Mesenchymal Stem Cell Heterogeneity and Ageing In Vitro: A Model Approach - Computational Modeling in Tissue Engineering - page 193

also help to solve the question whether proliferation alone (as assumed in the
models presented) or/and adaptation to changing environments is a source of
persistent clonal differences. For this purpose FACS analysis of selected markers
should be combined with gene expression analysis as demonstrated by Chang and
co-workers [ 10 ]. Moreover, time-lapse online analysis of the expression of
stemness and differentiation markers by individual MSCs could not only provide
direct evidence for the assumptions made in the noise-driven differentiation model,
it would also delineate the emerging structure of noise-landscapes.
The proposed model is capable of explaining an entire panel of experimental
observations regarding MSC heterogeneity. However, the molecular basis of
the assumed noise-profiles and their dependence on the differentiation states, the
environment and age remain speculative. Models have been suggested that involve
e.g. Wnt-pathway activity [ 3 ]. A general model framework linking noise-landscapes
to the dynamics of regulatory networks is missing. Thus, building up multi-scale
models that bridge the current gap between the increasing amount of molecular
data and observed cellular phenotypes represents a current need in order to
improve our understanding of the heterogeneity of MSCs in vitro. Their validation
will require sophisticated experimental studies on the single cell level.
References
1. Acar, M., Becskei, A., van Oudenaarden, A.: Enhancement of cellular memory by reducing
stochastic transitions. Nature 435(7039), 228-232 (2005)
2. Ahmadbeigi, N., Shafiee, A., Seyedjafari, E., Gheisari, Y., Vassei, M., Amanpour, S.,
Amini, S., Bagherizadeh, I., Soleimani, M.: Early spontaneous immortalization and loss of
plasticity of rabbit bone marrow mesenchymal stem cells. Cell Prolif. 44(1), 67-74 (2011)
3. Arias, A.M., Hayward, P.: Filtering transcriptional noise during development: concepts and
mechanisms. Nat. Rev. Genet. 7(1), 34-44 (2006)
4. Backofen, R., Bernhart, S.H., Flamm, C., Fried, C., Fritzsch, G., Hackermuller, J., Hertel, J.,
Hofacker, I.L., Missal, K., Mosig, A., Prohaska, S.J., Rose, D., Stadler, P.F., Tanzer, A.,
Washietl, S., Will, S.: RNAs everywhere: genome-wide annotation of structured RNAs.
J. Exp. Zool. B. Mol. Dev. Evol. 308(1), 1-25 (2007)
5. Ball, S.G., Shuttleworth, C.A., Kielty, C.M.: Mesenchymal stem cells and
neovascularization: role of platelet-derived growth factor receptors. J. Cell. Mol. Med.
11(5), 1012-1030 (2007)
6. Braccini, A., Wendt, D., Jaquiery, C., Jakob, M., Heberer, M., Kenins, L., Wodnar-
Filipowicz, A., Quarto, R., Martin, I.: Three-dimensional perfusion culture of human bone
marrow cells and generation of osteoinductive grafts. Stem Cells 23(8), 1066-1072 (2005)
7. Brooke, G., Cook, M., Blair, C., Han, R., Heazlewood, C., Jones, B., Kambouris, M., Kollar, K.,
McTaggart, S., Pelekanos, R., Rice, A., Rossetti, T., Atkinson, K.: Therapeutic applications of
mesenchymal stromal cells. Semin. Cell. Dev. Biol. 18(6), 846-858 (2007)
8. Brown, G., Drayson, M.T., Durham, J., Toellner, K.M., Hughes, P.J., Choudhry, M.A.,
Taylor, D.R., Bird, R., Michell, R.H.: HL60 cells halted in G1 or S phase differentiate
normally. Exp. Cell Res. 281(1), 28-38 (2002)
9. Caplan, A.I.: Why are MSCs therapeutic? New data: new insight. J. Pathol. 217(2), 318-324
(2009)