Staff Profile

Research Interests

Epigenetic control of stem cell differentiation and development of germ cells

The aim of my research is to understand how both adult and embryonic stem cells differentiate into given cell types, how the gene expression patterns required for this are established at an epigenetic level and what mechanism maintains the differentiated states (cellular memory). It has been possible to reverse the epigenotype of a somatic nucleus by transfer into an oocyte and to derive embryonic stem cells using this method. However, this is inefficient and has a low throughput method so I aim to use our growing knowledge of epigenetics to devise strategies for ‘reprogramming’ human somatic cells towards a stem cell like phenotype. These cells could be used for regenerative therapy without the logistical and ethical problems associated with ‘therapeutic cloning’ in humans.

Ovulated human oocytes are limited in availability, so to investigate epigenetic reprogramming, other sources of oocytes must be identified. Mouse embryonic stem cells are capable of differentiating into male and female germ cells in vitro and putative primordial germ cells (PGC’s) derived in this way contribute to spermatogenesis when transplanted into the adult testis and are capable of fertilising oocytes in vitro. Oocyte-like cells have been obtained from adherent cultures of differentiating mouse ES cells as indicated by morophology and the expression of germ cell specific genes such as Vasa, Gdf9 and Scp3. Germ cell specific markers are also expressed in embryoid bodies derived from human ES suggesting the presence of PGC’s, so I am developing methods to enhance their formation and isolation. Further culture systems are being developed to direct the differentiation and growth of PGC’s towards oocytes.

An understanding of the epigenotype of differentiated cells may provide better strategies to direct the differentiation of embryonic stem cells towards the production of tissues of therapeutic value. I am investigating the differentiation of hESC into mesodermal derivatives (eg the haematopoietic system and skeletal muscle). It is also important to determine how the epigenotype of a pluripotent cell such as an hESC is defined and maintained. I am creating ‘maps’ of modified histones (eg tri- and dimethylation of lysines 4 and 9 of histone H3) in both hESC and their differentiated progeny with particular reference to genomic loci involved in pluripotency. This work is based on microarray studies of similar cells and the observation of high levels of stress defence enzymes and specific signalling pathways unique to hESC and suggestive of a molecular ‘signature’.

• Neganova I, Vilella F, Atkinson SP, Lloret M, Passos JF, von Zglinicki T, O'Connor JE, Burks D, Jones R, Armstrong L, Lako M. An Important Role for CDK2 in G1 to S Checkpoint Activation and DNA Damage Response in Human Embryonic Stem Cells. Stem Cells 2011, 29(4), 651-659.
• Tilgner K, Armstrong L, Lako M. Positive effect of human ESC conditioned medium on somatic cell reprogramming. Serbian Journal of Experimental and Clinical Research 2010, 11(1), 3-5.
• Campbell SC, Ferris WF, Armstrong L, Hole N, Lako M, Macfarlane WM. Programmed cell death gene 4 (PDCD4): A novel gene upregulated during islet neogenesis and embryonic stem cell differentiation. In: Journal of Gene Medicine: 1st Annual Conference of the British Society for Gene Therapy. 2004, Oxford, UK: John Wiley & Sons, Inc.
• Armstrong L, Saretzki G, Peters H, Wappler I, Evans J, Hole N, Von Zglinicki T, Lako M. Overexpression of telomerase confers growth advantage, stress resistance, and enhanced differentiation of ESCs toward the hematopoietic lineage. Stem Cells 2005, 23(4), 516-529.
• Tilgner K, Atkinson SP, Yung S, Golebiewska A, Stojkovic M, Moreno R, Lako M, Armstrong L. Expression of GFP Under the Control of the RNA Helicase VASA Permits Fluorescence-Activated Cell Sorting Isolation of Human Primordial Germ Cells. Stem Cells 2010, 28(1), 84-92.
• Armstrong L, Lako M, Dean W, Stojkovic M. Epigenetic modification is central to genome reprogramming in somatic cell nuclear transfer. Stem Cells 2006, 24(4), 805-814.
• Armstrong L, Hughes O, Yung S, Hyslop L, Stewart R, Wappler I, Peters H, Walter T, Stojkovic P, Evans J, Stojkovic M, Lako M. The role of PI3K/AKT, MAPK/ERK and NFκβ signalling in the maintenance of human embryonic stem cell pluripotency and viability highlighted by transcriptional profiling and functional analysis. Human Molecular Genetics 2006, 15(11), 1894-1913.
