Guasti, Leonardo

Senior Lecturer in Endocrinology/BBSRC New Investigator

I obtained my degree at the University of Florence, Italy, in 1999 (BSc Biological sciences, MS in Pathophysiology). I was then awarded an Accademia Nazionale dei Lincei and a Telethon Fellowship from the University of Florence, Milano-Bicocca and Tulsa, (USA) to study the role of Ether-a’-go-go-Related Gene (ERG) in cancer progression, neural function and hormone secretion. I then undertook a PhD in Clinical and Experimental Oncology at the University of Florence, and spent half of the time at the University of Tulsa (USA) as a Fulbright Distinguished Fellow. My PhD studies uncovered a novel mechanism of post-translational regulation of ERG channels expression controlling ERG current density, neurite outgrowth and apoptosis. In 2006 I relocated to Queen Mary University of London, first at the school of Biological and Chemical Sciences and then at the William Harvey Research Institute’s Centre for Endocrinology, studying signaling pathways regulating adrenal cortex development and function. After a year at the UCL Institute of Child Health, I became a lecturer in Endocrinology in 2012, and a Senior Lecturer in 2015.

Summary of Research

Multilineage differentiation of human adipose tissue-derived stem cells (ADSCs)

Adult (somatic) stem cells are found in several organs, and they undergo self-renewal and have multipotent differentiation potential. Adipose tissue-Derived Stem Cells (ADSCs) have generated much interest as they too harbor significant differentiation capability. We have recently described, for the first time, the high plasticity of ADSCs obtained from paediatric donors (they express a variety of mesenchymal, ectodermal, epithelial as well as pluripotency markers, they can be reprogrammed to inducible pluripotent stem cells (iPSCs) and harbor multilineage differentiation ability). Autologous stem cell based therapies employing ADSCs could represent an important alternative to current therapeutic options for patients in need of new bone and cartilage. Before translational applications exploiting ADSCs in clinical settings can become widespread practice, essential information on the cellular and molecular events occurring during their skeletogenic differentiation must be obtained. My research focuses on understanding the pathways regulating ADSCs skeletogenic differentiation processes, with a focus on DLK1, an imprinted gene that has been implicated in a variety of clinically relevant developmental processes. Finally, we are looking into strategies to utilize ADSCs in vitro predictive models to assess growth hormone. responsiveness in children affected by idiopathic short stature (see Dunkel).

Figure 1: ADSCs growing out of a GFP-chick embryo fat explant (left panel). Vascularization of a bionanoscaffold containing human ADSCs differentiated towards cartilage (right panel).

Reprogramming strategies to obtain steroidogenic cells

The adrenal cortex is the primary site of steroid synthesis and controls essential metabolic processes. The ability to generate an individual-specific cell platform through the generation of human induced pluripotent stem cells or lineage conversion (transdifferentiation) offers a new paradigm for functional studies, for modelling human disease and for drug testing (Fig.2). There is an unmet need for developing such technology in the adrenal field, as current in vitro systems are not physiologically relevant and some animal models do not phenocopy the adrenal disease. Lineage conversion, a direct reprogramming of an adult cell into another differentiated lineage (without passage through an undifferentiated pluripotent stage) is a new area of research that has emerged alongside induced pluripotent stem cell reprogramming. We are aiming to reprogram ADSCs, late-outgrowth endothelial progenitor cells (L-EPCs, the latter established from a simple venipuncture) or fibroblasts into an adrenocortical phenotype, by forcing the expression of Steroidogenic Factor 1 or other adrenal-specific transcription factors. This strategy is being tested directly on patients’ cells and after reprogramming these cells to IPSCs. Reprogrammed cells are assessed by their ability to fulfil stringent criteria such as the expression of adrenal cortex specific genes, and the acquisition of the functional integrity of adrenal cortex specific signalling pathways. The versatility of this in vitro platform will make it well suitable for the study of adrenal cortex physiology and pathology as well as for drug testing. It will also be an important first step in the field of regenerative medicine. In 2013, I was awarded a BBSRC New Investigator grant to work on this project.

Figure 2: Strategies used to reprogram human cells to an adrenocortical phenotype.

 

Members of the Group

Dr Gerard Ruiz-Babot, BBSRC postdoctoral researcher
Irene Hadjidemetriou, MRC PhD student
Ms Alessandra Mancini, Erasmus visiting student
Sharon Ajodha, Reseach Assistant

Key Publications

For a full list of publist publications click here
 
Guasti L, Vagaska B, Bulstrode NW et al. (2014). Chondrogenic differentiation of adipose tissue-derived stem cells within nanocaged POSS-PCU scaffolds: A new tool for nanomedicine. Nanomedicine Vol.10, (2) 279-289. 10.1016/j.nano.2013.08.006
 
Guasti L, Prasongchean W, Kleftouris G, Mukherjee S, Thrasher AJ, Bulstrode NW, Ferretti P. (2012). High plasticity of pediatric adipose-derived stem cells: too much for selective skeletogenic differentiation?Stem Cells Transl Med. 1(5):384-95. 10.5966/sctm.2012-0009

Meimaridou E, Kowalczyk J, Guasti L, et al. (2012). Mutations in Nicotinamide Nucleotide Transhydrogenase (NNT) are associated with familiar glucocorticoid deficiency.Nature Genetics 44(7):740-2. 10.1038/ng.2299

Hughes C, Guasti L, Meimaridou E, Chuang C, Schimenti J, King P, Costigan C, Clark A, Metherel L. (2012). MCM4 mutations causes adrenal failure, short stature and natural killer cell deficiency in humans. J Clin Invest. 122(3):814-20. Cover picture 10.1172/JCI60224

Guasti L, Paul A, Laufer E, King P. (2011). Expression of the components of the Sonic Hedgehog pathway in the developing and adult rat adrenal cortex. Mol. Cell. Endocrinol. 336(1-2): 117-22. (Corresponding author) 10.1016/j.mce.2010.11.010

Guasti L, Crociani O, Redaelli E, Polvani S, Pillozzi S, Masselli M, Mello T, Wymore RS, Wanke E and Arcangeli A. (2008). A post-translational mechanism of K+ channels expression: alternative herg1 transcripts containing the USO-exon modulate endogenous hERG1 channels trafficking in tumour cells. Mol Cell Biol. 28(16):5043-60. Cover picture 10.1128/MCB.00304-08

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