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Title: Exploring the potential of the physio-mechanical environment and circadian timing in adult progenitor cell differentiation
Author: Rogers, E. H.
ISNI:       0000 0004 7964 2187
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2019
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Optimising cell/tissue constructs so that they can be successfully accepted and integrated within a host body is an essential consideration in modern tissue engineering. To do this, adult progenitor cells are frequently utilised, but there are many aspects of their environment in vivo that are not completely understood. There is evidence to suggest that circadian rhythms and daily circadian temporal cues have substantial effects on progenitor cell activation and differentiation, and that the mammalian circadian rhythm may be influenced by the cell's mechanical environment. Therefore, the hypothesis presented was that the physio-mechanical environment influences the differentiation capacity of progenitor cells and this may be mediated, at least in part, by the influence of the circadian rhythm. Moreover, it was also hypothesised that the responses of the progenitor cells, as a result of changes in the physio-mechanical environment or in the progenitor cells' circadian rhythms, may differ depending on the anatomical source that the cells were derived from. To investigate this, a unique mechanical stretch paradigm was designed to subject human adult progenitor cells derived from bone marrow, dental pulp and subcutaneous adipose tissue to varying levels of mechanical stimulation. This set up was then modified to determine how further altering the progenitor cells' physio-mechanical environment affected their response to rhythmic mechanical stretch, in terms of their differentiation capacity and circadian rhythm, including alterations to the protein substrate and the supplementation of bioactive synthetic peptides. The research presented here demonstrates that progenitor cells respond very differently to the same signals, depending on the cells' origin of derivation. This is likely to be possible due to the fact that the cell types differ in their signal transduction mechanisms; this is necessary as the cells will be exposed to different signals depending on the anatomical location of derivation, developmental origin and level of maturity. One way in which the progenitor cells are shown to differ includes that of their circadian rhythms. Cyclical uniaxial stretch is here presented as a novel methodology to synchronise the cellular circadian rhythm with the ability to even synchronise more primitive cells that did not respond to chemical entrainment. It is here proposed that alterations in the cellular mechano-environment directly lead to changes in the circadian rhythm, which in turn affects the differentiation capacity of progenitor cells. Any alterations in progenitor cell function then have profound implications on tissue function, proposing a mechanism for how various pathologies become established. These findings also suggest that incorporating the temporal circadian information of different human adult progenitor cells will have profound implications in optimising tissue engineering approaches and progenitor cell therapies.
Supervisor: Hunt, John ; Pekovic-Vaughan, Vanja Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral