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 Developmental Cell, HSCI Scientific Co-Director, Douglas Melton and collaborators at the Department of Molecular and Cellular Biology, Harvard University, report findings that define a multipotent compartment within the developing pancreas and suggest a model of how branching is coordinated with cell type specification.
| | A Multipotent Progenitor Domain Guides Pancreatic Organogenesis
The mammalian pancreas is constructed during embryogenesis by multipotent progenitors, the identity and function of which remain poorly understood. We performed genome-wide transcription factor expression analysis of the developing pancreas to identify gene expression domains that may represent distinct progenitor cell populations. Five discrete domains were discovered. Genetic lineage-tracing experiments demonstrate that one specific domain, located at the tip of the branching pancreatic tree, contains multipotent progenitors that produce exocrine, endocrine, and duct cells in vivo. These multipotent progenitors are Pdx1+Ptf1a+cMycHighCpa1+ and negative for differentiated lineage markers. The outgrowth of multipotent tip cells leaves behind differentiated progeny that form the trunk of the branches. These findings define a multipotent compartment within the developing pancreas and suggest a model of how branching is coordinated with cell type specification. In addition, this comprehensive analysis of >1,100 transcription factors identified genes that are likely to control critical decisions in pancreas development and disease.
 (A) Cpa1+ multipotent progenitors give rise to exocrine, endocrine, and duct cells in vivo and may undergo limited self-renewal. (B) Early pancreatic buds are composed primarily of multipotent progenitors. At the onset of branching morphogenesis (not, vert, similarE12), the multipotent cells may divide asymmetrically such that they are propelled away from the center of the pancreatic buds, thus producing branches. Continued fast proliferation and differentiation of these progenitors into endocrine and duct cells generate the trunk of the branches. When the branching tip divides, Cpa1 downregulates in the cleft region. Around E14, Cpa1+ tip cells restrict to exocrine fate during the secondary transition.
Zhou Q, Law AC, Rajagopal J, Anderson WJ, Gray PA, Melton DA. A multipotent progenitor domain guides pancreatic organogenesis. Dev Cell. 2007 Jul;13(1):103-14. Read Abstract. | Review and Commentary Articles - Ramaswamy S. Rational design of cancer-drug combinations. N Engl J Med. 2007 Jul 19;357(3):299-300. Read Abstract.
- Rosenzweig A. Scanning the genome for coronary risk. N Engl J Med. 2007 Aug 2;357(5):497-9. Read Abstract.
- Kim S, Walsh CA. Numb, neurogenesis and epithelial polarity. Nat Neurosci. 2007 Jul;10(7):812-3. Read Abstract.
- Mathis D, Benoist C. A decade of AIRE. Nat Rev Immunol. 2007 Aug;7(8):645-50. Read Abstract.
- McKinney-Freeman SL, Daley GQ. Towards hematopoietic reconstitution from embryonic stem cells: a sanguine future. Curr Opin Hematol. 2007 Jul;14(4):343-7. Read Abstract.
- Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007 Jul 26;448(7152):427-34. Read Abstract.
- Lensch MW, Daley GQ. Human embryonic stem cells flock together. Nat Biotechnol. 2007 Jul;25(7):748-750. Read Abstract.
- Moore A, Medarova Z, Evgenov NV, Dai G, Bonner-Weir S. Reply to 'In vivo imaging of islet transplantation'. Nat Med. 2007 Jul;13(7):773. Read Abstract.
| Blood Disease - Shin J, Monti S, Aires DJ, Duvic M, Golub T, Jones DA, Kupper TS. Lesional gene expression profiling in cutaneous T cell lymphoma reveals natural clusters associated with disease outcome. Blood. 2007 Jul 16. Read Abstract.
- Wu X, Lensch MW, Wylie-Sears J, Daley GQ, Bischoff J. Hemogenic Endothelial Progenitors Cells Isolated from Human Umbilical Cord Blood. Stem Cells. 2007 Jul 19. Read Abstract.
| Cancer - Costa DB, Kobayashi S, Tenen DG, Huberman MS. Pooled analysis of the prospective trials of gefitinib monotherapy for EGFR-mutant non-small cell lung cancers. Lung Cancer. 2007 Jul 2. Read Abstract.
- 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 Jul 10. Read Abstract.
| Cardiovascular Disease - 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 Jul 5;64(9):718-725. Read Abstract.
- Liao R, Pfister O, Jain M, Mouquet F. The bone marrow--cardiac axis of myocardial regeneration. Prog Cardiovasc Dis. 2007 Jul-Aug;50(1):18-30. Read Abstract.
- Knoll R, Postel R, Wang J, Kratzner R, Hennecke G, Vacaru AM, Vakeel P, Schubert C, Murthy K, Rana BK, Kube D, Knoll G, Schafer K, Hayashi T, Holm T, Kimura A, Schork N, Toliat MR, Nurnberg P, Schultheiss HP, Schaper W, Schaper J, Bos E, Den Hertog J, van Eeden FJ, Peters PJ, Hasenfuss G, Chien KR, Bakkers J. Laminin-alpha4 and integrin-linked kinase mutations cause human cardiomyopathy via simultaneous defects in cardiomyocytes and endothelial cells. Circulation. 2007 Jul 31;116(5):515-25. Read Abstract.
| Development - Kolpakova-Hart E, Jinnin M, Hou B, Fukai N, Olsen BR. Kinesin-2 controls development and patterning of the vertebrate skeleton by Hedgehog- and Gli3-dependent mechanisms. Dev Biol. 2007 Jul 24. Read Abstract.
