Mesenchymal Stem Cell Heterogeneity and Ageing In Vitro: A Model Approach - Computational Modeling in Tissue Engineering - page 192

While even the isolated populations are heterogeneous regarding different
functional aspects, this heterogeneity further evolves during amplification.
Thereby the actual changes depend on the details of the culture conditions which
will essentially impact the cell harvest. Thus, to understand the origin and
development of MSC heterogeneity will help to improve their cell culture con-
ditions. Moreover, it represents a basic step towards individualised therapies [ 31 ].
We here presented a mathematical approach to MSC populations which allows
considering each cell individually. Thus, the approach enables us to simulate the
changes in the population behaviour based on changes in single cells which are
assumed to depend on their particular regulatory state. Our model allows simu-
lations to closely follow standard in vitro expansion and differentiation protocols
of MSCs such that they may be viewed as experiments 'in silico' (on the com-
puter) and the results can directly be compared to those found from experiments.
The approach presented here assumes that noise is predominant in most cellular
states. Its essence is that MSC population structures are determined by state-
specific noise [ 37 ] forming a 'noise landscape', where low noise states represent
the attractor states. Cells subjected to an environment not matching their internal
state are assumed to be destabilised by a high noise amplitude. They subsequently
adapt to this environment by travelling towards low noise states. Extensions of the
proposed noise-driven approach to lineage specification and functional differen-
tiation have been described [ 47 ]. Thereby, decision making in individual cells
during these processes was linked to particular differentiation states and cell-cell
interactions. In particular, lineage specification was assumed to require sufficiently
high stemness, i.e. a values below a certain threshold. In this application MSC
ageing was not considered. However, while changing the distribution of the
differentiation states, obviously ageing will also affect the lineage specification
dynamics, with aged cells rarely or never able to switch lineage. Accordingly, we
expect also functional differentiation to be hampered.
A question not raised so far is whether there is a functional relevance of MSC
heterogeneity regarding expansion and differentiation. The observed heterogeneity
of MSCs could actually represent a functional aspect of their organisation. For
example high proliferation potential of a subpopulation could originate from
secretory properties of another subpopulation in the close neighbourhood. In a
recent study Krinner et al. analysed the expansion and differentiation properties of
single cell derived clones and compared them with the properties of their mother
clone (unpublished results). As the high expansion potential of individual clones
outcompetes that of their mother population, they were not able to provide any
evidence for a specification of subclones into fast expanding clones and expansion
supporting secretory clones.
In order to get deeper insights into MSC organisation a detailed characterisation
of the microenvironments in which MSCs reside in vivo is required. Effective
methods for screening MSC properties in complex in vitro environments have
been already developed [ 55 , 56 ]. Moreover, regeneration experiments on primary
MSCs as suggested in Krinner et al. [ 46 ] will help to understand MSC adaptation
to changing environments and to identify properties that are inherited. This would