Research Newsletter - August 2010
Spotlight
This month we highlight two papers by HSCI Principal Faculty members published in the journals Nature and Nature Biotechnology.
Epigenetic memory in induced pluripotent stem cells
Abstract:
Somatic cell nuclear transfer and transcription-factor-based reprogramming revert adult cells to an embryonic state, and yield pluripotent stem cells that can generate all tissues. Through different mechanisms and kinetics, these two reprogramming methods reset genomic methylation, an epigenetic modification of DNA that influences gene expression, leading us to hypothesize that the resulting pluripotent stem cells might have different properties. Here we observe that low-passage induced pluripotent stem cells (iPSCs) derived by factor-based reprogramming of adult murine tissues harbour residual DNA methylation signatures characteristic of their somatic tissue of origin, which favours their differentiation along lineages related to the donor cell, while restricting alternative cell fates. Such an 'epigenetic memory' of the donor tissue could be reset by differentiation and serial reprogramming, or by treatment of iPSCs with chromatin-modifying drugs. In contrast, the differentiation and methylation of nuclear-transfer-derived pluripotent stem cells were more similar to classical embryonic stem cells than were iPSCs. Our data indicate that nuclear transfer is more effective at establishing the ground state of pluripotency than factor-based reprogramming, which can leave an epigenetic memory of the tissue of origin that may influence efforts at directed differentiation for applications in disease modelling or treatment.
Kim K, Doi A, Wen B, Ng K, Zhao R, Cahan P, Kim J, Aryee MJ, Ji H, Ehrlich LI, Yabuuchi A, Takeuchi A, Cunniff KC, Hongguang H, McKinney-Freeman S, Naveiras O, Yoon TJ, Irizarry RA, Jung N, Seita J, Hanna J, Murakami P, Jaenisch R, Weissleder R, Orkin SH, Weissman IL, Feinberg AP, Daley GQ. Epigenetic memory in induced pluripotent stem cells. Nature. 2010 Jul 19. [Epub ahead of print] Read Paper.
Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells
Abstract:
Induced pluripotent stem cells (iPSCs) have been derived from various somatic cell populations through ectopic expression of defined factors. It remains unclear whether iPSCs generated from different cell types are molecularly and functionally similar. Here we show that iPSCs obtained from mouse fibroblasts, hematopoietic and myogenic cells exhibit distinct transcriptional and epigenetic patterns. Moreover, we demonstrate that cellular origin influences the in vitro differentiation potentials of iPSCs into embryoid bodies and different hematopoietic cell types. Notably, continuous passaging of iPSCs largely attenuates these differences. Our results suggest that early-passage iPSCs retain a transient epigenetic memory of their somatic cells of origin, which manifests as differential gene expression and altered differentiation capacity. These observations may influence ongoing attempts to use iPSCs for disease modeling and could also be exploited in potential therapeutic applications to enhance differentiation into desired cell lineages.
Polo JM, Liu S, Figueroa ME, Kulalert W, Eminli S, Tan KY, Apostolou E, Stadtfeld M, Li Y, Shioda T, Natesan S, Wagers AJ, Melnick A, Evans T, Hochedlinger K. Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nat Biotechnol. 2010 Aug;28(8):848-55. Epub 2010 Jul 19. Read Paper.
Review and Commentary
Abou-Khalil R, Brack AS. Muscle stem cells and reversible quiescence: The role of sprouty. Cell Cycle. 2010 Jul 26;9(13). [Epub ahead of print]
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Beerman I, Maloney WJ, Weissmann IL, Rossi DJ. Stem cells and the aging hematopoietic system. Curr Opin Immunol. 2010 Jul 20. [Epub ahead of print]
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Domian IJ, Buikema JW, de Boer RA, van der Meer P. Stem cells in heart failure. Eur J Heart Fail. 2010 Jul;12(7):642-4.
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Durand EM, Zon LI. Newly emerging roles for prostaglandin E2 regulation of hematopoiesis and hematopoietic stem cell engraftment. Curr Opin Hematol. 2010 Jul;17(4):308-12.
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Figueiredo JL, Nahrendorf M, Vinegoni C, Weissleder R. Intraoperative Near-infrared Fluorescent Cholangiography (NIRFC) in Mouse Models of Bile Duct Injury: Reply. World J Surg. 2010 Jul 20. [Epub ahead of print]
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Lensch MW, Rao M. Induced pluripotent stem cells: opportunities and challenges. Regen Med. 2010 Jul;5(4):483-4.
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Martinez NJ, Gregory RI. MicroRNA gene regulatory pathways in the establishment and maintenance of ESC identity. Cell Stem Cell. 2010 Jul 2;7(1):31-5.
