Harvard Stem Cell Institute Research Newsletter
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| | | |  | Research Commentary Synergy between human embryonic stem cell and nuclear reprogramming research accelerates pace of understanding disease by Lisa Girard, PhD
HSCI Science Editor The area of nuclear reprogramming has exploded within the past year with the publication of several landmark papers whose implications will continue to be elaborated for a long time to come. Nuclear reprogramming is a way to essentially "turn back the clock" of a cell, returning it to a stem cell-like, pluripotent state. Reprogramming somatic cells into pluripotent cells is a potentially powerful approach for making stem cell lines that are genetically identical to that of the cell donor. This is significant from a therapeutic standpoint because it creates the possibility, for example, of being able to introduce a source of healthy replacement cells into a patient to cure a disease, or using principles in tissue engineering, use stem cells to grow replacement parts-avoiding potentially lethal immune rejection issues and eliminating long waits for compatible donors. Additionally, nuclear reprogramming can be used to make disease cell lines. The existence of such lines, providing a theoretically unlimited number of cells, would circumvent the problem of generating a sufficient amount of material for studying disease pathways and performing high throughput screens for compounds that modify disease phenotypes and which may represent a new drug. Exciting recent experiments provide proof of principle for using reprogramming techniques to cure disease. Earlier this month, Hanna et al. (Hanna et al., 2007) published their results showing rescue of a sickle cell anemia mouse model using nuclear reprogramming techniques. Briefly, fibroblast cells were taken from the mouse; the cells were induced with a cocktail of transcription factors to become pluripotent; molecular techniques were used to repair the gene responsible for the sickle cell disease in these cells; the cells were induced to become hematopoietic progenitor cells (blood cell precursors); and finally the hematopoietic progenitor cells were introduced back into the donor mice. Follow up studies on these mice showed that the introduced cells were able to differentiate correctly and ameliorate the sickle cell phenotype. These experiments demonstrate what may be an exciting first instance of using nuclear reprogramming to treat disease. Reprogramming somatic cell nuclei to a pluripotent state is currently being achieved using three different approaches: cell fusion, somatic cell nuclear transfer (SCNT) or "therapeutic cloning", and the creation of induced pluripotent (iPS) cells. Cell fusion protocols for reprogramming mix human embryonic stem cells with somatic cells under conditions that promote (Cowan, 2005) fusion. The resulting cell has twice as many chromosomes as normal and may become pluripotent. SCNT creates pluripotent cell lines genetically identical to a donor by inserting the nucleus of a cell from the donor into an unfertilized oocyte that has had its nucleus removed. This process is, at a low efficiency, able to reprogram the donor nucleus to a pluripotent state. The third approach is the creation of iPS cells, which was the technique used in the sickle cell experiments described above. Creating iPS cells involves introducing four transcription factors critical for pluripotency into a somatic cell (Okita et al., 2007; Wernig et al., 2007; Maherali et al., 2007). Significant to each of these reprogramming approaches is the degree to which they were enabled by the study of human embryonic stem cells (hESCs) and how advances among the different approaches facilitated their individual progress, creating a vital synergy that allowed the field to progress so quickly. For example, work in human embryonic stem cells characterizing the factors necessary for pluripotency identified four transcription factors essential for reprogramming: Oct4, Sox2, KLF4, c-Myc (Takahashi et al., 2006). Also, hESC research described cell markers identifying distinct differentiation states which have been instrumental in developing and optimizing iPS, SCNT, and cell fusion procedures. Additionally, the idea to create iPS cells emerged as a result of cell fusion experiments (Cowan, 2005) with hESCs which implied the existence of definable pluripotency factors. Thus, these advances were not made in a vacuum and their progress was intricately intertwined with our advancing knowledge about hESCs. A erroneous and dangerous conclusion from the excitement surrounding the advances in reprogramming is that these approaches obviate the need for continued studies using hESCs. In a recent commentary by Hyun et al. (Hyun et al., 2007), the authors clearly describe why this is most certainly not the case. They point out first, that iPS research is relatively new and many issues, such as tumors and mutations associated with the use of oncogenes and retroviruses currently used in the protocols, prevent use in its current form for human therapeutics. While the kinks are being worked out of iPS approaches, hESC research is available and should keep moving forward. Second, hESCs represent an unsurpassable control for iPS cell experiments that is invaluable for ensuring the integrity of iPS findings, since embryo-derived ES cells are the only genetically unmodified pluripotent cells. Finally, iPS cells may not be useful for all applications and it would be short-sighted to limit our options so early in our understanding of reprogramming. While advances in nuclear reprogramming are demonstrating exciting potential, we must continue to move forward with hESC research in order to pursue a panoramic underatanding of stem cell biology. This will create a firm foundation for a field in which we still have much to learn and ultimately accelerate our progress toward achieving cures for injury and disease. References - Cowan, C.A., Atienza, J., Melton, D.A., Eggan, K. (2005). Science 309, 1369-73.
