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Research Newsletter - July 2007

Spotlight

This month, HSCI has choosen to spolight an article that's findings may lead to a clinical trial, and two additional papers that report progress towards cellular reprogramming.

Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis

In an article paper published in Nature, HSCI Principal Faculty Members, Leonard Zon and George Daley, of Children's Hospital Boston, Stuart Orkin of the Dana-Farber Cancer Institute, and their team of researchers, report finding a new way to increase stem cells in blood, suggesting a possible treatment to help patients who undergo chemotherapy or bone marrow transplant for leukemia and other cancers recover their immune function more quickly. In the June 21 issue of Nature, they demonstrate that a stable analog of prostaglandin can enhance the blood-forming system, both during embryonic development and after it's been damaged.

The discovery, made possible through high-volume drug screening in zebrafish, marks the first time stem-cell production has been induced by a small-molecule drug, says the study's senior author, Leonard Zon, of the Children's Hospital Boston Stem Cell Program and Division of Hematology/Oncology. Other studies, including one from Zon's own lab, have identified ways of increasing formation of blood stem cells, which give rise to each of the body's various blood cell types. However, the methods are technically complex and haven't lent themselves to broad medical use.

Currently, patients undergoing bone marrow transplant must wait for marrow from a matched donor to replenish their stem cells and reproduce the full array of blood cell types, including all the cells of the immune system. When there's no suitable donor for a marrow match, patients can receive umbilical cord blood, which also contains blood stem cells. But the number of stem cells in one cord of blood is often not adequate for older children and adults, leaving them with diminished immune function and high risk for infections.

A long-active derivative of prostaglandin E2 known as dmPGE2 was identified by screening more than 2,500 chemicals in zebrafish. Knowing that two genes, runx1 and cmyb, are required for blood stem cells to develop in vertebrate embryos, they looked for compounds that altered the expression of these genes. The screen identified 82 chemicals that markedly increased or decreased gene activity. Of these, 10 turned out to affect the prostaglandin pathway: five increased the formation of blood stem cells, and five decreased it. "We weren't specifically looking for prostaglandins," says Zon, a Howard Hughes Medical Institute investigator who is also a member of the Harvard Stem Cell Institute. "This was a surprise finding."

A variety of experiments confirmed that prostaglandins, particularly dmPGE2, promote blood stem cell formation, while chemicals that block prostaglandin synthesis (such as aspirin or ibuprofen), suppress blood stem cell formation. Finally, in zebrafish whose marrow was depleted by irradiation, those given dmPGE2 recovered blood cell populations more quickly.

Prostaglandins are known to be released by the body when inflammation is present -- such as after an injury -- and may be among the compounds that aid recovery. "So it makes some sense that prostaglandins would have the ability to enhance regrowth of cells," Zon says.

"The zebrafish is ideal for investigating blood formation," says North. "It reproduces quickly and in large number and has a blood-forming system that shares many similarities with that of mammals." Zebrafish embryos develop outside the mother's body and can take up chemicals through their skin, making it easy to test the developmental effects of large numbers of compounds very rapidly, while their transparent skin makes it possible to visualize the blood stem cells in live fish.

The researchers also confirmed their observations in mammalian models. When dmPGE2 was added to mouse embryonic stem cells in the lab, production of blood stem cells increased. In mice that underwent bone marrow transplant, treatment with dmPGE2 led to enhanced blood-stem-cell formation, and the stem cells remained present in the marrow more than six months after transplantation, indicating long-term engraftment. "The fact that we confirmed the zebrafish discovery in a mammalian system suggests it may also be applicable in humans," says Goessling.

A clinical trial for dmPGE2 is projected to begin in 2008 at Children's Hospital Boston in conjunction with the Dana-Farber/Harvard Cancer Center. The trial will recruit patients undergoing cord blood transplant for leukemia. Patients will receive cord blood to replenish their blood systems, some of it treated with dmPGE2 to enhance blood-stem-cell formation. "Having more stem cells should help the blood system to regrow faster and minimize complications, such as infections," says North.

North TE, Goessling W, Walkley CR, Lengerke C, Kopani KR, Lord AM, Weber GJ, Bowman TV, Jang IH, Grosser T, Fitzgerald GA, Daley GQ, Orkin SH, Zon LI. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature. 2007 Jun 21;447(7147):1007-11. Read Abstract.

Scientific Papers

Review and Commentary

  • Kim S, Walsh CA. Numb, neurogenesis and epithelial polarity. Nat Neurosci. 2007 Jul;10(7):812-3. Read Abstract.
  • Lensch MW, Daley GQ. Human embryonic stem cells flock together. Nat Biotechnol. 2007 Jul;25(7):748-750. 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.
  • 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.
  • 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.
  • Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007 Jul 26;448(7152):427-34. Read Abstract.

Blood

  • 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

  • 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.
  • 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.

Cardiovascular System

  • 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.
  • 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.
  • 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.

Developmental Biology

  • 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.
  • 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.
  • 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.
  • 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.

Diabetes

  • 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.
  • 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.

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

  • "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.
  • Kim Y, Choi Y, Weissleder R, Tung CH. Membrane permeable esterase-activated fluorescent imaging probe. Bioorg Med Chem Lett. 2007 Jul 20. 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.
  • 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.

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

  • 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

  • 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.
  • 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.