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.

Background
Research
Group Members
Key Publications

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@gmail.com

Cecilia Laterza

Postdoc

cecilial3@hotmail.it

Federica Michielin

Postdoc

federica.michielin@gmail.com

Anna Urciuolo

Postdoc

anna.urciuolo@unipd.it

Silvia Galvanin

PhD student

silvia.galvanin@gmail.com

Annamaria Tolomeo

PhD student

annamaria.tolomeo@hotmail.it

Erika Torchio

PhD student

erikatorchio@gmail.com

Massimo Vetralla

PhD student

massimo.vetralla@unipd.it

Yang Yang

PhD student

yang.yang@studenti.unipd.it

Michele Zanatta

PhD student

michele.zanatta.1@studenti.unipd.it

Ida Maroni

PhD student

ida.maroni88@gmail.com

Davide Mattioli

M.Sc fellow

davide.mattioli91@gmail.com

Alberto Gava

M.Sc fellow

alberto.gava.2@studenti.unipd.it

  1. Martewicz S, Serena E, Zatti S, Keller G, Elvassore N. Substrate and mechanotransduction influence SERCA2a localization in human pluripotent stem cell-derived cardiomyocytes affecting functional performance. Stem Cell Res. 2017 Dec;25:107-114.
  2. Brigo L, Urciuolo A, Giulitti S, Della Giustina G, Tromayer M, Liska R, Elvassore N, Brusatin G. 3D high-resolution two-photon crosslinked hydrogel structures for biological studies. Acta Biomater. 2017 Jun;55:373-384.
  3. Grespan E, Martewicz S, Serena E. Le Houerou V, Rühe J, Elvassore N. Analysis of Calcium Transients and Uniaxial Contraction Force in Single Human Embryonic Stem Cell-Derived Cardiomyocytes on Microstructured Elastic Substrate with Spatially Controlled Surface Chemistries. Langmuir, 2016, 32 (46), pp 12190–12201.
  4. Luni C, Giulitti S, Serena E, Ferrari L, Zambon A, Gagliano O, Giobbe GG, Michielin F, Knobel S, Bosio A, Elvassore N. 2016. High-efficiency cellular reprogramming with microfluidics. Nat Methods. 13:446-452.
  5. Giobbe GG, Michielin F, Luni C, Giulitti S, Martewicz S, Dupont S, Floreani A, Elvassore N. 2015. Functional differentiation of human pluripotent stem cells on a chip. Nat Methods. 12:637–640.
  6. Giobbe GG, Michielin F, Luni C, Giulitti S, Martewicz S, Dupont S, Floreani A, Elvassore N. 2015. Functional differentiation of human pluripotent stem cells on a chip. Nat Methods. 12:637–640.
  7. Luni C, Michielin F, Barzon L, Calabrò V, Elvassore N (2013) Stochastic model-assisted development of efficient low-dose viral transduction in microfluidics. Biophys J 104:934-42.
  8. Serena E, Cimetta E, Zatti S, Zaglia T, Zagallo M, Keller G, Elvassore N (2012) Micro-arrayed human embryonic stem cells-derived cardiomyocytes for in vitro functional assay. PLoS One 7:e48483.
  9. Zatti S, Zoso A, Serena E, Luni C, Cimetta E, Elvassore N (2012) Micropatterning topology on soft substrates affects myoblast proliferation and differentiation. Langmuir 28:2718-26.
  10. Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, Zanconato F, Le Digabel J, Forcato M, Bicciato S, Elvassore N, Piccolo S (2011) Role of YAP/TAZ in mechanotransduction. Nature 474:179-83.

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 – current)
    • 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)

SELECTED AWARDS

  • 2005 – Fulbright visiting scientist at Harvard – M.I.T. Division of Health Sciences-Technology, Cambrige, USA.