SPOTLIGHTED RESEARCH REVIEW ARTICLES SCIENTIFIC PAPERS blood disease cancer cardiovascular disease development diabetes imaging immunology lung disease nervous system diseases reproductive system

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. If you are having problems viewing this newletter, click here to view it in your web browser. Spotlighted Research In a review paper published in Nature, HSCI Scientific Co-Director David Scadden explores the interplay between stem cells and their niche, and how this relationship sustains tissues and its role in the design of stem cell therapies. Title: The Stem-Cell Niche as an Entity of Action Author: David T. Scadden, MD

Abstract:

Stem-cell populations are established in 'niches' - specific anatomic locations that regulate how they participate in tissue generation, maintenance and repair. The niche saves stem cells from depletion, while protecting the host from over-exuberant stem-cell proliferation. It constitutes a basic unit of tissue physiology, integrating signals that mediate the balanced response of stem cells to the needs of organisms. Yet the niche may also induce pathologies by imposing aberrant function on stem cells or other targets. The interplay between stem cells and their niche creates the dynamic system necessary for sustaining tissues, and for the ultimate design of stem-cell therapeutics.

Figure 1

Refining elements necessary for an adult stem-cell niche. (a) Early studies provided evidence that heterologous cell types created a three-dimensional structure in which stem cells reside. (b) Recent data raises the possibility that a regulatory microenvironment might include stem cells simply resident on the basement membrane with homologous cellÐcell interactions. Stem cells are shown in deep green and more mature offspring are represented by a lighter shade.

Figure 3

Inputs feeding back on stem-cell function in the niche. Elements of the local environment that participate in regulating the system of a stem cell in its tissue state are depicted. These include the constraints of the architectural space, physical engagement of the cell membrane with tethering molecules on neighbouring cells or surfaces, signalling interactions at the interface of stem cells and niche or descendent cells, paracrine and endocrine signals from local or distant sources, neural input and metabolic products of tissue activity.

Scadden DT. The stem-cell niche as an entity of action. Nature. 2006 Jun 29;441(7097):1075-9. Read Abstract.

Review Papers

• Scadden DT. The stem-cell niche as an entity of action. Nature. 2006 Jun 29;441(7097):1075-9. Read Abstract.
• Hochedlinger K, Jaenisch R. Nuclear reprogramming and pluripotency. Nature. 2006 Jun 29;441(7097):1061-7. Read Abstract.

Scientific Papers

Blood Disease

• Azam M, Nardi V, Shakespeare WC, Metcalf CA 3rd, Bohacek RS, Wang Y, Sundaramoorthi R, Sliz P, Veach DR, Bornmann WG, Clarkson B, Dalgarno DC, Sawyer TK, Daley GQ. Activity of dual SRC-ABL inhibitors highlights the role of BCR/ABL kinase dynamics in drug resistance. Proc Natl Acad Sci USA. 2006 Jun 13;103(24):9244-9. Read Abstract.
• Mercher T, Wernig G, Moore SA, Levine RL, Gu TL, Frohling S, Cullen D, Polakiewicz RD, Bernard OA, Boggon TJ, Lee BH, Gilliland DG. JAK2T875N is a novel activating mutation that results in myeloproliferative disease with features of megakaryoblastic leukemia in a murine bone marrow transplantation model. Blood. 2006 Jun 27. Read Abstract.
• Lee YJ, Jones LC, Timchenko NA, Perrotti D, Tenen DG, Kogan SC. CCAAT/enhancer binding proteins alpha and epsilon cooperate with all-trans retinoic acid in therapy but they differ in their anti-leukemic activities. Blood. 2006 Jun 20. Read Abstract.
• Ma Y, Cui W, Yang J, Qu J, Di C, Amin HM, Lai R, Ritz J, Krause DS, Chai L. SALL4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (AML) and induces AML in transgenic mice. Blood. 2006 Jun 8. Read Abstract.
• Loh ML, Goldwasser MA, Silverman LB, Poon WM, Vattikuti S, Cardoso A, Neuberg DS, Shannon KM, Sallan SE, Gilliland DG. Prospective analysis of TEL/AML1-positive patients treated on Dana-Farber Cancer Institute Consortium Protocol 95-01. Blood. 2006 Jun 1;107(11):4508-13. Read Abstract.
• Wernig G, Mercher T, Okabe R, Levine RL, Lee BH, Gilliland DG. Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model. Blood. 2006 Jun 1;107(11):4274-81. Read Abstract.
• Swirski FK, Pittet MJ, Kircher MF, Aikawa E, Jaffer FA, Libby P, Weissleder R. Monocyte accumulation in mouse atherogenesis is progressive and proportional to extent of disease. Proc Natl Acad Sci U S A. 2006 Jun 26. Read Abstract.

