How do endogenous and extrinsic factors contribute to cell behaviour?
How does individual cell heterogeneity affect cell fate?
How do rhythmic oscillatory factors affect cell behaviour?
BioERA: Biological Engineering, Research and Applications
We are interested in combining engineering principles with basic biological science to rationally understand the mechanisms governing cell behaviour. We are focused on understanding how cells and environment interact with each other leading to a self-regulation of the biological processes by combining exogenous and endogenous factors. We use microfluidic cell culture systems coupled with 3D scaffolds and patterning to mimic the in vivo environment and have a close look to cell behaviour.
Currently available in vitro models to study human cell biology, human tissue organization or human diseases often fail to correctly recapitulate the in vivo cell behaviour, resulting in not fully representative systems. Nevertheless accurate in vitro models are indeed necessary to bridge the gap between animal models and patients in the process of drug and therapy development. The BioERA lab is an interdisciplinary environment composed by people from biology, biotechnology, material science, chemical and biomedical engineering that work together to develop in vitro human models based on human artificial tissues for screening therapies and for the investigation of relevant molecular and biological mechanisms in a high-throughput fashion. In the recent years the lab worked on the elucidation of the intricate 3D structure-function relationship in human tissues, developing technological solutions for mimicking the in vivo pathophysiology or as means to test biological hypotheses. In particular, microfluidic devices that allow accurate control of culture soluble microenvironment both in space and time have been designed. With the help of such devices, new breakthrough discoveries in the field of cell reprogramming and cell differentiation were achieved. The BioERA lab developed a high-efficient and low-cost microfluidic cell reprogramming protocol that allows to obtain patient-specific, clinical-grade human induced pluripotent stem cells (hiPSC). Pluripotent stem cells can then be differentiated into reliable cell tissue models with high-efficient protocols that the lab developed, combining soluble microenvironment control with engineered biomaterials, scaffolds of patterning.
With our research, we try to answer to three main biological questions:
1 - How do endogenous and extrinsic factors contribute to cell behaviour? Our work tries to shed light on how the extrinsic environment affects cell behaviour and, on the other hand, on how cells modify their surroundings. – Multi-omics, high throughput screenings: By combining proteomic and transcriptomic high throughput approaches we want to detect the response of the cells to stimuli induced either by endogenous or extrinsic factors. – In vitro tissue models: The role of 3D environment in stem cell identity, organogenesis and homeostasis is an established concept that brought life scientists and engineers to develop new strategies for cell culture systems able to mimic in vivo conditions. To reach this goal, we combine innovative biomaterials, micro-fabrication techniques and human induced pluripotent stem cell engineering and differentiation. Moreover, by using such in vitro culture we aim at elucidate the intricate crosstalk that exist between three-dimensional structure and differentiation, as well as function of tissues, which are on the basis of physiological and physio-pathological processes. – In vivo models of skeletal muscle regeneration: A number of congenital or acquired pathologies can lead to a considerable loss of the muscle mass, which cannot be correctly repaired by the regenerative machinery of the tissue or other treatments, leading to loss of muscle function. By using established animal model of volumetric muscle loss, we combine biomaterials and stem cells to promote muscle regeneration. Our aim is to develop new therapeutic strategies for volumetric muscle loss condition, as well as clarify the role of specific cellular and extrinsic components essential for functional muscle regeneration.
2- How does individual cell heterogeneity affect cell fate? The idea of considering cells as a clonal, homogeneous population is slowly fading away, and so is the concept of univocal cell model. On one hand, recent developments in single-cell analysis allow to distinguish the behaviour of every single cell from the average of the population. On the other hand, genomic analysis underline how patient-to-patient genetic or epigenetic variability influences the phenotypic outcome of certain pathologies. – Single-cell high-throughput sequencing: with microfluidic platforms it is possible to analyse the transcriptome of thousands of single cells at the same time. We developed different approaches to perform single-cell RNA sequencing with the aim of reconstructing cell heterogeneous behaviour both in space and in time. – Patient-specific disease modelling: We developed robust and efficient techniques to reprogram adult somatic cells back to their pluripotent state, and to program them towards a variety of differentiated tissue-specific cells, such as hepatocytes and neurons. Therefore we can obtain patient-specific stem cells that can be differentiated into the disease-affected cell type and provide in vitro models of various pathologies, such as Alpha1-antitrypsin Deficiency and Fragile X Syndrome, recapitulating the genotypic influence on the pathological phenotype for personalized medicine. Alpha1-antitrypsin Deficiency is a inherited metabolic disease due to a point mutation in the gene encoding A1AT protein, resulting in chronic liver disease including fibrosis, cirrhosis and high risk to develop hepatocellular carcinoma. We use patient-specific induced pluripotent stem cells derived from a cohort of patients with rare and more common variants to develop a correlation between the in vitro phenotype and the clinical status of patients. Fragile X Syndrome (FXS) is the leading cause of inherited cognitive disability and one of the major monogenetic causes for autism. FXS is based on the trinucleotide repeat expansion and epigenetic silencing of fragile X mental retardation 1 (FMR1) gene promoter and subsequent loss in the production of fragile X mental retardation protein (FMRP). There are still many unanswered questions related to the molecular mechanism that fails in FXS developing foetuses. We take advantage of the microfluidic platform and naïve induced pluripotent stem cells (iPSCs) derived from FXS patients to investigate the very early events during embryonic development that lead to trinucleotide repeat expansion and silencing of FMR1 promoter. Moreover we will use various approaches to obtain neuroectoderm and neurons from patient-specific iPSCs and generate an in vitro reliable model of this disease.
