HYALSTEMAGE

Effect of controlled hyaluronan synthesis on the stemness of aged mesenchymal stem cells

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 Obiettivo del progetto (Objective)

'Hyaluronan (HA), a linear polysaccharide in the extracellular matrix (ECM) of higher animals is a key player in tissue remodelling. Mesenchymal stem cells (MSC) exhibit multipotential differentiation capacities and are therefore of high clinical importance. Novel cell therapeutic approaches based on the differentiation and regeneration potential of MSC have been developed and successfully applied in numerous clinical studies. The stemness of MSC is described by their ability to form colonies and to differentiate into mesenchymal tissues. Prior clinical applications MSC are propagated in vitro to increase the number of multipotential cells and thereby maximising the chance of a therapeutic success. So far however, cell expansion can only be achieved at the expense of MSC stemness and diminished multipotentiality. The aim of this project is to unravel forces that drive these detrimental processes during MSC propagation. In particular, the proposed work addresses alterations in HA content of the extracellular matrix during cultivation. Depending on the HA length, cell proliferation and differentiation is either inhibited or promoted. High molecular weight HA restrains cell division whereas short HA fragments are shown mitotic. Hyaluronan synthases (HAS) generate the unbranched biopolymer at the plasma membrane. HAS are differentially expressed when comparing young against aged cells. In particular HAS3 was found to be upregulated in senescent fibroblasts and MSC. The goal of this project is to investigate the role of HAS3 during MSC ageing and to rate whether elevated levels of HA production advances the progression of cell senescence. We hypothesise that controlling the HA content in the pericellular space may not only allow to decelerate the progression of MSC senescence but also to yield sustained fitness of expanded MSC for therapeutic applications.'

Introduzione (Teaser)

Understanding how stem cells behave in their residing niche is of central importance for designing regenerative strategies. European researchers investigated how this microenvironment changes with ageing.

Descrizione progetto (Article)

Mesenchymal stem cells (MSCs) are a small reservoir of progenitor cells that can be induced to differentiate into bone, connective tissue and fat. This capacity renders them invaluable tools for regenerative purposes. MSCs reside in the bone marrow in an undifferentiated state and can be activated by various stress signals.

Central to many cellular processes and tissue homeostasis is the extracellular matrix (ECM) and its most abundant constituent, hyaluronan (HA). Loose ECM regions seem to support the differentiation of various stem cell populations, including MSCs. MSCs possess enzymes that synthesise and secrete HA, a process that is up-regulated in aged individuals.

The hypothesis investigated by the EU-funded project 'Effect of controlled hyaluronan synthesis on the stemness of aged mesenchymal stem cells' (HYALSTEMAGE) was that an ECM rich in HA interferes with proper cellular activity and hampers the regenerative potential of MSCs. In this context, scientists investigated differences in gene expression levels in MSCs isolated from differently aged donors.

Supplementing MSC cultures with HA had no impact on the cells, but blocking of HA synthesis induced a proliferation arrest. When scientists looked deeper into the mechanism, they found an overall increase in the glycosylation pattern of MSC proteins and a greater capacity to differentiate into osteocytes. They concluded that HA synthesis essentially compensates for the need for more osteogenic precursors in aged cells.

HYALSTEMAGE observations underscore the importance of the ECM in controlling stem cell behaviour and unveil putative mechanisms that are implicated in ageing. The results also indicate the presence of a novel sensor system that can induce cell proliferation and differentiation in response to a changing microenvironment.