Cancer

• Yin H, Radomska HS, Tenen DG, Glass J. Down regulation of prostate specific antigen (PSA) by CCAAT/enhancer binding protein-alpha (C/EBPa) is associated with loss of androgen receptor expression and inhibition of PSA promoter activity in the human prostate cancer cell line, LNCaP. BMC Cancer. 2006 Jun 14;6(1):158. Read Abstract.

Cardiovascular

• Jeong D, Cha H, Kim E, Kang M, Yang DK, Kim JM, Yoon PO, Oh JG, Bernecker OY, Sakata S, Thu LT, Cui L, Lee YH, Kim DH, Woo SH, Liao R, Hajjar RJ, Park WJ. PICOT Inhibits Cardiac Hypertrophy and Enhances Ventricular Function and Cardiomyocyte Contractility. Circ Res. 2006 Jun 29. Read Abstract.
• Arany Z, Novikov M, Chin S, Ma Y, Rosenzweig A, Spiegelman BM. Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-{gamma} coactivator 1{alpha}. Proc Natl Acad Sci USA. 2006 Jun 27;103(26):10086-91. Read Abstract.
• Morissette MR, Cook SA, Foo S, McKoy G, Ashida N, Novikov M, Scherrer-Crosbie M, Li L, Matsui T, Brooks G, Rosenzweig A. Myostatin Regulates Cardiomyocyte Growth Through Modulation of Akt Signaling. Circ Res. 2006 Jun 8. Read Abstract.
• Walkley CR, Orkin SH. Rb is dispensable for self-renewal and multilineage differentiation of adult hematopoietic stem cells. Proc Natl Acad Sci USA. 2006 Jun 13;103(24):9057-62. Read Abstract.
• Chen X, Shevtsov SP, Hsich E, Cui L, Haq S, Aronovitz M, Kerkela R, Molkentin JD, Liao R, Salomon RN, Patten R, Force T. The beta-catenin/T-cell factor/lymphocyte enhancer factor signaling pathway is required for normal and stress-induced cardiac hypertrophy. Mol Cell Biol. 2006 Jun;26(12):4462-73. Read Abstract.

Development

• Tam BY, Wei K, Rudge JS, Hoffman J, Holash J, Park SK, Yuan J, Hefner C, Chartier C, Lee JS, Jiang S, Niyak NR, Kuypers FA, Ma L, Sundram U, Wu G, Garcia JA, Schrier SL, Maher JJ, Johnson RS, Yancopoulos GD, Mulligan RC, Kuo CJ. VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis. Nat Med. 2006 Jun 25. Read Abstract.
• Lehtinen MK, Yuan Z, Boag PR, Yang Y, Villen J, Becker EB, DiBacco S, de la Iglesia N, Gygi S, Blackwell TK, Bonni A. A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell. 2006 Jun 2;125(5):987-1001. Read Abstract.
• Pyati UJ, Cooper MS, Davidson AJ, Nechiporuk A, Kimelman D. Sustained Bmp signaling is essential for cloaca development in zebrafish. Development. 2006 Jun;133(11):2275-84. Read Abstract.
• Wildner H, Muller T, Cho SH, Brohl D, Cepko CL, Guillemot F, Birchmeier C. dILA neurons in the dorsal spinal cord are the product of terminal and non-terminal asymmetric progenitor cell divisions, and require Mash1 for their development. Development. 2006 Jun;133(11):2105-13. Read Abstract.
• Gupta S, Zhu H, Zon LI, Evans T. BMP signaling restricts hemato-vascular development from lateral mesoderm during somitogenesis. Development. 2006 Jun;133(11):2177-87. Read Abstract.

Diabetes

• Inada A, Nienaber C, Fonseca S, Bonner-Weir S. Timing and expression pattern of carbonic anhydrase II in pancreas. Dev Dyn. 2006 Jun;235(6):1571-7. Read Abstract.
• Deramaudt TB, Takaoka M, Upadhyay R, Bowser MJ, Porter J, Lee A, Rhoades B, Johnstone CN, Weissleder R, Hingorani SR, Mahmood U, Rustgi AK. N-cadherin and keratinocyte growth factor receptor mediate the functional interplay between Ki-RASG12V and p53V143A in promoting pancreatic cell migration, invasion, and tissue architecture disruption. Mol Cell Biol. 2006 Jun;26(11):4185-200. Read Abstract.

