The Mesenchymal-to-Epithelial Transition (MET) is a Critical Event for Generating iPSCs
Expression of four transcription factors: Oct4, Klf4, Sox2 and c-Myc (OKMS), is sufficient to reprogram somatic cells to become induced pluripotent stem cells (iPSCs), which have a similar pluripotent potential to embryonic stem cells. In the July issue of Cell Stem Cell, Drs. Jeffrey Wrana’s and Andras Nagy’s laboratories showed that the mesenchymal-to-epithelial transition (MET) is a critical initiating event during the reprogramming of mouse embryonic fibroblasts (MEFs) to iPSCs.
The team used gene expression profiling and a functional siRNA screen to investigate mechanisms underlying the stages of reprogramming, and defined three phases: initiation, maturation and stabilization. They found that broad, temporal alterations in gene expression occur during reprogramming and that a BMP-miRNA-MET signalling axis regulates the initiation phase. The researchers also revealed that embryonic stem cell-associated genes cluster into the middle or late phases of reprogramming, and that the initiation phase is “elastic”, meaning that cells can revert back to their differentiated state if the OKMS factors are removed.
This study is helping to define the functional pathways that drive reprogramming. MET, as well as the reverse process, epithelial-to-mesenchymal transition (EMT), are important events that occur during organ development and cancer metastasis. These results indicate that there are significant similarities between cellular reprogramming, development and cancer and that the acquisition of an epithelial state is an important event when cells are reprogrammed to a pluripotent state.
Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming. Samavarchi-Tehrani P, Golipour A, David L, Sung H-K, Beyer T, Datti A, Woltjen K*, Nagy A*, Wrana J*. Cell Stem Cell. 2010 July 2. [Abstract] *co-corresponding authors
Congratulations to McEwen Investigators on their Acceleration Award Success!
The McEwen Centre Acceleration Awards were established with the goal of funding projects that make use of stem cells and have deliverable outcomes leading to potential clinical or commercial applications.
Congratulations to the McEwen scientists who were successfully funded for up to $175,000/year for two years on the following projects:
Michael Fehlings (PI), Andras Nagy, Molly Shoichet and Derek van der Kooy “iPS derived neuronal stem cells and bioengineered strategies to treat chronic spinal cord injury”
Mansoor Husain (PI), Freda Miller and Peter Zandstra “Diagnostic & therapeutic potential of vascular smooth muscle cells differentiated from skin-derived precursors”
Norman Iscove(PI) and Peter Zandstra “A microfluidics platform for rapid and direct enumeration of rare stem cells in unenriched cell populations”
Freda Miller(PI), Mansoor Husain, David Kaplan and Michael Sefton “Stem cell approaches to wound-healing”
Andras Nagy(PI), Derek van der Kooy, Molly Shoichet and Shelley Boyd “Combined cell and gene therapy to treat/cure age-related macular degeneration and diabetic retinopathy”
Derek van der Kooy (PI), Molly Shoichet and Shelley Boyd “Overcoming blindness with regenerative medicine”
Thomas Waddell (PI), Shaf Keshavjee, Nadeem Moghal, Armand Keating and Alison McGuigan “Long Segment Tracheal Replacement using a decellularized Allograft”
Mark Your Calendars!
Deadlines for several Stem Cell Network (SCN) related events are fast approaching:
Registration is now open for the 2010 Stem Cell Network Annual Scientific Meeting, which will be held in Calgary, Alberta from November 22-24, 2010. The deadline for abstract submission is Thursday, September 30.
SCN will also be holding a graduate course in regenerative medicine, open to all SCN members. This web-based course features lectures from prominent researchers across Canada, and can be taken for credits towards an MSc/PhD diploma. Topics will include stem cells and regenerative medicine, the business of regenerative medicine and regenerative medicine ethics and society. Contact Sophie Charge to enroll and obtain course details and requirements, no later than August 15, 2010. Enrollment is limited to 20 trainees, so register early!
Funding opportunity: The SCN Global Research competition (deadline October 13, 2010), is intended for projects that have the potential to make a major global impact. Projects will be funded for 3.5 years, for a total of up to $3M/team.
Save the Date
The McEwen Science Day “Celebrate Science” will be held on September 23, 2010. More details to follow in next month’s newsletter!
July 15, 2010 - Dr. Dan S. Kaufman Associate Professor of Medicine in the Division of Hematology, Oncology and Transplantation; and the Stem Cell Institute, University of Minnesota
Title: Therapeutic Potential of Hematopoietic Cells Derived from Human Pluripotent Stem Cells
Location and Time: MSB 2173, 1 King's College Circle, University of Toronto. 4-5pm.