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Musunuru K, Domian IJ, Chien KR. Stem Cell Models of Cardiac Development and Disease. Annu Rev Cell Dev Biol. 2010 Jul 6. [Epub ahead of print]
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Orkin SH, Higgs DR. Medicine. Sickle cell disease at 100 years. Science. 2010 Jul 16;329(5989):291-2.
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Polo JM, Hochedlinger K. When fibroblasts MET iPSCs. Cell Stem Cell. 2010 Jul 2;7(1):5-6. Epub 2010 Jun 17.
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Segers VF, Lee RT. Protein Therapeutics for Cardiac Regeneration after Myocardial Infarction. J Cardiovasc Transl Res. 2010 Jul 7. [Epub ahead of print]
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Storer NY, Zon LI. Zebrafish models of p53 functions. Cold Spring Harb Perspect Biol. 2010 Aug 1;2(8):a001123. Epub 2010 May 5.
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Tamplin OJ, Zon LI. Blood flow: metalloproteases cut loose in primitive erythrocytes. Curr Biol. 2010 Jul 13;20(13):R561-2.
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Taylor PL, Barker RA, Blume KG, Cattaneo E, Colman A, Deng H, Edgar H, Fox IJ, Gerstle C, Goldstein LS, High KA, Lyall A, Parkman R, Pitossi FJ, Prentice ED, Rooke HM, Sipp DA, Srivastava A, Stayn S, Steinberg GK, Wagers AJ, Weissman IL. Patients beware: commercialized stem cell treatments on the web. Cell Stem Cell. 2010 Jul 2;7(1):43-9. Epub 2010 Jun 17.
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Weir GC, Bonner-Weir S. Dreams for type 1 diabetes: shutting off autoimmunity and stimulating beta-cell regeneration. Endocrinology. 2010 Jul;151(7):2971-3.
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Blood
Bradner JE, Mak R, Tanguturi SK, Mazitschek R, Haggarty SJ, Ross K, Chang CY, Bosco J, West N, Morse E, Lin K, Shen JP, Kwiatkowski NP, Gheldof N, Dekker J, DeAngelo DJ, Carr SA, Schreiber SL, Golub TR, Ebert BL. Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease. Proc Natl Acad Sci U S A. 2010 Jul 13;107(28):12617-22. Epub 2010 Jun 28.
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Guo S, Lu J, Schlanger R, Zhang H, Wang JY, Fox MC, Purton LE, Fleming HH, Cobb B, Merkenschlager M, Golub TR, Scadden DT. MicroRNA miR-125a controls hematopoietic stem cell number. Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14229-34. Epub 2010 Jul 8.
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Jeanson NT, Scadden DT. Vitamin D receptor (VDR) deletion leads to increased hematopoietic stem and progenitor cells residing in the spleen. Blood. 2010 Jul 27. [Epub ahead of print]
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Kao GS, Kim HT, Daley H, Ritz J, Burger SR, Kelley L, Vierra-Green C, Flesch S, Spellman S, Miller J, Confer D. Validation of short-term handling and storage conditions for marrow and peripheral blood stem cell products. Transfusion. 2010 Jul 1. [Epub ahead of print]
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Kharas MG, Lengner CJ, Al-Shahrour F, Bullinger L, Ball B, Zaidi S, Morgan K, Tam W, Paktinat M, Okabe R, Gozo M, Einhorn W, Lane SW, Scholl C, Fröhling S, Fleming M, Ebert BL, Gilliland DG, Jaenisch R, Daley GQ. Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia. Nat Med. 2010 Aug;16(8):903-8. Epub 2010 Jul 8.
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Loh YH, Hartung O, Li H, Guo C, Sahalie JM, Manos PD, Urbach A, Heffner GC, Grskovic M, Vigneault F, Lensch MW, Park IH, Agarwal S, Church GM, Collins JJ, Irion S, Daley GQ. Reprogramming of T cells from human peripheral blood. Cell Stem Cell. 2010 Jul 2;7(1):15-9.
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Cancer
Curtis SJ, Sinkevicius KW, Li D, Lau AN, Roach RR, Zamponi R, Woolfenden AE, Kirsch DG, Wong KK, Kim CF. Primary tumor genotype is an important determinant in identification of lung cancer propagating cells. Cell Stem Cell. 2010 Jul 2;7(1):127-33.