- Fujino A, Pieretti-Vanmarcke R, Wong A, Donahoe PK, Arango NA. Sexual dimorphism of G-protein subunit Gng13 expression in the cortical region of the developing mouse ovary. Dev Dyn. 2007 Jul;236(7):1991-6. Read Abstract.
- Corbo JC, Myers CA, Lawrence KA, Jadhav AP, Cepko CL. A typology of photoreceptor gene expression patterns in the mouse. Proc Natl Acad Sci USA. 2007 Jul 17;104(29):12069-74. Read Abstract.
- Hsiau TH, Diaconu C, Myers CA, Lee J, Cepko CL, Corbo JC. The cis-regulatory logic of the mammalian photoreceptor transcriptional network. PLoS ONE. 2007 Jul 25;2:e643. Read Abstract.
| Diabetes - Zhou Q, Law AC, Rajagopal J, Anderson WJ, Gray PA, Melton DA. A multipotent progenitor domain guides pancreatic organogenesis. Dev Cell. 2007 Jul;13(1):103-14. Read Abstract.
- Laybutt DR, Hawkins YC, Lock J, Lebet J, Sharma A, Bonner-Weir S, Weir GC. Influence of diabetes on the loss of beta cell differentiation after islet transplantation in rats. Diabetologia. 2007 Jul 20. Read Abstract.
| Genetics and Genomics - Kantarci S, Al-Gazali L, Hill RS, Donnai D, Black GC, Bieth E, Chassaing N, Lacombe D, Devriendt K, Teebi A, Loscertales M, Robson C, Liu T, Maclaughlin DT, Noonan KM, Russell MK, Walsh CA, Donahoe PK, Pober BR. Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes. Nat Genet. 2007 Aug;39(8):957-959. Read Abstract.
| Imaging - Sheth RA, Upadhyay R, Weissleder R, Mahmood U. Real-time multichannel imaging framework for endoscopy, catheters, and fixed geometry intraoperative systems. Mol Imaging. 2007 Jul-Sep;6(3):147-55. Read Abstract.
- Kim Y, Choi Y, Weissleder R, Tung CH. Membrane permeable esterase-activated fluorescent imaging probe. Bioorg Med Chem Lett. 2007 Jul 20. Read Abstract.
- Kelly KA, Carson J, McCarthy JR, Weissleder R. Novel peptide sequence ("IQ-tag") with high affinity for NIR fluorochromes allows protein and cell specific labeling for in vivo imaging. PLoS ONE. 2007 Jul 25;2:e665. Read Abstract.
- Pittet MJ, Grimm J, Berger CR, Tamura T, Wojtkiewicz G, Nahrendorf M, Romero P, Swirski FK, Weissleder R. In vivo imaging of T cell delivery to tumors after adoptive transfer therapy. Proc Natl Acad Sci USA. 2007 Jul 24;104(30):12457-61. Read Abstract.
| Immunology - Serwold T, Hochedlinger K, Inlay MA, Jaenisch R, Weissman IL. Early TCR expression and aberrant T cell development in mice with endogenous prerearranged T cell receptor genes. J Immunol. 2007 Jul 15;179(2):928-38. Read Abstract.
- Wu HJ, Sawaya H, Binstadt B, Brickelmaier M, Blasius A, Gorelik L, Mahmood U, Weissleder R, Carulli J, Benoist C, Mathis D. Inflammatory arthritis can be reined in by CpG-induced DC NK cell cross talk. J Exp Med. 2007 Aug 6;204(8):1911-1922. Read Abstract.
- Xu L, Peng H, Glasson S, Lee PL, Hu K, Ijiri K, Olsen BR, Goldring MB, Li Y. Increased expression of the collagen receptor discoidin domain receptor 2 in articular cartilage as a key event in the pathogenesis of osteoarthritis. Arthritis Rheum. 2007 Jul 30;56(8):2663-2673. Read Abstract.
| Nervous System Diseases - Brunlid G, Pruszak J, Holmes B, Isacson O, Sonntag KC. Immature and Neurally Differentiated Mouse ES Cells Do Not Express A Functional Fas/Fasl System. Stem Cells. 2007 Jul 5. Read Abstract.
- Mizuno Y, Guyon JR, Okamoto K, Kunkel LM. Synemin expression in brain. Muscle Nerve. 2007 Jul 24. Read Abstract.
| Technology - Hong S, Hwang DY, Yoon S, Isacson O, Ramezani A, Hawley RG, Kim KS. Functional Analysis of Various Promoters in Lentiviral Vectors at Different Stages of In Vitro Differentiation of Mouse Embryonic Stem Cells. Mol Ther. 2007 Jul 3. Read Abstract.
- Stahl JE, Vacanti JP, Gazelle S. Assessing emerging technologies--the case of organ replacement technologies: volume, durability, cost. Int J Technol Assess Health Care. 2007 Summer;23(3):331-6. Read Abstract.
| Tissue Engineering - Weinand C, Gupta R, Weinberg E, Madisch I, Jupiter JB, Vacanti JP. Human shaped thumb bone tissue engineered by hydrogel-beta-tricalciumphosphate/poly-epsilon-caprolactone scaffolds and magnetically sorted stem cells. Ann Plast Surg. 2007 Jul;59(1):46-52. Read Abstract.
- Shin M, Abukawa H, Troulis MJ, Vacanti JP. Development of a biodegradable scaffold with interconnected pores by heat fusion and its application to bone tissue engineering. J Biomed Mater Res A. 2007 Jul 16. 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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