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.
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