- Okita, K., Ichisaka, T., Yamanaka, S. (2007) Nature 448, 313-7.
- Hanna J, Wernig M, Markoulaki S, Sun CW, Meissner A, Cassady JP, Beard C, Brambrink T, Wu LC, Townes TM, Jaenisch R Science. 2007 Dec 6 [Epub ahead of print]
- Hyun, I., Hochedlinger, K., Jaenisch, R., Yamanaka, S. (2007) Cell Stem Cell 1, 367-368.
- Maherali, N., Sridharan, R., Xie, W., Utikal, J., Eminli, S., Arnold, K., Stadtfeld, M., Yachechko, R., Tchieu, J., Jaenisch, R., Plath, K., Hochedlinger, K. (2007) Cell Stem Cell 1, 55-70.
- Okita, K., Ichisaka, T., Yamanaka, S. (2007) Nature 448, 313-7.
- Takahashi, K., and Yamanaka, S. (2006). Cell 126, 663-676.
- Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K, Bernstein BE, Jaenisch R. (2007) Nature 448, 318-24.
| | | Spotlight Article SOCS3 Protein Developmentally Regulates the Chemokine Receptor CXCR4-FAK Signaling Pathway during B Lymphopoiesis This month's spotlighted article is by HSCI Principal Faculty Member Les Silberstein of Children's Hospital Boston. The chemokine receptor CXCR4 plays an important role in the localization of hematopoietic stem and progenitor cells within the extravascular compartment of the bone marrow. However, the mechanism by which stem and progenitor cells lodge and migrate between niches is not known. By investigating developing B cell populations in the bone marrow, Le et al. demonstrate that the suppressor of cytokine signaling 3 (SOCS3) protein developmentally regulates CXCR4-induced Focal Adhesion Kinase signaling and pro-adhesive cellular responses. The studies provide a mechanism whereby low levels of SOCS3 allow for the retention of progenitor B cells in the endosteal niche for prolonged periods for growth and differentiation, whereas high amounts of SOCS3 in mature B cells promote their migration to the central medullary region and subsequent exit into the peripheral circulation. A better understanding of the signals that control the residence and movement of stem/progenitor cells in the bone marrow should offer insight into previously unrecognized pathogenetic mechanims of leukemogenesis and immunodeficiency. Le Y, Zhu BM, Harley B, Park SY, Kobayashi T, Manis JP, Luo HR, Yoshimura A, Hennighausen L, Silberstein LE. SOCS3 Protein Developmentally Regulates the Chemokine Receptor CXCR4-FAK Signaling Pathway during B Lymphopoiesis. Immunity. 2007 Nov;27(5):811-23. Read Abstract. | Review and Commentary Articles - Liao R, Force T. Not all hypertrophy is created equal. Circ Res. 2007 Nov 26;101(11):1069-72. Read Abstract.
- Fiegel HC, Kaufmann PM, Bruns H, Kluth D, Horch RE, Vacanti JP, Kneser U. Review: Hepatic Tissue Engineering. J Cell Mol Med. 2007 Nov 16. Read Abstract.
- Adams GB, Scadden DT. A niche opportunity for stem cell therapeutics. Gene Ther<. 2007 Nov 15. Read Abstract.
- Ceol CJ, Pellman D, Zon LI. APC and colon cancer: two hits for one. Nat Med. 2007 Nov;13(11):1286-7. Read Abstract.
| Scientific Papers
Blood - Pardanani A, Fridley BL, Lasho TL, Gilliland DG, Tefferi A. Host genetic variation contributes to phenotypic diversity in myeloproliferative disorders. Blood. 2007 Nov 15. Read Abstract.
- Huang G, Zhang P, Hirai H, Elf S, Yan X, Chen Z, Koschmieder S, Okuno Y, Dayaram T, Growney JD, Shivdasani RA, Gilliland DG, Speck NA, Nimer SD, Tenen DG. PU.1 is a major downstream target of AML1 (RUNX1) in adult mouse hematopoiesis. Nat Genet. 2007 Nov 11. Read Abstract.
- Massberg S, Schaerli P, Knezevic-Maramica I, Kollnberger M, Tubo N, Moseman EA, Huff IV, Junt T, Wagers AJ, Mazo IB, von Andrian UH. Immunosurveillance by Hematopoietic Progenitor Cells Trafficking through Blood, Lymph, and Peripheral Tissues. Cell. 2007 Nov 30;131(5):994-1008. Read Abstract.
- Huang G, Zhang P, Hirai H, Elf S, Yan X, Chen Z, Koschmieder S, Okuno Y, Dayaram T, Growney JD, Shivdasani RA, Gilliland DG, Speck NA, Nimer SD, Tenen DG. PU.1 is a major downstream target of AML1 (RUNX1) in adult mouse hematopoiesis. Nat Genet. 2007 Nov 11. Read Abstract.
- Au P, Daheron LM, Duda DG, Cohen KS, Tyrrell JA, Lanning RM, Fukumura D, Scadden DT, Jain RK. Differential in vivo potential of endothelial progenitor cells from human umbilical cord blood and adult peripheral blood to form functional long-lasting vessels. Blood. 2007 Nov 9. Read Abstract.
- Wu CJ, Gladwin M, Tisdale J, Hsieh M, Law T, Biernacki M, Rogers S, Wang X, Walters M, Zahrieh D, Antin JH, Ritz J, Krishnamurti L. Mixed haematopoietic chimerism for sickle cell disease prevents intravascular haemolysis. Br J Haematol. 2007 Nov;139(3):504-7. Read Abstract.
| Cancer - Krivtsov AV, Armstrong SA. MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer. 2007 Nov;7(11):823-33. Review. Read Abstract.
- Kurozumi K, Hardcastle J, Thakur R, Yang M, Christoforidis G, Fulci G, Hochberg FH, Weissleder R, Carson W, Chiocca EA, Kaur B. Effect of Tumor Microenvironment Modulation on the Efficacy of Oncolytic Virus Therapy. J Natl Cancer Inst. 2007 Nov 27. Read Abstract.
- Yu Z, Boggon TJ, Kobayashi S, Jin C, Ma PC, Dowlati A, Kern JA, Tenen DG, Halmos B. Resistance to an irreversible epidermal growth factor receptor (EGFR) inhibitor in EGFR-mutant lung cancer reveals novel treatment strategies. Cancer Res. 2007 Nov 1;67(21):10417-27. Read Abstract.
| Cardiovascular System - Aikawa E, Nahrendorf M, Figueiredo JL, Swirski FK, Shtatland T, Kohler RH, Jaffer FA, Aikawa M, Weissleder R. Osteogenesis Associates With Inflammation in Early-Stage Atherosclerosis Evaluated by Molecular Imaging In Vivo. Circulation. 2007 Nov 26. Read Abstract.
- Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL, Libby P, Weissleder R, Pittet MJ. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med. 2007 Nov 26;204(12):3037-47. Read Abstract.
| Developmental Biology - Bennett JT, Stickney HL, Choi WY, Ciruna B, Talbot WS, Schier AF. Maternal nodal and zebrafish embryogenesis. Nature. 2007 Nov 8;450(7167):E1-2. Read Abstract.