Imaging

• Kang HW, Torres D, Wald L, Weissleder R, Bogdanov AA. Targeted imaging of human endothelial-specific marker in a model of adoptive cell transfer. Lab Invest. 2006 Jun;86(6):599-609. Read Abstract.
• Deguchi JO, Aikawa M, Tung CH, Aikawa E, Kim DE, Ntziachristos V, Weissleder R, Libby P. Inflammation in atherosclerosis: visualizing matrix metalloproteinase action in macrophages in vivo. Circulation. 2006 Jul 4;114(1):55-62. Read Abstract.

Immunology

• Hirai H, Zhang P, Dayaram T, Hetherington CJ, Mizuno S, Imanishi J, Akashi K, Tenen DG. C/EBPbeta is required for 'emergency' granulopoiesis. Nat Immunol. 2006 Jul;7(7):732-9. Read Abstract.

Lung Disease

• Meyer AM, Dwyer-Nield LD, Hurteau G, Keith RL, Ouyang Y, Freed BM, Kisley LR, Geraci MW, Bonventre JV, Nemenoff RA, Malkinson AM. Attenuation of the pulmonary inflammatory response following butylated hydroxytoluene treatment of cytosolic phospholipase A2 null mice. Am J Physiol Lung Cell Mol Physiol. 2006 Jun;290(6):L1260-6. Read Abstract.
• Figueiredo JL, Alencar H, Weissleder R, Mahmood U. Near infrared thoracoscopy of tumoral protease activity for improved detection of peripheral lung cancer. Int J Cancer. 2006 Jun 1;118(11):2672-7. Read Abstract.
• Costa DB, Dayaram T, D'Alo F, Wouters BJ, Tenen DG, Meyerson M, Tsao MS, Halmos B. C/EBPalpha mutations in lung cancer. Lung Cancer. 2006 Jun 8. Read Abstract.
• Ji H, Li D, Chen L, Shimamura T, Kobayashi S, McNamara K, Mahmood U, Mitchell A, Sun Y, Al-Hashem R, Chirieac LR, Padera R, Bronson RT, Kim W, Janne PA, Shapiro GI, Tenen D, Johnson BE, Weissleder R, Sharpless NE, Wong KK. The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies. Cancer Cell. 2006 Jun;9(6):485-95. Read Abstract.

Nervous System Diseases

• Basel-Vanagaite L, Muncher L, Straussberg R, Pasmanik-Chor M, Yahav M, Rainshtein L, Walsh CA, Magal N, Taub E, Drasinover V, Shalev H, Attia R, Rechavi G, Simon AJ, Shohat M. Mutated nup62 causes autosomal recessive infantile bilateral striatal necrosis. Ann Neurol. 2006 Jun 19. Read Abstract.
• Chung S, Shin BS, Hwang M, Lardaro T, Kang UJ, Isacson O, Kim KS. Neural precursors derived from embryonic stem cells, but not those from fetal ventral mesencephalon, maintain the potential to differentiate into dopaminergic neurons after expansion in vitro. Stem Cells. 2006 Jun;24(6):1583-93. Read Abstract.
• Chung S, Shin BS, Hedlund E, Pruszak J, Ferree A, Kang UJ, Isacson O, Kim KS. Genetic selection of sox1GFP-expressing neural precursors removes residual tumorigenic pluripotent stem cells and attenuates tumor formation after transplantation. J Neurochem. 2006 Jun;97(5):1467-80. Read Abstract.

Reproductive System

• Eggan K, Jurga S, Gosden R, Min IM, Wagers AJ. Ovulated oocytes in adult mice derive from non-circulating germ cells. Nature. 2006 Jun 29;441(7097):1109-14. Read Abstract.
• Tran TT, Segev DL, Gupta V, Kawakubo H, Yeo G, Donahoe PK, Maheswaran S. Mullerian Inhibiting Substance regulates androgen-induced gene expression and growth in prostate cancer cells through a NFkB-dependent Smad-independent mechanism. Mol Endocrinol. 2006 Jun 1. Read Abstract.

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