3- How do rhythmic oscillatory factors affect cell behaviour? In mammals, circadian rhythms function to coordinate a diverse panel of physiological processes with environmental conditions such as food and light. The circadian clock consists of endogenous self-sustained molecular oscillations of specific proteins, that are synchronized to the environment by extrinsic factors. We developed experimental strategies to create an highly physiological in vitro model that allows to study the influence of frequency-encoded metabolic signals, resembling the day-life routine. With specific focus on liver, we study the circadian system in regulating metabolism and energy homeostasis and other mechanisms of hepatic circadian clock to gain better understanding of liver physiology and associated diseases.
Onelia Gagliano
Postdoc
onelia.gagliano@unipd.it
Cecilia Laterza
Postdoc
cecilia.laterza@unipd.it
Andrea Maset
Post-doc
andrea.maset90@gmail.com
Wei Qin
PhD student
wei.qin@studenti.unipd.it
Silvia Angiolillo
PhD student
silviaangiolillo94@gmail.com
Elisa Cesare
PhD student
elisa.cesare@phd.unipd.it
Luca Brandolino
PhD student
luca.brandolino@gmail.com
Carmela Ribecco
PhD student
carmela.ribecco.1@studenti.unipd.it
Alessia Gesualdo
PhD student
alessia.gesualdo@phd.unipd.it
Lisa Agostini
agostini.lisa7@gmail.com
Fellow
Martina D'Ercole
Fellow
marti.dercole@gmail.com
Pietro Bellet
Fellow
pietro.bellet@studenti.unipd.it
Gaia Dupont
Student
dupontgaia@gmail.com
2022
Gagliano O.,Cascione, S., Michielin, F., Elvassore N. The emergence of the circadian clock network in hiPSC-derived hepatocytes on chip. Biochemical and Biophysical Research Communications, 2022, 601, pp. 109–115.
Tonon F, Cemazar M, Kamensek U, Zennaro C, Pozzato G, Caserta S, Ascione F, Grassi M, Guido S, Ferrari C, Cansolino L, Trotta F, Kuzmanov BG, Forte G, Martino F, Perrone F, Bomben R, Gattei V, Elvassore N, Murano E, Truong NH, Olson M, Farra R, Grassi G, Dapas. B5-Azacytidine Downregulates the Proliferation and Migration of Hepatocellular Carcinoma Cells In Vitro and In Vivo by Targeting miR-139-5p/ROCK2 Pathway. Cancers (Basel). 2022 Mar 23;14(7):1630.
Luni C, Gagliano O, Elvassore N. Derivation and Differentiation of Human Pluripotent Stem Cells in Microfluidic Devices. Annu Rev Biomed Eng. 2022 Apr 4.
Romani P, Nirchio N, Arboit M, Barbieri V, Tosi A, Michielin F, Shibuya S, Benoist T, Wu D, Hindmarch CCT, Giomo M, Urciuolo A, Giamogante F, Roveri A, Chakravarty P, Montagner M, Calì T, Elvassore N, Archer SL, De Coppi P, Rosato A, Martello G, Dupont S. Mitochondrial fission links ECM mechanotransduction to metabolic redox homeostasis and metastatic chemotherapy resistance. Nat Cell Biol. 2022 Feb;24(2):168-180.
Zorzan I, Gagliano O, Elvassore N, Martello G. Using Microfluidics to Generate Human Naïve and Primed Pluripotent Stem Cells .Methods Mol Biol. 2022;2416:53-71.