Recent Publications
Zonadhesin is essential for species specificity of sperm adhesion to the egg's zona pellucida. Tardif S, Wilson MD, Wagner R, Hunt P, Gertsenstein M, Nagy A, Lobe C, Koop BF, Hardy DM. J Biol Chem. 2010 June 7. [Abstract]
{beta}-catenin initiates tooth neogenesis in adult rodent incisors. Liu F, Dangaria S, Andl T, Zang Y, Wright AC, Damek-Poprawa M, Piccolo S, Nagy A, Taketo M, Diekwisch TG, Akintoye SO, Millar SE. J Dent Res. 2010 June 8. [Abstract]
Synergistic antitumor effects of regulatory T cell blockade combined with pemetrexed in murine malignant mesothelioma. Anraku M, Tagawa T, Wu L, Yun Z, Keshavjee S, Zhang L, Johnston MR, de Perrot M. J Immunol. 2010 June 14. [Abstract]
Mitochondrial fission leads to Smac/DIABLO release quenced by ARC. Li J, Li Y, Qin D, von Harsdorf R, Li P. Apoptosis. 2010 June 16. [Abstract]
Stem cell tharapy for the kidney: A cautionary tale. Nagy A, Quaggin SE. J Am Soc Nephrol. 2010 June 17. [Abstract]
p75NTR is an obligate signaling receptor required for cues that cause sympathetic neuron growth cone collapse. Naska S, Lin DC, Miller FD, Kaplan DR. Mol Cell Neurosci. 2010 June 17. [Abstract]
Adenosine A1 and A2A receptors are not upstream of caffeine's dopamine D receptor-dependent aversive effects and dopamine-independent rewarding effects. Sturgess JE, Ting-A-Kee RA, Podbielski D, Sellings LH, Chen JF, van der Kooy D. Eur J Neurosci. 2010 June 22. [Abstract]
Efficient generation of germ line transmitting chimeras from C57BL/6N ES cells by aggregation with outbred host embryos. Gertsenstein M, Nutter LM, Reid T, Pereira M, Stanford WL, Rossant J, Nagy A. PLoS One. 2010 June 22. [Abstract]
The effect of umbilical cord blood cells on outcomes after experimental traumatic spinal cord injury. Chua SJ, Bielecki R, Yamanaka N, Fehlings MG, Rogers IM, Casper RF. Spine. 2010 June 24. [Abstract]
The use of immobilized neurotrophins to support neuron survival and guide nerve fiber growth in compartmentalized chambers. Yu LM, Miller FD, Shoichet MS. Biomaterials. 2010 June 25. [Abstract]
The effect of age on the efficacy of human mesenchymal stem cell transplantation after a myocardial infarction. Fan M, Chen W, Liu W, Du GQ, Jiang SL, Tian WC, Sun L, Li RK, Tian H. Rejuvenation Res. 2010 June 29. [Abstract]
Design of three-dimensional biomimetic scaffolds. Owen SC, Shoichet MS. J Biomed Mater Res A. 2010 July 1. [Abstract]
An RNAi screen identifies Msi2 and Prox1 as having opposite roles in the regulation of hematopoietic stem cell activity. Hope KJ, Cellot S, Ting SB, MacRae T, Mayotte N, Iscove NN, Sauvageau G. Cell Stem Cell. 2010 July 2. [Abstract]
An adult uterine hemangioblast: Evidence for extramedullary self-renewal and clonal bilineage potential. Sun Z, Zhang Y, Brunt KR, Wu J, Li SH, Fazel S, Weisel RD, Keating A, Li RK. Blood. 2010 July 6. [Abstract]
A distinctive DNA damage response in human hematopoietic stem cells reveals an apoptosis-independent role for p53 in self-renewal. Milyavsky M, Gan OI, Trottier M, Komosa M, Tabach O, Notta F, Lechman E, Hermans KG, Eppert K, Konovalova Z, Ornatsky O, Domany E, Meyn MS, Dick JE. Cell Stem Cell. 2010 July 7. [Abstract]
The McEwen Centre for Regenerative Medicine, led by director Dr. Gordon Keller, includes 15 scientists at the University of Toronto and five Toronto hospitals, working to advance the development of more effective treatments for conditions including heart disease, diabetes, respiratory disease and spinal cord injury.
The Centre is located at University Health Network, MaRS Centre, Toronto Medical Discovery Tower, 101 College Street, 8th Floor, Room 701, Toronto, Ontario, Canada M5G 1L7
Email: mcewencentre@uhn.on.ca
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