Investigation of MSCs energy metabolism
Mesenchymal stem cells（MSCs）are multipotent adult stem cells that are present in multiple tissues, including umbilical cord, bone marrow and fat tissue. MSCs can self-renew by dividing and can differentiate into multiple tissues including bone, cartilage, muscle and fat cells, and connective tissue. Numerous studies have shown that MSCs have tremendous therapeutic potential, with over 400 clinical trials currently registered. However, storage and transport of viable and active MSCs from labs to clinical sites is a major bottleneck for such therapies. There is a clear need for improvement in this regard for routine clinical use of MSCs.
MSCs reside in a hypoxic niche in vivo, thus there have been a limited number of studies into their behavior under hypoxia. To date, little is known about their basic cell metabolic pathways or about substrate requirements and metabolite production at different stages of expansion and differentiation. There is virtually no information on membrane transport of nutrient substrates nor about their substrate sensitivity.
Through collaboration with University of Oxford, we aim to investigate pathways of energy metabolism, glycolytic or oxidative, during different stages of MSC expansion and differentiation. At these stages, we will determine rates of substrate utilisation and metabolite and reactive oxygen species production in relation to substrate and metabolite extracellular concentrations. We will measure the influence of the substrate/metabolite environment on transporter expression and activity. We will investigate the influence of different substrates (such as oxygen, glucose, glutamine, pyruvate) on these processes. We will also investigate expansion on soft substrates, reported to maintain quiescence.
The study will provide a new understanding of metabolic pathways of MSCs and the conditions for promoting expansion and differentiation on the one hand, or quiescence on the other. The information obtained will allow us to tailor medium composition as required at different stages of in vitro manipulation, cell storage and transportation.
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Photo illustrating composition of stem cell niche: Stem cell niches are complex, heterotypic, dynamic structures, which include different cellular components, secreted factors, immunological control, ECM, physical parameters and metabolic control. ” Ref: “Modulating the stem cell niche for tissue regeneration. SW Lane, DA Williams, FM Watt. Nature Biotechnology, 32,795–803 (2014).