Mesenchymal Stem Cell Heterogeneity and Ageing In Vitro: A Model Approach - Computational Modeling in Tissue Engineering - page 191

Fig. 8 Simulation results applying the ageing-model. a The observed distribution of the
generations is comparable to that observed without ageing. b Age-dependent noise profiles as set
before (red) and observed after expansion (grey). A considerable heterogeneity regarding age has
developed. c Distribution of differentiation states depending on the age. Young cells (blue,
m = 8-11) include a relevant fraction of undifferentiated cells with a \ 0.2, while most of the
old cells (black,m= 24-27) reside in a differentiation state of a [ 0.8

expansion a few cells of the population have nearly reached r(a = 0) = 0.15 as
assumed in the other applications. However, a large heterogeneity regarding age
has been established (7 \ m \ 28). With increasing age the cells tend to accu-
mulate more and more in differentiated, senescent states (here, a [ 0.8). This is in
nice agreement with experimental observations on ageing MSCs [ 45 , 95 ].
As found in our simulation studies comparing MSCs that were expanded at high
and low oxygen tension ( Sect. 5.2 ,[ 47 ]), these differences between young and old
cells in the distribution of the differentiation states will also manifest in differences
in their lineage specification and functional differentiation potential. Accordingly,
aged cells are characterised by a lower regenerative potential compared to young
cells. This is again in agreement with experimental findings [ 45 , 95 ].
In summary the model is capable of describing experimental findings on the
environmental dependent MSC ageing. The underlying concept is general in the
sense that in vitro and in vivo ageing can be assumed to base on the same prin-
ciples. This is supported by recent experimental findings demonstrating that ageing
and replicative senescence have related effects on stem cells [ 94 ].

7 Discussion

Grafting of MSCs is an emerging technology to repair tissues and organs of
mesenchymal origin. A prerequisite of these applications is rapid and massive
MSC expansion. This becomes obvious considering the isolation process of these
cells. Bone marrow is an important source of MSCs from where they can be easily
isolated and purified. However, only about 0.01% of nucleated bone marrow cells
carry MSC properties. Accordingly from a 20 ml aspirate usually only up to
50.000 MSCs are obtained [ 6 ]. Consequently, at least 5PDs are required in order to
obtain the 10 6 -10 7 cells that are required in a typical application.