- Lengner CJ, Camargo FD, Hochedlinger K, Welstead GG, Zaidi S, Gokhale S, Scholer HR,Tomilin A, Jaenisch R. Oct4 Expression Is Not Required for Mouse Somatic Stem Cell Self-Renewal. Cell Stem Cell, Vol 1, 403-415, 11 October 2007. Read Abstract.
| Diabetes - Feuerer M, Jiang W, Holler PD, Satpathy A, Campbell C, Bogue M, Mathis D, Benoist C. Enhanced thymic selection of FoxP3+ regulatory T cells in the NOD mouse model of autoimmune diabetes. Proc Natl Acad Sci USA. 2007 Nov 13;104(46):18181-6. Read Abstract.
| Gastrointestinal System - Yamamoto-Furusho JK, Podolsky DK. Innate immunity in inflammatory bowel disease. World J Gastroenterol. 2007 Nov 14;13(42):5577-80. Read Abstract.
| Imaging - Shepherd J, Hilderbrand SA, Waterman P, Heinecke JW, Weissleder R, Libby P. A fluorescent probe for the detection of myeloperoxidase activity in atherosclerosis-associated macrophages. Chem Biol. 2007 Nov;14(11):1221-31. Read Abstract.
- Barnes KR, Blois J, Smith A, Yuan H, Reynolds F, Weissleder R, Cantley LC, Josephson L. Fate of a Bioactive Fluorescent Wortmannin Derivative in Cells. Bioconjug Chem. 2007 Nov 8. Read Abstract.
- Upadhyay R, Sheth RA, Weissleder R, Mahmood U. Quantitative real-time catheter-based fluorescence molecular imaging in mice. Radiology. 2007 Nov;245(2):523-31. Read Abstract.
- Taktak S, Sosnovik D, Cima MJ, Weissleder R, Josephson L. Multiparameter Magnetic Relaxation Switch Assays. Anal Chem. 2007 Dec 1;79(23):8863-8869. Read Abstract.
| Immunology - Le Y, Zhu BM, Harley B, Park SY, Kobayashi T, Manis JP, Luo HR, Yoshimura A, Hennighausen L, Silberstein LE. SOCS3 Protein Developmentally Regulates the Chemokine Receptor CXCR4-FAK Signaling Pathway during B Lymphopoiesis. Immunity. 2007 Nov;27(5):811-23. Read Abstract.
- Hill JA, Feuerer M, Tash K, Haxhinasto S, Perez J, Melamed R, Mathis D, Benoist C. Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature. Immunity. 2007 Nov;27(5):786-800. Read Abstract.
- Gray DH, Gavanescu I, Benoist C, Mathis D. Danger-free autoimmune disease in Aire-deficient mice. Proc Natl Acad Sci USA. 2007 Nov 13;104(46):18193-8. Read Abstract.
- Venanzi ES, Gray DH, Benoist C, Mathis D. Lymphotoxin pathway and Aire influences on thymic medullary epithelial cells are unconnected. J Immunol. 2007 Nov 1;179(9):5693-700. Read Abstract.
| Muscular System - Kang PB, Feener CA, Estrella E, Thorne M, White AJ, Darras BT, Amato AA, Kunkel LM. LGMD2I in a North American population. BMC Musculoskelet Disord. 2007 Nov 24;8(1):115. Read Abstract.
- van Wageningen S, Breems-de Ridder MC, Nigten J, Nikoloski G, Erpelinck-Verschueren CA, Lowenberg B, de Witte T, Tenen DG, van der Reijden BA, Jansen JH. Gene transactivation without direct DNA-binding defines a novel gain-of-function for PML-RAR{alpha} Blood. 2007 Nov 19. Read Abstract.
| Nervous System - Cubelos B, Sebastián-Serrano A, Kim S, Moreno-Ortiz C, Redondo JM, Walsh CA, Nieto M. Cux-2 Controls the Proliferation of Neuronal Intermediate Precursors of the Cortical Subventricular Zone. Cereb Cortex. 2007 Nov 21. Read Abstract.
- Rajab A, Manzini MC, Mochida GH, Walsh CA, Ross ME. A novel form of lethal microcephaly with simplified gyral pattern and brain stem hypoplasia. Am J Med Genet A. 2007 Nov 1;143A(23):2761-2767. Read Abstract.
| Renal System - Bonventre JV. Urine neutrophil gelatinase-associated lipocalin as a marker of acute kidney injury in critically ill children. Nat Clin Pract Nephrol. 2007 Nov 27.. Read Abstract.
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