesylate in patients with chronic myeloid leukemia who have failed prior single-agent therapy with imatinib. Cancer. 2007 Sep 15;110(6):1295-302. Read Abstract.
- Kang S, Dong S, Gu TL, Guo A, Cohen MS, Lonial S, Khoury HJ, Fabbro D, Gilliland DG, Bergsagel PL, Taunton J, Polakiewicz RD, Chen J. FGFR3 activates RSK2 to mediate hematopoietic transformation through tyrosine phosphorylation of RSK2 and activation of the MEK/ERK pathway. Cancer Cell. 2007 Sep;12(3):201-14. Read Abstract.
- Faber J, Armstrong SA. Mixed lineage leukemia translocations and a leukemia stem cell program. Cancer Res. 2007 Sep 15;67(18):8425-8. Read Abstract.
| Cardiovascular System - Zhao Y, Lim CC, Sawyer DB, Liao R, Zhang X. Simultaneous orientation and cellular force measurements in adult cardiac myocytes using three-dimensional polymeric microstructures. Cell Motil Cytoskeleton. 2007 Sep;64(9):718-25. Read Abstract.
- Karkera JD, Lee JS, Roessler E, Banerjee-Basu S, Ouspenskaia MV, Mez J, Goldmuntz E, Bowers P, Towbin J, Belmont JW, Baxevanis AD, Schier AF, Muenke M. Loss-of-Function Mutations in Growth Differentiation Factor-1 (GDF1) Are Associated with Congenital Heart Defects in Humans. Am J Hum Genet. 2007 Nov;81(5):987-94. Epub 2007 Sep 28. Read Abstract.
| Cell Biology - Yang H, Yang T, Baur JA, Perez E, Matsui T, Carmona JJ, Lamming DW, Souza-Pinto NC, Bohr VA, Rosenzweig A, de Cabo R, Sauve AA, Sinclair DA. Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell. 2007 Sep 21;130(6):1095-107. Read Abstract.
- Kim K, Ng K, Rugg-Gunn PJ, Shieh JH, Kirak O, Jaenisch R, Wakayama T, Moore MA, Pedersen RA, and Daley GQ. Recombination Signatures Distinguish Embryonic Stem Cells Derived by Parthenogenesis and Somatic Cell Nuclear Transfer Cell Stem Cell, Vol 1, 253-258, 13 September 2007. Read Abstract.
- Shibolet O, Giallourakis C, Rosenberg I, Mueller T, Xavier RJ, Podolsky DK. AKAP13 a rhoa GTPase-specific guanine exchange factor is a novel regulator of TLR2 signaling. J Biol Chem. 2007 Sep 18. Read Abstract.
| Developmental Biology - Zhou W, Lin L, Majumdar A, Li X, Zhang X, Liu W, Etheridge L, Shi Y, Martin J, Van de Ven W, Kaartinen V, Wynshaw-Boris A, McMahon AP, Rosenfeld MG, Evans SM. Modulation of morphogenesis by noncanonical Wnt signaling requires ATF/CREB family-mediated transcriptional activation of TGFbeta2. Nat Genet. 2007 Oct;39(10):1225-34. Epub 2007 Sep 2. Read Abstract.
- Kim BM, Miletich I, Mao J, McMahon AP, Sharpe PA, Shivdasani RA. Independent functions and mechanisms for homeobox gene Barx1 in patterning mouse stomach and spleen. Development. 2007 Oct;134(20):3603-13. Epub 2007 Sep 12. Read Abstract.
- Salinas LS, Maldonado E, Macias-Silva M, Blackwell TK, Navarro RE. The DEAD box RNA helicase VBH-1 is required for germ cell function in C. elegans. Genesis. 2007 Sep;45(9):533-46. Read Abstract.
- 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 Sep 25;80(5):406-416.Read Abstract.
| Diabetes - Nir T, Melton DA, Dor Y. Recovery from diabetes in mice by beta cell regeneration. J Clin Invest. 2007 Sep;117(9):2553-61. Read Abstract.
- Marchetti P, Bugliani M, Lupi R, Marselli L, Masini M, Boggi U, Filipponi F, Weir GC, Eizirik DL, Cnop M. The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients. Diabetologia. 2007 Sep 30. Read Abstract.
| Immunology - Monach PA, Verschoor A, Jacobs JP, Carroll MC, Wagers AJ, Benoist C, Mathis D. Circulating C3 is necessary and sufficient for induction of autoantibody-mediated arthritis in a mouse model. Arthritis Rheum. 2007 Sep;56(9):2968-74. Read Abstract.
- Obst R, van Santen HM, Melamed R, Kamphorst AO, Benoist C, Mathis D. Sustained antigen presentation can promote an immunogenic T cell response, like dendritic cell activation. Proc Natl Acad Sci USA. 2007 Sep 25;104(39):15460-5. Epub 2007 Sep 19. Read Abstract.
- Yamanaka KI, Dimitroff CJ, Fuhlbrigge RC, Kakeda M, Kurokawa I, Mizutani H, Kupper TS. Vitamins A and D are potent inhibitors of cutaneous lymphocyte-associated antigen expression. J Allergy Clin Immunol. 2007 Sep 29. Read Abstract.
| Technology - Shen Y, Miller DT, Cheung SW, Lip V, Sheng X, Tomaszewicz K, Shao H, Fang H, Tang HS, Irons M, Walsh CA, Platt O, Gusella JF, Wu BL. Development of a Focused Oligonucleotide-Array Comparative Genomic Hybridization Chip for Clinical Diagnosis of Genomic Imbalance. Clin Chem. 2007 Sep 27. Read Abstract.
| Tissue Engineering - Zhang Y, Ryan JA, Di Cesare PE, Liu J, Walsh CA, You Z. Doublecortin is expressed in articular chondrocytes. Biochem Biophys Res Commun. 2007 Nov 23;363(3):694-700. Epub 2007 Sep 19. 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. Visit our website at www.hsci.harvard.edu. If there is anything that you would like to see added to this email alert, please email maureen_lyons@harvard.edu. | |
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