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da Silva RG, Tavora B, Robinson SD, Reynolds LE, Szekeres C, Lamar J, Batista S, Kostourou V, Germain MA, Reynolds AR, Jones DT, Watson AR, Jones JL, Harris A, Hart IR, Iruela-Arispe ML, Dipersio CM, Kreidberg JA, Hodivala-Dilke KM. Endothelial {alpha}3{beta}1-Integrin Represses Pathological Angiogenesis and Sustains Endothelial-VEGF. Am J Pathol. 2010 Jul 16. [Epub ahead of print]
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Gutierrez A, Dahlberg SE, Neuberg DS, Zhang J, Grebliunaite R, Sanda T, Protopopov A, Tosello V, Kutok J, Larson RS, Borowitz MJ, Loh ML, Ferrando AA, Winter SS, Mullighan CG, Silverman LB, Chin L, Hunger SP, Sallan SE, Look AT. Absence of Biallelic TCR{gamma} Deletion Predicts Early Treatment Failure in Pediatric T-Cell Acute Lymphoblastic Leukemia. J Clin Oncol. 2010 Jul 19. [Epub ahead of print]
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Yeo WL, Riely GJ, Yeap BY, Lau MW, Warner JL, Bodio K, Huberman MS, Kris MG, Tenen DG, Pao W, Kobayashi S, Costa DB. Erlotinib at a dose of 25 mg daily for non-small cell lung cancers with EGFR mutations. J Thorac Oncol. 2010 Jul;5(7):1048-53.
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Chemisty
Atochin DN, Yuzawa I, Li Q, Rauwerdink KM, Malhotra R, Chang J, Brouckaert P, Ayata C, Moskowitz MA, Bloch KD, Huang PL, Buys ES. Soluble guanylate cyclase alpha1beta1 limits stroke size and attenuates neurological injury. Stroke. 2010 Aug;41(8):1815-9. Epub 2010 Jul 1. Kim YW, Kutchukian PS, Verdine GL. Introduction of all-hydrocarbon i,i+3 staples into alpha-helices via ring-closing olefin metathesis. Org Lett. 2010 Jul 2;12(13):3046-9.
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Developmental Biology
Bai X, Kim J, Yang Z, Jurynec MJ, Akie TE, Lee J, LeBlanc J, Sessa A, Jiang H, DiBiase A, Zhou Y, Grunwald DJ, Lin S, Cantor AB, Orkin SH, Zon LI. TIF1gamma controls erythroid cell fate by regulating transcription elongation. Cell. 2010 Jul 9;142(1):133-43.
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Chen L, Wang D, Wu Z, Ma L, Daley GQ. Molecular basis of the first cell fate determination in mouse embryogenesis. Cell Res. 2010 Jul 13. [Epub ahead of print]
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Kim K, Doi A, Wen B, Ng K, Zhao R, Cahan P, Kim J, Aryee MJ, Ji H, Ehrlich LI, Yabuuchi A, Takeuchi A, Cunniff KC, Hongguang H, McKinney-Freeman S, Naveiras O, Yoon TJ, Irizarry RA, Jung N, Seita J, Hanna J, Murakami P, Jaenisch R, Weissleder R, Orkin SH, Weissman IL, Feinberg AP, Daley GQ. Epigenetic memory in induced pluripotent stem cells. Nature. 2010 Jul 19. [Epub ahead of print]
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Mauney JR, Ramachandran A, Yu RN, Daley GQ, Adam RM, Estrada CR. All-trans retinoic acid directs urothelial specification of murine embryonic stem cells via GATA4/6 signaling mechanisms. PLoS One. 2010 Jul 13;5(7):e11513.
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O'Brien KB, Alberich-Jordà M, Yadav N, Kocher O, Diruscio A, Ebralidze A, Levantini E, Sng NJ, Bhasin M, Caron T, Kim D, Steidl U, Huang G, Halmos B, Rodig SJ, Bedford MT, Tenen DG, Kobayashi S. CARM1 is required for proper control of proliferation and differentiation of pulmonary epithelial cells. Development. 2010 Jul;137(13):2147-56.
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Polo JM, Liu S, Figueroa ME, Kulalert W, Eminli S, Tan KY, Apostolou E, Stadtfeld M, Li Y, Shioda T, Natesan S, Wagers AJ, Melnick A, Evans T, Hochedlinger K. Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nat Biotechnol. 2010 Aug;28(8):848-55. Epub 2010 Jul 19.
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Qin J, Van Buren D, Huang HS, Zhong L, Mostoslavsky R, Akbarian S, Hock H. Chromatin protein L3mbtl1 is dispensable for development and tumor suppression in mice. J Biol Chem. 2010 Jul 2. [Epub ahead of print]
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Diabetes
Li WC, Rukstalis JM, Nishimura W, Tchipashvili V, Habener JF, Sharma A, Bonner-Weir S. Activation of pancreatic-duct-derived progenitor cells during pancreas regeneration in adult rats. J Cell Sci. 2010 Aug 15;123(Pt 16):2792-802. Epub 2010 Jul 27.
