SATCELLOMICS

Integrated signalling networks in muscle stem cells: cell fate regulation by heparan sulfates

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 Obiettivo del progetto (Objective)

'Skeletal muscle stem cells (satellite cells - SCs), are undifferentiated progenitors that reside mitotically quiescent in a specialized anatomical niche between the plasma membrane of muscle fibres and the basal lamina: the SC niche. SCs can remain quiescent for long periods of time, but in response to injury become rapidly activated, proliferate and then undergo terminal differentiation. The molecular mechanisms that coordinate the multiple signals involved in regulation of SC fate decisions are still largely unknown. Many of these mechanisms reside within the SC niche, possibly integrated by highly plastic components of the niche such as heparan sulfate proteoglycans (HSPGs). HS is a glycosaminoglycan polysaccharide containing variably sulfated disaccharide sequences and is present on the cell surface and in the extracellular matrix associated with core proteins to form HSPGs. These are key components of stem cell niches where they play important roles in regulating signalling events that control cell fate decisions. Here I will undertake advanced training-through-research in key post-genomic technologies (particularly glycomics, quantitative affinity proteomics, transcriptomics and bioinformatics) to underpin a systems biology approach to explore the role played by the SC niche in regulating SC fate decisions. The specific focus of the research project will be molecular mechanisms that are coordinated and integrated by HS and associated with two specific SC states: proliferation and differentiation. I will define the HS profiles, the set of proteins that interact with HS (HS-interactome) and whole transcriptomes in each state. I will then use bioinformatics tools to generate signalling network models to predict the molecular mechanisms involved in HS-coordinated integration of cell fate signals. Lastly, I will validate bioinformatics predictions by examining HS-dependence of candidate molecular mechanisms associated with SC fate transition.'

Introduzione (Teaser)

Understanding how stem cells behave in health and disease could provide a novel angle for the therapy of various diseases.

Descrizione progetto (Article)

Skeletal muscle contains a specialised population of undifferentiated stem cells known as satellite cells (SCs). In response to injury, SCs rapidly activate, proliferate and then undergo terminal differentiation. However, the precise molecular mechanisms implicated in the regulation of SC fate decisions are still largely unknown.

In answer to this, the EU-funded SATCELLOMICS (Integrated signalling networks in muscle stem cells: cell fate regulation by heparan sulfates) project set out to test the hypothesis that the extracellular environment influences disease and ageing.

Initially, the consortium studied how the composition of the muscle extracellular environment changes in degenerative diseases such as muscular dystrophy. During muscular dystrophy, stem cells lose their regenerative capacity, a phenomenon most likely linked with a defective environment.

To delineate the alterations associated with a dystrophic environment, researchers analysed the composition of the muscle extracellular environment in dystrophic and healthy mice. Using mass spectrometry, they identified a class of proteins which accumulated during muscular dystrophy progression and affected muscle stem cells. Addition of these proteins to healthy stem cells in vitro dramatically impaired cell proliferation and differentiation, clearly underscoring the role of the environment on stem cells.

Furthermore, the consortium analysed the gene expression profile of stem cells attached to their normal niche or on their own in a petri dish. Significant changes were observed in signalling pathways implicated in cell-environment communication, cell proliferation and differentiation.

Taken together, the findings of the SATCELLOMICS study demonstrate that the extracellular environment controls muscle stem cell homeostasis and fate decisions. They also pave the way for manipulating the regenerative capacity of these cells through alteration of the extracellular environment, potentially with a targeted pharmacological approach.