Mesenchymal Stem Cell Heterogeneity and Ageing In Vitro: A Model Approach - Computational Modeling in Tissue Engineering - page 177

1 Introduction
Mesenchymal stem cells (MSCs, also known as multipotent mesenchymal stromal
cells) have been characterised as a heterogeneous cell population of adherent
spindle-shaped cells capable of differentiating into bone-marrow stromal cells,
osteoblasts, chondrocytes, adipocytes and myocytes. Related lineage priming of
MSCs has been nicely demonstrated in monoclonal culture [ 23 ]. In some tissue
types, e.g. bone-marrow stroma, adipose, skeletal muscle and synovium, MSCs
persist in adult life without loosing their capacity to proliferate and differentiate
[ 41 , 76 ]. Accordingly, MSCs have been proposed as innovative therapeutic tools in
tissue regeneration. Their therapeutic deployment comprises treatment of various
diseases, including osteoarthritis [ 12 ] and myocardial infarction [ 40 ]. MSC
application in asthma, radiation exposure, and neurological disorders has been
explored as well [ 9 ]. Moreover, beside of having high regenerative potential these
cells have been shown to carry immunosuppressive capacities, to improve angi-
ogenesis and to prevent fibrosis [ 24 ].
Therapeutic applications of MSCs require massive in vitro expansion of the
isolated cells [ 7 , 21 ]. The populations typically can be expanded for up to 20
population doublings (PDs) until they enter a senescent state. Figure 1 a shows a
single cell-derived, expanding clone of MSCs. As shown in Fig. 1 b the growth
properties of such clones can vary largely during expansion. Various culture pro-
tocols have been suggested in order to isolate MSCs with high regenerative potential
[ 18 , 88 , 92 ]. However, independent of the culture condition applied, massive rep-
lication of MSCs was found to be associated with continuous decline of the cell's
functional competence, which was called ''MSC ageing'' [ 91 ]. During expansion the
MSCs show a decreasing proliferation potential [ 84 , 88 ]. Moreover, the efficiency of
differentiating into local tissue after transplantation was found to severely decrease
during expansion [ 75 ]. During prolonged in vitro culture MSCs frequently undergo
spontaneous malignant transformation which represents a biohazard in long-term
expansion [ 77 ]. Both ageing and transformation appear to be stochastic in nature and
render the MSC populations an additional layer of heterogeneity.
In the following we discuss different hypotheses on the origin and development
of MSC heterogeneity and introduce a model framework which allows addressing
related questions. We show that a noise-driven approach to MSC differentiation
combined with a model of intrinsic MSC ageing can explain MSC heterogeneity
on both the individual and population level. We highlight open questions on MSC
heterogeneity and suggest future investigations.
2 MSC Heterogeneity on Different Scales
Due to a growing body of evidence it is has been generally accepted that tissue
stem cells are heterogeneous with regard to their function. This heterogeneity has
been suggested to involve properties like their cycling activity, engraftment