2021
Giobbe GG, Bonfante F, Jones BC, Gagliano O, Luni C, Zambaiti E, Perin S, Laterza C, Busslinger G, Stuart H, Pagliari M, Bortolami A, Mazzetto E, Manfredi A, Colantuono C, Di Filippo L, Pellegata AF, Panzarin V, Thapar N, Li VSW, Eaton S, Cacchiarelli D, Clevers H, Elvassore N, De Coppi P. SARS-CoV-2 infection and replication in human gastric organoids. Nat Commun. 2021 Nov 16;12(1):6610.
Gagliano O, Luni C, Li Y, Angiolillo S, Qin W, Panariello F, Cacchiarelli D, Takahashi JS, Elvassore N. Synchronization between peripheral circadian clock and feeding-fasting cycles in microfluidic device sustains oscillatory pattern of transcriptome.Nat Commun. 2021 Oct 26;12(1):6185.
Liu H, Ding X, Liu L, Mi Q, Zhao Q, Shao Y, Ren C, Chen J, Kong Y, Qiu X, Elvassore N, Yang X, Yin Q, Jiang B. Discovery of novel BCR-ABL PROTACs based on the cereblon E3 ligase design, synthesis, and biological evaluation. Eur. J. Med Chem. 2021 Nov 5;223:113645.
Boso D, Carraro E, Maghin E, Todros S, Dedja A, Giomo M, Elvassore N, De Coppi P, Pavan PG, Piccoli M. Porcine Decellularized Diaphragm Hydrogel: A New Option for Skeletal Muscle Malformations. Biomedicines. 2021 Jun 22;9(7):709.
Selmin G, Gagliano O, De Coppi P, Serena E, Urciuolo A, Elvassore N. MYOD modified mRNA drives direct on-chip programming of human pluripotent stem cells into skeletal myocytes.Biochem Biophys Res Commun. 2021 Jun 30;560:139-145.
Tolomeo AM, Laterza C, Grespan E, Michielin F, Canals I, Kokaia Z, Muraca M, Gagliano O, Elvassore N. NGN2 mmRNA-Based Transcriptional Programming in Microfluidic Guides hiPSCs Toward Neural Fate With Multiple Identities. Front Cell Neurosci. 2021 Feb 12;15:602888.
Michielin F, Giobbe GG, Luni C, Hu Q, Maroni I, Orford MR, Manfredi A, Di Filippo L, David AL, Cacchiarelli D, De Coppi P, Eaton S, Elvassore N. The Microfluidic Environment Reveals a Hidden Role of Self-Organizing Extracellular Matrix in Hepatic Commitment and Organoid Formation of hiPSCs. Cell Rep. 2020 Dec 1;33(9):108453.
2020
Martewicz S, Luni C, Zhu X, Cui M, Hu M, Qu S, Buratto D, Yang G, Grespan E, Elvassore N. Nuclear Morphological Remodeling in Human Granulocytes Is Linked to Prenylation Independently from Cytoskeleton..Cells. 2020 Nov 20;9(11):2509.
Raffa P, Scattolini V, Gerli MFM, Perin S, Cui M, De Coppi P, Elvassore N, Caccin P, Luni C, Urciuolo A. Decellularized skeletal muscles display neurotrophic effects in three-dimensional organotypic cultures.Stem Cells Transl Med. 2020 Oct;9(10):1233-1243.
Barilani M, Cherubini A, Peli V, Polveraccio F, Bollati V, Guffanti F, Del Gobbo A, Lavazza C, Giovanelli S, Elvassore N, Lazzari L. A circular RNA map for human induced pluripotent stem cells of foetal origin. EBioMedicine. 2020 Jul;57:102848.
Urciuolo A, Poli I, Brandolino L, Raffa P, Scattolini V, Laterza C, Giobbe GG, Zambaiti E, Selmin G, Magnussen M, Brigo L, De Coppi P, Salmaso S, Giomo M, Elvassore N. Intravital three-dimensional bioprinting.Nat Biomed Eng. 2020 Sep;4(9):901-915.
Martewicz S, Magnussen M, Elvassore N. Beyond Family: Modeling Non-hereditary Heart Diseases With Human Pluripotent Stem Cell-Derived Cardiomyocytes. Front Physiol. 2020 Apr 22;11:384.
Urciuolo A, Serena E, Ghua R, Zatti S, Giomo M, Mattei N, Vetralla M, Selmin G, Luni C, Vitulo N, Valle G, Vitiello L, Elvassore N. Engineering a 3D in vitro model of human skeletal muscle at the single fiber scale. PLoS One. 2020 May 6;15(5):e0232081.
Dong Y, Cui M, Qu J, Wang X, Kwon SH, Barrera J, Elvassore N, Gurtner GC. Conformable hyaluronic acid hydrogel delivers adipose-derived stem cells and promotes regeneration of burn injury. Acta Biomater. 2020 May;108:56-66.