• Stojkovic M, Stojkovic P, Leary C, Hall VJ, Armstrong L, Herbert M, Nesbitt M, Lako M, Murdoch A. Derivation of a human blastocyst after heterologous nuclear transfer to donated oocytes. Reproductive BioMedicine Online 2005, 11(2), 226-231.
• Stojkovic P, Lako M, Stewart R, Przyborski S, Armstrong L, Evans J, Herbert M, Hyslop L, Ahmad S, Murdoch A, Strachan T, Stojkovic M. An Autogeneic Feeder Cell System That Efficiently Supports Growth of Undifferentiated Human Embryonic Stem Cells. Stem Cells 2005, 23(3), 306-314.
• Kamarudin TA, Bojic S, Collin J, Yu M, Alharthi S, Buck H, Shortt A, Armstrong L, Figueiredo FC, Lako M. Differences in the activity of endogenous BMP signalling impact on the ability of induced pluripotent stem cells to differentiate to corneal epithelial like cells. Stem Cells 2018, 36(3), 337-348.
• Volarevic V, Markovic BS, Gazdic M, Volarevic A, Jovicic N, Arsenijevic N, Armstrong L, Djonov V, Lako M, Stojkovic M. Ethical and safety issues of stem cell-based therapy. International Journal of Medical Sciences 2018, 15(1), 36-45.
• Hallam D, Hilgen G, Dorgau B, Zhu L, Yu M, Bojic S, Hewitt P, Schmitt M, Uteng M, Kustermann S, STEEL D, Nicholds M, Thomas R, Treumann A, Porter A, Sernagor E, Armstrong L, Lako M. Human induced pluripotent stem cells generate light responsive retinal organoids with variable and nutrient dependent efficiency. Stem Cells 2018, 36(10), 1501-1513.
• Hallam D, Rawlings D, Steel D, Armstrong L, Lako M. In Reply to the Letter to the Editor from Hallam et al.: An Induced Pluripotent Stem Cell Patient Specific Model of Complement Factor H (Y402H) Polymorphism Displays Characteristic Features of Age-Related Macular Degeneration and Indicates a Beneficial Role for UV Light Exposure. Stem Cells 2018, 36(4), 627-629.
• Sanchis DM, Xu Y, Taheem D, Yu M, Tilgner K, Barta T, Gassner K, Anyfanftis G, Wan T, Elango R, Alharthi S, Elharouni AA, Pryzborski S, Adam S, Saretzki G, Samarasinghe S, Armstrong L, Lako M. iPSC modelling of severe aplastic anemia reveals impaired differentiation and telomere shortening in blood progenitors. Cell Death & Disease 2018, 9, 128.
• Neganova I, Chichagova V, Armstrong L, Lako M. A critical role for p38MAPK signalling pathway during reprogramming of human fibroblasts to iPSCs. Scientific Reports 2017, 7, 41693.
• Hallam D, Collin j, Bojic S, Chichagova V, Buskin A, Xu Y, Lafage L, Otten EG, Anyfantis G, Mellough C, Przyboski S, Alhart S, Korolchuk V, Lotery A, Saretzki G, McKibbin M, Armstrong L, Steel D, Kavanagh D, Lako M. An iPSC patient specific model of CFH (Y402H) polymorphism displays characteristic features of AMD and indicates a beneficial role for UV light exposure. Stem Cells 2017, 35(11), 2305-2320.
• Meader E, Barta T, Melguzo SD, Tilgner K, Montaner D, ElHarouni A, Armstrong L, Lako M. Brief Report: Pluripotent Stem Cell-Derived Hematopoietic Progenitors Are Unable to Downregulate Key Epithelial-Mesenchymal Transition-Associated miRNAs. Stem Cells (Durham) 2017, 36(1), 55–64.
• Adam S, Melguzo Sanchis D, El-Kamah D, Samarasinghe S, Alharti S, Armstrong L, Lako M. Concise review: Getting to the core of inherited bone marrow failures. Stem Cells 2017, 35(2), 284-298.
• Chichagova V, Hallam D, Collin J, Buskin A, Saretzki G, Armstrong L, Yu-Wai-Man P, Lako M, Steel DH. Human iPSC disease modelling reveals functional and structural defects in retinal pigment epithelial cells harbouring the m.3243A>G mitochondrial DNA mutation. Scientific Reports 2017, 7, 12320.
