Research
My research focus is in understanding the cellular and genetic mechanisms that underlie cell-fate decisions during:
- Embryogenesis, maintenance and repair/regeneration of the cardiovascular and pulmonary systems, and
- Direct nuclear programming of somatic cells to pluripotency and cardiovascular/pulmonary fates.
The knowledge gained from this understanding is being used to bring cellular and gene therapies to the translational phase for drug development, tissue regeneration and replacement and gene corrections/enhancements in vivo. We are also working to better understand the different states of pluripotency in mammals.
The role of TGF-beta superfamily signalling in cardiovascular and pulmonary development and disease
The genetic networks that underlie the embryogenesis of the cardiovascular and pulmonary systems remain active during the processes of their maintenance and repair/regeneration. By studying the normal embryogenesis of these systems and applying the knowledge gained to the in vitro 3D modelling of them, we hope to better understand human disease states affecting the cardiovascular and pulmonary systems. In these modelling studies, we use genetically-labelled differentiated cells, progenitor cells and pluripotent stem cells (ES cells and iPSCs, see below) or combinations thereof.
We have a particular focus on modelling Pulmonary Arterial Hypertension (PAH) in collaboration with Prof Nick Morrell’s group and studying the role of TGF-beta superfamily signalling in endothelial, smooth muscle and cardiac cells. We also have interests in other disease states such as Fibrodysplasia Ossificans Progressiva (FOP). Our goals are to use our 3D models in drug and toxicology screens for the development of drugs tailored to individual patients.
The nature of mammalian pluripotency and the translation of pluripotent stem and progenitor cells for viable cell and gene therapies
Induced pluripotent stem cells (iPSC) offer a powerful technology that will revolutionise the field of medicine, allowing us to generate patient specific pluripotent stem cells, which can be used for tailored drug discovery and toxicology screens and to regenerate and replace lost, damaged or dysfunctional tissue.
However, to progress iPSC technology to the translational phase we need to overcome the following challenges:
- Practicalities of obtaining bankable patient specific tissues/cells for the reprogramming process
- Reprogramming efficiencies associated with iPSC generation
- Genomic integrity of the iPSCs generated.
Resolving these issues is vital to ensure that the cells are free from genomic abnormalities, such as defective chromosomes, and safe to use in cellular therapies or transplantation. Recently we have discovered a new peripheral blood derived reprogramming substrate which is:
- Obtainable from almost any patient, without blood mobilisation
- Exhibits efficiencies and kinetics of reprogramming suitable for the high-throughput generation of iPSC
- Can be used to generate iPSCs relatively free from genomic rearrangements.
Our goals are to progress with the development and application of this new cell type and the iPSCs generated from it to the translational phase of cellular therapies, in drug/toxicology screening, and their potential use in the delivery of gene therapies. We are also elucidating the mechanisms behind the striking reprogramming capacity of these cells and using this to understand mammalian pluripotency.
Publications
TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling. Hurst LA, Dunmore BJ, Long L, Crosby A, Al-Lamki R, Deighton J, Southwood M, Yang X, Nikolic MZ, Herrera B, Inman GJ, Bradley JR, Rana AA, Upton PD, Morrell NW. Nat Commun. 2017 Jan 13;8:14079.
Generation and Culture of Blood Outgrowth Endothelial Cells from Human Peripheral Blood. Ormiston ML, Toshner MR, Kiskin FN, Huang CJ, Groves E, Morrell NW, Rana AA. J Vis Exp. 2015 Dec 23;(106).
Applications of nuclear reprogramming and directed differentiation in vascular regenerative medicine. Rana AA, Callery EM. N Biotechnol. 2015 Jan 25;32(1):191-8.
Transcript analysis reveals a specific HOX signature associated with positional identity of human endothelial cells. Toshner M, Dunmore BJ, McKinney EF, Southwood M, Caruso P, Upton PD, Waters JP, Ormiston ML, Skepper JN, Nash G, Rana AA, Morrell NW. PLoS One. 2014 Mar 20;9(3):e91334.
A stochastic model dissects cell states in biological transition processes. Armond JW, Saha K, Rana AA, Oates CJ, Jaenisch R, Nicodemi M, Mukherjee S. Sci Rep. 2014 Jan 17;4:3692.
A practical and efficient cellular substrate for the generation of induced pluripotent stem cells from adults: blood-derived endothelial progenitor cells. Geti I, Ormiston ML, Rouhani F, Toshner M, Movassagh M, Nichols J, Mansfield W, Southwood M, Bradley A, Rana AA, Vallier L, Morrell NW. Stem Cells Transl Med. 2012 Dec;1(12):855-65.
Therapeutic revascularisation of ischaemic tissue: the opportunities and challenges for therapy using vascular stem/progenitor cells. O'Neill CL, O'Doherty MT, Wilson SE, Rana AA, Hirst CE, Stitt AW, Medina RJ. Stem Cell Res Ther. 2012 Aug 16;3(4):31.