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Marselli L, Thorne J, Dahiya S, Sgroi DC, Sharma A, Bonner-Weir S, Marchetti P, Weir GC. Gene expression profiles of Beta-cell enriched tissue obtained by laser capture microdissection from subjects with type 2 diabetes. PLoS One. 2010 Jul 13;5(7):e11499.
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Genetics and Genomics
Boyden SE, Salih MA, Duncan AR, White AJ, Estrella EA, Burgess SL, Seidahmed MZ, Al-Jarallah AS, Alkhalidi HM, Al-Maneea WM, Bennett RR, Alshemmari SH, Kunkel LM, Kang PB. Efficient identification of novel mutations in patients with limb girdle muscular dystrophy. Neurogenetics. 2010 Jul 13. [Epub ahead of print]
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Imaging
Nguyen BT, Vemula PK, Mitsouras D, Yu P, Tao M, Campagna C, Mulkern RV, Rybicki FJ, Karp JM, Ozaki CK. Immobilization of Iron Oxide Magnetic Nanoparticles for Enhancement of Vessel Wall Magnetic Resonance Imaging-An Ex Vivo Feasibility Study. Bioconjug Chem. 2010 Jul 7. [Epub ahead of print]
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Reiner T, Kohler RH, Liew CW, Hill JA, Gaglia J, Kulkarni RN, Weissleder R. Near-infrared fluorescent probe for imaging of pancreatic Beta cells. Bioconjug Chem. 2010 Jul 21;21(7):1362-8.
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Immunology
Jacobs JP, Ortiz-Lopez A, Campbell JJ, Gerard CJ, Mathis D, Benoist C. Deficiency of CXCR2, but not other chemokine receptors, attenuates autoantibody-mediated arthritis in a murine model. Arthritis Rheum. 2010 Jul;62(7):1921-32.
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Koh AS, Kingston RE, Benoist C, Mathis D. Global relevance of Aire binding to hypomethylated lysine-4 of histone-3. Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):13016-21. Epub 2010 Jul 6.
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Muscular System
Nervous System
Cooper O, Hargus G, Deleidi M, Blak A, Osborn T, Marlow E, Lee K, Levy A, Perez-Torres E, Yow A, Isacson O. Differentiation of human ES and Parkinson's disease iPS cells into ventral midbrain dopaminergic neurons requires a high activity form of SHH, FGF8a and specific regionalization by retinoic acid. Mol Cell Neurosci. 2010 Jul 23. [Epub ahead of print]
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Haramati S, Chapnik E, Sztainberg Y, Eilam R, Zwang R, Gershoni N, McGlinn E, Heiser PW, Wills AM, Wirguin I, Rubin LL, Misawa H, Tabin CJ, Brown R Jr, Chen A, Hornstein E. miRNA malfunction causes spinal motor neuron disease. Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):13111-6. Epub 2010 Jun 29.
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Seo H, Isacson O. The hAPP-YAC transgenic model has elevated UPS activity in the frontal cortex similar to Alzheimer's disease and Down's syndrome. J Neurochem. 2010 Jul 13. [Epub ahead of print]
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Skeletal System
Hjortnaes J, Butcher J, Figueiredo JL, Riccio M, Kohler RH, Kozloff KM, Weissleder R, Aikawa E. Arterial and aortic valve calcification inversely correlates with osteoporotic bone remodelling: a role for inflammation. Eur Heart J. 2010 Jul 2. [Epub ahead of print]
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Technology
Amadi OC, Steinhauser ML, Nishi Y, Chung S, Kamm RD, McMahon AP, Lee RT. A low resistance microfluidic system for the creation of stable concentration gradients in a defined 3D microenvironment. Biomed Microdevices. 2010 Jul 27. [Epub ahead of print]
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Ozsolak F, Ting DT, Wittner BS, Brannigan BW, Paul S, Bardeesy N, Ramaswamy S, Milos PM, Haber DA. Amplification-free digital gene expression profiling from minute cell quantities. Nat Methods. 2010 Aug;7(8):619-21. Epub 2010 Jul 18.
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Tissue Engineering
Ott HC, Clippinger B, Conrad C, Schuetz C, Pomerantseva I, Ikonomou L, Kotton D, Vacanti JP. Regeneration and orthotopic transplantation of a bioartificial lung. Nat Med. 2010 Aug;16(8):927-33. Epub 2010 Jul 13.
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