Mesenchymal Stem Cell Heterogeneity and Ageing In Vitro: A Model Approach - Computational Modeling in Tissue Engineering - page 182

DNA-replication and mitosis. However, under stress the metabolic activity of the
stem cells increases. The stem cells are exposed to higher levels of DNA-damage-
inducing metabolic side products such as reactive oxygen species [ 85 ]. It has been
suggested that the damages induced thereby impact not only the stem cells but the
whole organism. In fact, excess replicative demands alone can induce progeroid
phenotypes [ 78 ].
Recent experiments demonstrated that artificial in vitro ageing and in vivo
ageing of MSCs induce related changes on the cellular as well as on the molecular
scale [ 45 , 94 ]. Thereby, pre-mature senescence has been implicated as a major
cause of the in vitro decline in MSC function [ 90 ]. The accumulation of this
phenotype, also called replicative senescence, has been demonstrated to be a
continuous process in MSCs [ 95 ]. Interestingly, expansion at low oxygen pressure
and low glucose culture decreases the number of accumulating senescent cells
compared to high oxygen pressure and high glucose culture, respectively [ 89 , 101 ].
Whether the accumulation of damage is actually pre-requisite for MSC ageing is
still unknown. However, DNA-damage rarely affects the 2% of protein-coding
sequences. Instead, it is expected to alter regulatory regions [ 69 ] and expression
and function of non-coding RNAs that are involved in chromatin regulation [ 4 ].
Accordingly, an increasing number of ageing studies investigate the impact of
epigenetic changes, such as DNA hyper/hypo-methylation, and histone modifi-
cations [ 65 , 86 ]. The results suggest that decreasing accessibility of certain reg-
ulatory states of MSCs due to epigenetic remodelling may represent an alternative
or at least a complementary explanation of ageing.
Without any question, the distribution of MSC states changes over time,
i.e. with age and in a tissue specific manner. Whether this is due to changing
environments or due to epigenetic remodelling and accumulation of damage is
currently not fully understood.

4 General Model Approaches

A large number of theoretical approaches to MSC culture aim at quantitatively
describing culture conditions and their impact on processes such as matrix forma-
tion [ 81 ]. Theoretical models of MSC expansion and differentiation are rather
rare [ 22 , 51 ] and do not include single cell-level population heterogeneity. In order to
provide reliable predictions on the dynamics of such systems, theoretical approaches
are required that account for: (i) composition and structure of the cell environment and
(ii) particular stem cell properties such as functional differentiation and self-renewal
in individual cells. Currently there are different concepts to approach these problems
in general. In particular there are different concepts of modelling stem cell organi-
sation. The most prominent are the 'pedigree concept' and the 'plasticity concept'.
The pedigree concept treats 'stemness' as a property that if once lost is lost
forever. In the models that obey this concept this loss can be a deterministic or a
stochastic process. Accordingly the development of individual progenitors may
more or less differ. However, over time they all will approach a defined