Mesenchymal Stem Cell Heterogeneity and Ageing In Vitro: A Model Approach - Computational Modeling in Tissue Engineering - page 183

state (Fig. 3 a). Stem cells inherit 'stemness' by performing asymmetric cell
divisions. This concept was very successful in describing the hierarchical orga-
nisation of tissues. However, experimental results on HSCs have led to the
development of a concept that allows for more flexibility, the plasticity concept.
According to this concept cells can loose and gain stem cell properties. If this
applies to all possible states of a population, the states approach a stationary
distribution which will be in general a broad distribution (Fig. 3 b). In the fol-
lowing we will focus on models based on the plasticity concept.
The reversibility and stochasticity of cellular fate decisions has been studied by
Loeffler and Roeder [ 54 ]. In their models [ 34 , 73 , 74 ] individual cells gain and
loose stem cell properties depending on whether they localise inside or outside a
specific niche environment, respectively. Thus, the environment directs the cel-
lular fate and the reversibility of cell fate decisions is enabled by probabilistic
switches between different micro-environments. The models were successfully
applied to in vivo organisation of normal and malignant HSC populations.
However, MSC populations have been shown to expand while maintaining stem
cell properties also in a homogenous environment. For modelling these systems we
have expanded the ideas of Loeffler and Roeder by assuming that cells gain and
loose stem cell properties according to a probabilistic process whose state-specific
amplitudes are set by the environment. Within this approach cell fate decisions are
basically reversible. The assumed fluctuations are hypothesised to be generated by
intra- and extracellular noise triggering random transitions between different
regulatory network activation patterns. This assumption is supported by experi-
mental findings demonstrating that epigenetic gene silencing has a strong sto-
chastic component [ 70 , 96 ]. In the following we will give a brief description of a
MSC population model that is based on this approach.
5 The Concept of Noise-Driven Differentiation
A growing body of evidence indicates that noise is not generally detrimental to
biological systems but can be employed to generate genotypic, phenotypic, and
behavioural diversity [ 44 , 79 , 80 ]. In particular, noise-driven solutions are
expected to prevail in cellular adaptation to variable environments. Moreover, it
has been proposed that biological systems have built-in molecular devices for
noise control [ 1 , 3 , 28 ]. Together with the experimental results on MSCs, reviewed
above, this has led us to suggest a model of noise-driven differentiation [ 37 , 47 ],
which will be introduced in the following.
5.1 General Assumption
In the model of noise-driven differentiation, cell differentiation is defined as loss of
stem cell properties. It is quantified by a continuous state variable a that can adopt
values between 0 (full stem cell competency) and 1 (fully differentiated cell).