Mesenchymal Stem Cell Heterogeneity and Ageing In Vitro: A Model Approach - Computational Modeling in Tissue Engineering - page 186

population. It appears that this is given under artificial in vitro conditions, as e.g.
high oxygen tension, leading to fast accumulation of cells in senescent states [ 101 ].

5.2 Exemplifying the Environmental Impact

A factor that strongly impacts MSC proliferation and differentiation is oxygen.
It has been shown that MSC-derived cell populations show higher proliferative
activity when cultured under low oxygen tension (2-5% pO 2 ) compared to high
oxygen tension (20-21% pO 2 )[ 19 , 52 , 71 ]. Moreover, cell populations expanded
at low oxygen tension show a faster and more directed differentiation into
osteoblasts, adipocytes [ 35 , 52 ] and chondrocytes [ 59 , 97 ]. As shown in Fig. 5 d,
our model predicts that increased proliferation increases the population hetero-
geneity. This would suggest describing the oxygen dependence in terms of the
growth rate, i.e. by assuming a higher growth rate 1/s at low oxygen tension.
However, in case of a proliferation stop, e.g. according to contact inhibition of
growth (see below), cells at 5% pO 2 would acquire a senescent state as fast as at
20% pO 2 , which has not been observed. Thus, we decided to model the observed
effects of oxygen tension by changes of the noise-profile exclusively.
Actually, we assumed that cell adaptation to non-physiological high oxygen
tension results in decreased state fluctuations which subsequently lead to an
accumulation of cells in differentiated states. In contrast, low oxygen tension
conserves stem cell and progenitor states by enabling high amplitudes of the state
fluctuation. f(pO 2 /pO 2 max ) We described this dependency by a Hill function

approaching 0 and 1 at low and high pO 2 , respectively:

with f ð X Þ¼

X n
X n þ K n

1 a fpO 2 = pO max r ð a Þ¼ r 0 ð 4 Þ

2

The related 'noise landscape' is shown in Fig. 6 together with the differentia-
tion state profiles for 5% and 20% pO 2 . The parameters of the profiles were
obtained by reproducing the clonal growth properties at these conditions [ 47 ].
Using these distributions as input we were able to simulate the experimentally
observed impact of low oxygen expansion on subsequent differentiation in pellet
culture which appears to be a result of limited lineage plasticity of MSC

populations.

5.3 Impact of Cell2Cell Interactions (Contact Inhibition
of Growth)

The above assumptions exclusively consider intrinsic regulation of the MSC state.
The impact of cell-cell interaction has been neglected so far. However, it is well
known that MSC expansion, lineage specification and terminal differentiation