• Yang C, Xu Y, Yu M, Lee D, Alharti S, Hellen N, Shaik NA, Banaganapalli B, Mohamoud H, Elango R, Przyborski S, Tenin G, Williams S, O'Sullivan J, Al-Radi OO, Atta J, Harding S, Keavney B, Lako M, Armstrong L. Induced pluripotent stem cell modelling of HLHS underlines the contribution of dysfunctional NOTCH signalling to impaired cardiogenesis. Human Molecular Genetics 2017, 26(16), 3031-3045.
• Baud A, Wessely F, Mazzacuva F, McCormick J, Camuzeaux S, Heywood WE, Little D, Vowles J, Tuefferd M, Mosaku O, Lako M, Armstrong L, Webber C, Cader MZ, Peeters P, Gissen P, Cowley SA, Mills K. Multiplex High-Throughput Targeted Proteomic Assay to Identify Induced Pluripotent Stem Cells. Analytical Chemistry 2017, 89(4), 2440-2448.
• De Sousa PA, Steeg R, Wachter E, Bruce K, King J, Hoeve M, Khadun S, McConnachie G, Holder J, Kurtz A, Seltmann S, Dewender J, Reimann S, Stacey G, O'Shea O, Chapman C, Healy L, Zimmermann H, Bolton B, Rawat T, Atkin I, Veiga A, Kuebler B, Serano BM, Saric T, Hescheler J, Brustle O, Peitz M, Thiele C, Geijsen N, Holst B, Clausen C, Lako M, Armstrong L, Gupta SK, Kvist AJ, Hicks R, Jonebring A, Brolen G, Ebneth A, Cabrera-Socorro A, Foerch P, Geraerts M, Stummann TC, Harmon S, George C, Streeter I, Clarke L, Parkinson H, Harrison PW, Faulconbridge A, Cherubin L, Burdett T, Trigueros C, Patel MJ, Lucas C, Hardy B, Predan R, Dokler J, Brajnik M, Keminer O, Pless O, Gribbon P, Claussen C, Ringwald A, Kreisel B, Courtney A, Allsopp TE. Rapid establishment of the European Bank for induced Pluripotent Stem Cells (EBiSC) - the Hot Start experience. Stem Cell Research 2017, 20, 105-114.
• Wilmes A, Rauch C, Carta G, Kern G, Meier F, Posch W, Wilflingseder D, Armstrong L, Lako M, Beilmann M, Gstraunthaler G, Jennings P. Towards optimisation of induced pluripotent cell culture: Extracellular acidification results in growth arrest of iPSC prior to nutrient exhaustion. Toxicology in Vitro 2017, 45(3), 445-454.
• Jin S, Collin J, Zhu L, Montaner D, Armstrong L, Neganova I, Lako M. A Novel role for miR-1305 in Regulation of Pluripotency-Differentiation Balance, Cell Cycle and Apoptosis in Human Pluripotent Stem Cells. Stem Cells 2016, 34(9), 2306-2317.
• Nurkovic J, Volarevic V, Lako M, Armstrong L, Arsenijevic N, Stojkovic M. Aging of Stem and Progenitor Cells: Mechanisms, Impact on Therapeutic Potential, and Rejuvenation. Rejuvenation Research 2016, 19(1), 3-12.
• Barta T, Peskova L, Collin J, Montaner D, Neganova I, Armstrong L, Lako M. Inhibition of miR-145 Enhances Reprogramming of Human Dermal Fibroblasts to Induced Pluripotent Stem Cells. Stem Cells 2016, 34(1), 246-251.
• Neganova A, Shmeleva E, Munkley J, Chichagova V, Anyfantis G, Anderson R, Passos AJ, Elliott DJ, Armstrong L, Lako M. JNK/SAPK signalling is essential for efficient reprogramming of human fibroblasts to induced pluripotent stem cells. Stem Cells 2016, 34(5), 1198-1212.
• Nikolic A, Volarevic V, Armstrong L, Lako M, Stojkovic M. Primordial Germ Cells: Current Knowledge and Perspectives. Stem Cells International 2016.
• Zhu L, Gomez-Duran A, Saretzki G, Jin S, Tilgner K, Melguzo-Sanchis D, Anyfantis G, Al-Aama J, Vallier L, Chinnery P, Lako M, Armstrong L. The mitochondrial protein CHCHD2 primes the differentiation potential of human induced pluripotent stem cells to neuroectodermal lineages. Journal of Cell Biology 2016, 215(2), 187-202.
• Yang C, Al-Aama J, Stojkovic M, Keavney B, Trafford A, Lako M, Armstrong L. Concise Review: Cardiac Disease Modeling Using Induced Pluripotent Stem Cells. Stem Cells 2015, 33(9), 2643-2651.
