Nanotopography controls cell cycle changes involved with skeletal stem cell self-renewal and multipotency

Abstract

In culture isolated bone marrow mesenchymal stem cells (more precisely termed skeletal stem cells, SSCs) spontaneously differentiate into fibroblasts, preventing the growth of large numbers of multipotent SSCs for use in regenerative medicine. However, the mechanisms that regulate the expansion of SSCs, while maintaining multipotency and preventing fibroblastic differentiation are poorly understood. Major hurdles to understanding how the maintenance of SSCs is regulated are (a) SSCs isolated from bone marrow are heterogeneous populations with different proliferative characteristics and (b) a lack of tools to investigate SSC number expansion and multipotency. Here, a nanotopographical surface is used as a tool that permits SSC proliferation while maintaining multipotency. It is demonstrated that retention of SSC phenotype in culture requires adjustments to the cell cycle that are linked to changes in the activation of the mitogen activated protein kinases. This demonstrates that biomaterials can offer cross-SSC culture tools and that the biological processes that determine whether SSCs retain multipotency or differentiate into fibroblasts are subtle, in terms of biochemical control, but are profound in terms of determining cell fate.

Stimulation of 3D osteogenesis by mesenchymal stem cells using a nanovibrational bioreactor

“…Thus, to measure their effect on nanovibration-induced MSC differentiation, a very early stage marker of cell response was selected. Mitogen activated protein kinases, such as extracellular signal-related kinase 1/2 (ERK 1/2), provide a likely marker for the switch between MSC growth and osteogenic differentiation phases 40 , with the onset of differentiation typified by growth repression through high levels of ERK 1/2 activation (phosphorylation) 41 .…”

Novel cellulose/hydroxyapatite scaffolds for bone tissue regeneration: In vitro and in vivo study

“…Cell proliferation was found to be increased in cellulose/nHA, as compared with cellulose/μHA, as significantly higher MTT reduction values were verified for cultures grown for 3 and 6 days within the seeded materials. Early morphological features may greatly influence the cell proliferative behaviour, as anchorage‐dependent cells greatly rely on cytoplasmic expansion over the substrate to switch into the G1 and S phases of the cell cycle (Lee et al, ). During the adhesion process, the degree of spreading and the spreading area positively correlate with the proliferative activity and seem to induce cell proliferation through biochemical and mechanical processes, given the activation of integrin‐dependent and non‐integrin‐dependent pathways (Bacakova, Filova, Parizek, Ruml, & Svorcik, ).…”

Mechanotransduction and Growth Factor Signalling to Engineer Cellular Microenvironments

“…[74,75] On the other end of the size scale, surface nano-and microtopography influence size and shape of cell-matrix adhesion points and thus also play an important role in cell mechanotransduction, as well as in stem cell self-renewal and multipotency. [76][77][78][79][80][81][82] There are excellent reviews on the effect of nanotopography on (stem) cells. [81,83] …”