Project Title: Regulation of human skeletal stem cell differentiation using microRNAs – potential for bone tissue regeneration
Supervisor 1: Richard Oreffo (University of Southampton)
Supervisor 2: Tilman Sanchez-Elsner (University of Southampton)
Supervisor 3: Alan Dalton (University of Surrey)
Skeletal stem cells also commonly referred to as mesenchymal stem cells (MSCs) have the potential to form a variety of stromal lineages including bone, cartilage, fat and muscle and display plasticity between lineages. Lineage modulation offers significant therapeutic potential for the use of skeletal populations in regenerative medicine. MicroRNAs (miRNAs) are a class of endogenous non-protein-coding single-stranded RNAs, ranging from 18-25 nucleotides in length that regulate gene transcription post-transcriptionally with fundamental and diverse roles in a variety of biological and pathological processes. A number of miRNAs are specifically expressed in stem cells, control stem cell self-renewal, and differentiation while other miRNAs have been linked with disease or prognosis. The project will to utilise miRNA to control human stem cell differentiation toward specific lineages. The approach will also include the use of carbon nanotube scaffolds for cellular growth and as transfection matrices through a joint collaboration with the University of Surrey (Dr Alan Dalton) This will provide unique platforms for the regeneration of bone, cartilage as well as soft tissues like fat with therapeutic applications in tissue regeneration and builds on-going projects within the Bone and Joint Research Group within the Academic Unit of Human Development and Health at Southampton.. These studies offer, for the first time the ability to demonstrate the efficacy of miRNA strategies for use in skeletal repair in vivo.
Applicants for this 4-year PhD, starting in October 2012, should possess or expect to be awarded an Upper Second or 1st Class Honours degree (or equivalent) in a relevant subject. Studentships are available to UK nationals and EU students who meet the UK residency requirements. The studentship will support the student’s stipend and tuition fees. Informal enquiries to Dr Richard Oreffo: roco@soton.ac.uk
References:
Matthew J Dalby, Nikolaj Gadegaard, Rahul Tare, Abhay Andar, Mathis O Riehle, Pawel Herzyk, Chris D W Wilkinson, Oreffo ROC (2007) The control of human mesenchymal cell differentiation using nanoscale symmetry and disorder – Nature Materials Dec 6 (12):997-1003.
Rosanna Gonzalalez-McQuire, David W Green, Kris A Partridge, Richard O C Oreffo, Stephen Mann, Sean A Davis (2007) Coating of human mesenchymal cells in 3D culture with bioinorganic nanoparticles promotes osteoblastic differentiation and gene transfection – Advanced Materials (19) 2236-2240.
Kanczler JM, Ginty PJ, White L, Clarke NM, Howdle SM, Shakesheff KM, Oreffo ROC. The effect of the delivery of vascular endothelial growth factor and bone morphogenic protein-2 to osteoprogenitor cell populations on bone formation. Biomaterials. 2010 Feb;31(6):1242-50.
Dawson JI, Kanczler JM, Yang XB, Attard GS, Oreffo ROC. Clay Gels For the Delivery of Regenerative Microenvironments. Adv Mater. 2011 Aug 2;23(29):3304-8
Nanoscale surfaces for the long-term maintenance of mesenchymal stem cell phenotype and multipotency. McMurray RJ, Gadegaard N, Tsimbouri M, Burgess KV, McNamara LE, Tare R, Murawski K, Kingham E, Oreffo ROC and MJ. Dalby. Nature Materials. 2011 Jul 17;10(8):637-44.
Martinez-Nunez RT, Louafi F, Sanchez-Elsner T. The Interleukin 13 (IL-13) pathway in human macrophages is modulated by microRNA-155 via direct targeting of interleukin 13 receptor alpha 1 (IL13R1). J Biol Chem. 2011 Jan 21;286(3):1786-94. Epub 2010 Nov 19.
Louafi F, Martinez-Nunez RT, Sanchez-Elsner T. Microrna-155 (miR-155) targets SMAD2 and modulates the response of macrophages to transforming growth factor-{beta}(TGF-{beta}). J Biol Chem. 2010 Dec 31;285(53):41328-36. Epub 2010 Oct 29.
Abdullah CA, Asanithi P, Brunner EW, Jurewicz I, Bo C, Azad CL, Ovalle-Robles R, Fang S, Lima MD, Lepro X, Collins S, Baughman RH, Sear RP, Dalton AB. 'Aligned, isotropic and patterned carbon nanotube substrates that control the growth and alignment of Chinese hamster ovary cells.'. Nanotechnology: 22 (20)