• Chichagova V, Sanchez-Vera I, Armstrong L, Steel D, Lako M. Generation of Human Induced Pluripotent Stem Cells Using RNA-Based Sendai Virus System and Pluripotency Validation of the Resulting Cell Population. Methods in Molecular Biology 2015, 1353, 285-307.
• Jiang Y, Habibollah S, Tilgner K, Collin J, Barta T, Al-Aama JY, Tesarov L, Hussain R, Trafford AW, Kirkwood G, Sernagor E, Eleftheriou CG, Przyborski S, Stojkovic M, Lako M, Keavney B, Armstrong L. An Induced Pluripotent Stem Cell Model of Hypoplastic Left Heart Syndrome (HLHS) Reveals Multiple Expression and Functional Differences in HLHS-Derived Cardiac Myocytes. Stem Cells Translational Medicine 2014, 3(4), 416-423.
• Armstrong L, Al-Aama J, Stojkovic M, Lako M. Concise Review: The Epigenetic Contribution to Stem Cell Ageing: Can We Rejuvenate Our Older Cells?. Stem Cells 2014, 32(9), 2291-2298.
• Lako M, Armstrong L. Engraftment's Holy Grail: is one signal enough?. Blood 2014, 124(20), 3035-3036.
• Tilgner K, Neganova I, Moreno-Gimeno I, Al-Aama JY, Burks D, Yung S, Singhapol C, Saretzki G, Evans J, Gorbunova V, Gennery A, Pryzborski S, Stojkovic M, Armstrong L, Jeggo P, Lako M. A human iPSC model of Ligase IV deficiency reveals an important role for NHEJ-mediated-DSB repair in the survival and genomic stability of induced pluripotent stem cells and emerging haematopoietic progenitors. Cell Death and Differentiation 2013, 20, 1089-1100.
• Moad M, Pal D, Hepburn AC, Williamson SC, Wilson L, Lako M, Armstrong L, Hayward SW, Franco O, Cates J, Fordham SE, Przyborski S, Carr-Wilkinson J, Robson CN, Heer R. A novel model of urinary tract differentiation, tissue regeneration, and disease: Reprogramming human prostate and bladder cells into induced pluripotent stem cells. European Urology 2013, 64(5), 753-761.
• Tilgner K, Neganova I, Singhapol C, Saretzki G, Al-Aama JY, Evans J, Gorbunova V, Gennery A, Przyborski S, Stojkovic M, Armstrong L, Jeggo P, Lako M. Brief Report: A Human Induced Pluripotent Stem Cell Model of Cernunnos Deficiency Reveals an Important Role for XLF in the Survival of the Primitive Hematopoietic Progenitors. Stem Cells 2013, 31(9), 2015-2023.
• Yung SK, Tilgner K, Ledran MH, Habibollah S, Neganova I, Singhapol C, Saretzki G, Stojkovic M, Armstrong L, Przyborski S, Lako M. Brief Report: Human Pluripotent Stem Cell Models of Fanconi Anemia Deficiency Reveal an Important Role for Fanconi Anemia Proteins in Cellular Reprogramming and Survival of Hematopoietic Progenitors. Stem Cells 2013, 31(5), 1022-1029.
• Atkinson SP, Lako M, Armstrong L. Potential for Pharmacological Manipulation of Human Embryonic Stem Cells. British Journal of Pharmacology 2013, 169(2), 269-289.
• Atkinson SP, Collin J, Irina N, Anyfantis G, Kyung BK, Lako M, Armstrong L. A Putative Role for the Immunoproteasome in the Maintenance of Pluripotency in Human Embryonic Stem Cells. Stem Cells 2012, 30(7), 1373-1384.
• Siler U, Jiang Y, Cowley SA, Melguzo D, Tilgner K, Browne C, deWilton A, Pryzborski S, Saretzki G, James WS, Seger RA, Reichenbach J, Lako M, Armstrong L. Derivation and functional analysis of patient specific induced pluripotent stem cells (IPSCS) as an in vitro model of chronic granulomatous disease. In: 15th Biennial Meeting European Society for Immunodeficiency (ESID). 2012, Florence, Italy: Springer.
• Siler U, Jiang Y, Cowley SA, Melguzo D, Tilgner K, Browne C, Dewilton A, Pryzborski S, Saretzki G, James WS, Seger RA, Reichenbach J, Lako M, Armstrong L. Derivation and Functional Analysis of Patient Specific Induced Pluripotent Stem Cells as an In Vitro Model of Chronic Granulomatous Disease. In: 15th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT). 2012, Philadelphia, Pennsylvania, USA: Nature Publishing Group.
