MECHANO – From the mechanobiology of the glial to the management of multiple sclerosis

Summary

With over 700,000 affected patients in the EU, Multiple Sclerosis (MS) represents the most frequently occurring demyelinating disease of the central nervous system (CNS). Remyelination can be observed in MS plaques. But as the disease progresses this regenerative capacity ofoligodendrocyte progenitor cells (OPCs) stops. What are the reasons underneath this change? One accepted reason is the formation of the scar tissue, which is seen as a hostile terrain in the context of CNS regeneration. Although the process is inexorable, it is mutable in time. Can we use this knowledge as an opportunity to manage the disease progression?

There is growing evidence that matrix rigidity plays a key role in the process of OPC differentiation and oligodendrocyte myelination by unbalancing the intra/extracellular forces. Recent studies have established the effect of biophysical properties of the extracellular matrix (ECM) on these processes, pointing to the importance of ECM stiffness and topography, strain forces and spatial constraints. Based on current knowledge, our working hypothesis is that by tuning mechanosensing processes one can promote remyelination.

This innovative approach aimed to develop a biomimetic lesion microenvironment to function as a platform to allow the identification of molecules/mechanisms regulating OPC differentiation and study the impact of the mechanical properties on MS progress and prognosis, thus ultimately contributing to the development of new therapeutic approaches to treat MS.

The proposed tissue-engineered system should mimic the ECM features at the relapse and remitting stages of the disease, where a therapeutic intervention at the OPC level could promote a pro-regenerative response. Furthermore, the team aimed to miniaturize and automatize the screening process, by developing a custom-made bioprinter, to allow performing these studies on a high-throughput basis, thus reducing costs and increasing the power of analysis.

The proposed tunable TE-scar represents a revolutionizing attractive system that can be explored in the context of other neurological disorders or even neurodevelopmental studies. Furthermore, the bioprinter prototype can find application in many other uses in biomedicine.

 

Title From the mechanobiology of the glial to the management of multiple sclerosis
Reference UTAP-EXPL/NTec/0057/2017
Scientific Area Nanotechnologies
Funding € 99 212,00 plus matched funding at UT Austin
Leading Institution Instituto Nacional de Engenharia Biomédica (INEB Porto)
Participating Institutions The University of Austin at Texas (UT Austin)
Instituto Politécnico de Leiria (IPLeiria)
Nanohmics (Nanohm)
Duration 24 months
Begin date November 1, 2018
End date October 31, 2020
Keywords Nanomedicine, Molecularly Designed Hydrogels, Mechanobiology, Bioprinting

Main Highlights

  • Phototunable RGD-alginate hydrogels that allow the culture of macroglia cells (astrocytes, OPCs and oligodendrocytes);
  • An in vitro platform that allows the live follow up of the processes of (re)myelination;
  • A bioprinter able to print cell-laden hydrogel microarrays;
  • The postgraduate training of young researchers in the field of emerging technologies.

Indicators

  • 3 Published papers in peer-reviewed Journals and Conferences;
  • 3 Doctoral students and 2 MSc. students involved in research work;
  • 1 Bioprinter prototype (IPLeiria – PT);
  • 1 Mobility exchange supported;
  • 2 Awards granted to members of the team:

Best elevator pitch award given to Eva Carvalho (INEB – PT) with the work: Carvalho ED, Araújo MA, Hubbe H, Mendes E, Barrias CC, Pêgo AP. “Mechanosensing
the demyelinating lesions’ environment – Impact of environmental mechanostimulus on oligodendrocyte differentiation and myelination”. XXIII School of Pure and Applied Biophysics – Emerging Tools in Biomechanics: from tissues down to single molecules. 4-8 February 2019, Palazzo Franchetti, Venice, Italy;

Best Oral presentation award given to Eva Carvalho (INEB – PT) with the
work: Carvalho ED, Araújo M, Barrias C, Pêgo AP “Towards the development of biologically relevant platforms to study glial cell mechanotransduction: an alginate- based approach”. 3rd Doctoral Congress in Engineering (DCE 2019), Faculdade de Engenharia, Universidade do Porto, June 27-28, 2019, Porto, Portugal.

Papers and Communications

  • Moreno PMD, Ferreira AR, Salvador D, Rodrigues MT, Torrado M, Carvalho ED, Tedebark U, Sousa MM, Amaral IF, Wengel J, Pêgo AP. Hydrogel-assisted antisense LNA gapmer delivery for in situ gene silencing in spinal cord injury. Mol Ther Nucleic Acids. 2018; 11:393-406. https://doi.org/10.1016/j.omtn.2018.03.009
  • Carvalho ED, Araújo MA, Hubbe H, Mendes E, Barrias CC, Pêgo AP. Mechanosensing the (de)myelinating environment: development of a novel 3D tissue-engineered platform. Proceedings of the XIV European Meeting on Glia Cells in Health and Disease 2019, July 10-13 2019, Porto, Portugal. GLIA 67: E475 (2019)
  • Allen SC, Widman JA, Datta A, Suggs LJ. Dynamic Extracellular Matrix Stiffening Induces a Phenotypic Transformation and a Migratory Shift in Epithelial Cells. Integr. Biol. Integrative Biology, Volume 12, Issue 6, June 2020, Pages 161–174, https://doi.org/10.1093/intbio/zyaa012

Project Team

Ana Pêgo

Principal Investigator in Portugal
MECHANO

Laura Suggs

Principal Investigator in Austin
MECHANO