Problem/issue being addressed
Regenerative medicine aims to repair and recover the biological function of damaged tissues and organs often using stem cells. However, this requires the development of culture substrates that mimic the native environment of stem cells and can support their expansion and differentiation. Polymeric scaffolds are emerging as synthetic 3D environments capable of influencing cell growth and proliferation, together with feeder layers or other biological compounds that are employed to maintain the phenotype of stem cells. To overcome safety concerns associated with the use of such additives and feeder layers, the ERC NICHOID project developed a polymeric scaffold with grid architecture using a microfabrication technology called two-photon laser polymerisation. My approach led to the development of the user-friendly and safe Nichoid substrate.
Overall achievements of the project
The Nichoid was tested on mesenchymal stem cells (MSCs) known for their regenerative capacity in orthopaedic, plastic and reconstructive surgery applications, as well as for their immune-suppressive potential in organ transplantation. They are also sensitive to mechanical stimuli from the micro-environment. Mechanical cues transduced within cells are believed to determine cell fate as they alter nuclear shape and hence the import and export of transcription factors that are paramount for regulation of gene expression. With the help of colleagues at the Politecnico di Milano and at the National Research Council of Italy, researchers observed a roundish nuclear configuration in MSCs adhered to the Nichoid microscopic grid, while a spread configuration was seen in cells attached to the flat substrate surrounding the grid. The latter morphology coincided with an increase in nuclear permeability and in the flow of signalling molecules that induce cell differentiation. The Nichoid essentially prevents cell spreading during proliferation by mechanically confining cells in the grid, thus avoiding this master switch towards differentiation. The observation that, in stem cells, nuclear import of transcription factors activating cell differentiation is regulated primarily by nuclear membrane strains was also supported through computational prediction of nuclear import flow as a function of cell morphology.
Importance for society
This geometric control of cell stemness opens an avenue towards reprogramming multipotency or even pluripotency in cultured stem cells, without the need of chemical agents or genetic modifications. The nichoid led to the acquisition of two ERC-PoC grants that led to development of products for biological research integrating the nichoid culture substrate, already into commercialisation. Most importantly, in light of the current COVID-19 pandemic, Raimondi plans to promote the Nichoid substrate for the expansion of MSCs to cure COVID-19, based on a new therapeutic strategy already in clinical trial in China and in the United States. Moreover, she will use all the advanced research tools developed during the NICHOID project to speed up the preclinical testing necessary to bring new antiviral therapies and vaccines to the clinics.