• Jiang Y, Cowley SA, Siler U, Melguizo D, Tilgner K, Browne C, Dewilton A, Przyborski S, Saretzki G, James WS, Seger RA, Reichenbach J, Lako M, Armstrong L. Derivation and functional analysis of patient-specific induced pluripotent stem cells as an in vitro model of chronic granulomatous disease. Stem Cells 2012, 30(4), 599-611.
• Armstrong L. Epigenetic Control of Embryonic Stem Cell Differentiation. Stem Cell Reviews and Reports 2012, 8(1), 67-77.
• Armstrong L, Lako M, Buckley N, Lappin TRJ, Murphy MJ, Nolta JA, Pittenger M, Stojkovic M. Our Top 10 Developments in Stem Cell Biology over the Last 30 Years. Stem Cells 2012, 30(1), 2-9.
• Yung S, Ledran M, Moreno-Gimeno I, Conesa A, Montaner D, Dopazo J, Dimmick I, Slater NJ, Marenah L, Real PJ, Paraskevopoulou I, Bisbal V, Burks D, Santibanez-Koref M, Moreno R, Mountford J, Menendez P, Armstrong L, Lako M. Large-scale transcriptional profiling and functional assays reveal important roles for Rho-GTPase signalling and SCL during haematopoietic differentiation of human embryonic stem cells. Human Molecular Genetics 2011, 20(24), 4932-4946.
• Amps K, Andrews PW, Anyfantis G, Armstrong L, Avery S, Baharvand H, Baker J, Baker D, Munoz MB, Beil S, Benvenisty N, Ben-Yosef D, Biancotti JC, Bosman A, Brena RM, Brison D, Caisander G, Camarasa MV, Chen J, Chiao E, Choi YM, Choo AB, Collins D, Colman A, Crook JM, Daley GQ, Dalton A, De Sousa PA, Denning C, Downie J, Dvorak P, Montgomery KD, Feki A, Ford A, Fox V, Fraga AM, Frumkin T, Ge L, Gokhale PJ, Golan-Lev T, Gourabi H, Gropp M, Lu G, Hampl A, Harron K, Healy L, Herath W, Holm F, Hovatta O, Hyllner J, Inamdar MS, Irwanto AK, Ishii T, Jaconi M, Jin Y, Kimber S, Kiselev S, Knowles BB, Kopper O, Kukharenko V, Kuliev A, Lagarkova MA, Laird PW, Lako M, Laslett AL, Lavon N, Lee DR, Lee JE, Li C, Lim LS, Ludwig TE, Ma Y, Maltby E, Mateizel I, Mayshar Y, Mileikovsky M, Minger SL, Miyazaki T, Moon SY, Moore H, Mummery C, Nagy A, Nakatsuji N, Narwani K, Oh SK, Oh SK, Olson C, Otonkoski T, Pan F, Park IH, Pells S, Pera MF, Pereira LV, Qi O, Raj GS, Reubinoff B, Robins A, Robson P, Rossant J, Salekdeh GH, Schulz TC, Sermon K, Sheik Mohamed J, Shen H, Sherrer E, Sidhu K, Sivarajah S, Skottman H, Spits C, Stacey GN, Strehl R, Strelchenko N, Suemori H, Sun B, Suuronen R, Takahashi K, Tuuri T, Venu P, Verlinsky Y, Ward-van Oostwaard D, Weisenberger DJ, Wu Y, Yamanaka S, Young L, Zhou Q, International Stem Cell Initiative. Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage. Nature Biotechnology 2011, 29(12), 1132–1144.
• James AL, Chilvers KF, Perry JD, Armstrong L, Gould FK. Evaluation of p-naphtholbenzein-beta-D-galactoside as a substrate for bacterial beta-galactosidase. Applied and Environmental Microbiology 2000, 66(12), 5521-5523.
• Lako M, Lindsay S, Cairns PM, Lincoln J, Armstrong L, Hole N. Involvement of Wnt genes in early haematopoiesis and identification of Wnt3 as a regulator of haematopoietic commitment. In: BLOOD. 2000.
• Armstrong L, Lako M, Lincoln J, Cairns PM, Hole N. mTert expression correlates with telomerase activity during the differentiation of murine embryonic stem cells. Mechanics of Development 2000, 97(1-2), 109-116.