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.
Highlights
Adult mesenchymal stem cells are maintained in cellular microenvironments, termed ‘niches’, in the body
We have previously demonstrated the prolonged self-renewal of skeletal stem cells (SSCs) enriched populations selected for using the trypsin-resistant cell surface marker STRO-1 [19e22] as well as with commercially available SSCs selected for multiple markers [10]
To briefly confirm retention of SSC phenotype [10], we used densitometry of western blots probed with an anti-STRO-1 antibody for STRO-1 selected SSCs seeded at 3000 cells/cm2, showing more STRO-1 is expressed in SSCs on the SQ surface compared to flat control over a 7 day culture period (Fig. 1b)
Summary
Adult mesenchymal stem cells are maintained in cellular microenvironments, termed ‘niches’, in the body. These niches provide biochemical and physical cues to the cells to prevent undesired differentiation [1]. We note that more precisely, mesenchymal stem cells from the bone marrow should be described as skeletal stem cells (SSCs), differentiating them from mesenchymal cells from other niche locations [2,3]. