Abstract

Induced
pluripotent stem cells (iPSC), which can be derived from mature differentiated
cells, provide an excellent source of cells to study human diseases mechanisms
and screen for lead molecules for drug discovery¹. A fundamental
element needed to exploit the potential of stem cells throughout these
applications is the ability to produce a large number of cells of a consistent
quality and in a cost-effective manner².

3D cultures
systems are expected to meet the high demand for cells needed for such
applications. However, this approach faces problems with cell aggregation³.
Cells in the centre of large aggregates are generally underexposed to
nutrients, resulting in variable growth rates, apoptosis and uncontrolled
differentiation. This heterogeneity leads to challenges in standardization with
respect to culture and assay protocols, and data for analysis⁴.

Unlike any other
approach focusing on the maintenance and expansion of iPSC, our innovative research
project applies synthetic organic chemistry as an enabling tool to produce
cells of a consistent quality on a cost-effective clinically-relevant scale. A
screening of compounds has enabled the identification of teleocidin natural
products that led to derivatives that were thoroughly optimized and used as
medium additives allowing a better expansion of iPSC via an easy, standardized
and xeno-free suspension method. Treated iPSC formed significantly smaller
aggregates and dissociated more easily. Additionally, this control of aggregate
size was done in a scaffold-free manner while overcoming issues of diffusion
and lack of homogeneity.

In summary, our
innovative technology hypothesizes the fact that smaller and therefore more
viable aggregates can be cultured in the presence of small molecules by
disrupting cell-cell adhesion when targeting key adhesive molecules. Moreover,
this culturing technic could bridge the gap between in vitro and in vivo
studies with the potential to have huge impact on drug screening and possibly
decreasing the use of animal models.

References

¹Chen, K.G.et al., Cell Stem Cell, 2014, 14,
13.

²Nishikawa, S. et
al., Nature Rev: Mol. Cell. Biol., 2007, 8, 502

³Zweigerdt, R. et
al., Nature Protocols 2011, 6,
689

⁴Edmondson, R. et al., Assay Drug Dev. Technol., 2014, 12,
207