2019
Giobbe GG, Crowley C, Luni C, Campinoti S, Khedr M, Kretzschmar K, De Santis MM, Zambaiti E, Michielin F, Meran L, Hu Q, Van Son G, Urbani L, Manfredi A, Giomo M, Eaton S, Cacchiarelli D, Li VSW, Clevers H, Bonfanti P, Elvassore N and De Coppi P. 2019. Extracellular matrix hydrogel derived from decellularized tissues enables endodermal organoid culture. Nature Communications.
Tonon F, Giobbe GG, Zambon A, Luni C, Gagliano O, Floreani A, Grassi G, Elvassore N. 2019. In vitro metabolic zonation through oxygen gradient on a chip. Scientific Reports.
Gagliano O, Luni C, Qin W, Bertin E, Torchio E, Galvanin S, Urciuolo A, Elvassore N. 2019. Microfluidic reprogramming to pluripotency of human somatic cells. Nature Protocols.
Beninatto R, Barbera C, De Lucchi O, Borsato G, Serena E, Guarise C, Pavan M, Luni C, Martewicz S, Galesso D, Elvassore N. 2019. Photocrosslinked hydrogels from coumarin derivatives of hyaluronic acid for tissue engineering applications. Materials Science and Engineering.
Giulitti S, Pellegrini M, Zorzan I, Martini P, Gagliano O, Mutarelli M, Ziller MJ, Cacchiarelli D, Romualdi C, Elvassore N. and Martello G. 2019. Direct generation of human naive induced pluripotent stem cells from somatic cells in microfluidics. Nature Cell Biology.
Martewicz S, Luni C, Serena E, Pavan P, Chen HV, Rampazzo A, Elvassore N. 2019. Transcriptomic Characterization of a Human In Vitro Model of Arrhythmogenic Cardiomyopathy Under Topological and Mechanical Stimuli. Annals of Biomedical Engineering.
Zoso A, Zambon A, Gagliano O, Giulitti S, Prevedello L, Fadini GP, Luni C, Elvassore N. 2019. Cross-talk of healthy and impaired human tissues for dissection of disease pathogenesis.Biotechnology Process.
Prevedello L, Michielin F, Balcon M, Savio E, Pavan P and Elvassore N. 2019. A Novel Microfluidic Platform for Biomechano-Stimulations on a Chip. Annals of Biomedical Engineering.
2018
Giobbe GG, Zambon A, Vetralla M, Urbani L, Deguchi K, Pantano MF, Pugno NM, Elvassore N., De Coppi P and Spilimbergo S. 2018. Preservation over time of dried acellular esophageal matrix. Biomedical Physics and Engineering Express.
Dong Y, Rodrigues M, Kwon S, Li X, Sigen A, Brett E, Elvassore N., Wang X, and Gurtner G. 2018. Acceleration of Diabetic Wound Regeneration using an In Situ–Formed Stem‐Cell‐Based Skin Substitute. Advanced Healthcare Material.
Grespan E, Giobbe GG, Badique F, Anselme K, Rühe J, Elvassore.N. 2018. Effect of geometrical constraints on human pluripotent stem cell nuclei in pluripotency and differentiation. Integrative Biology.
Martewicz S, Gabrel G, Campesan M, Canton M, Di Lisa F, Elvassore N. 2018. Live Cell Imaging in Microfluidic Device Proves Resistance to Oxygen/Glucose Deprivation in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Anal. Chem.
Hu Q, Luni C, Elvassore N. 2018. Microfluidics for secretome analysis under enhanced endogenous signaling. Biochemical and Biophysical Research Communications.
NICOLA ELVASSORE
- PhD: Chemical Engineering at University of Padova (1999)
- Postdoc: Assistant Researcher at the Department of Chemical Engineering at University of Padova (1999-2001)
- Group leader: Venetian Institute of Molecular Medicine, Padova, Italy (2007-current)
- Professor:
- Associate Professor at the Department of Industrial Engineering at University of Padova, Italy (2014 – 2018)
- Professorial Research Associate, Faculty of Pop Health Sciences, Centre for Stem Cells & Regenerative Medicine, University College London, UK (2015 – current)
- Distinguished Professor-in-Residency at Shanghai Institute of Advanced Immunochemistry (SIAIS), ShanghaiTech University, Shanghai, China (2015 – current)
- Full Professor at the Department of Industrial Engineering at University of Padova, Italy (2018 - current)
SELECTED AWARDS
- 2005 – Fulbright visiting scientist at Harvard – M.I.T. Division of Health Sciences-Technology, Cambrige, USA.
Current funding
- Fondazione Afm
- Fondazione Cariparo
- Fondazione telethon
- Fondazione FRAXA
- Erc advanced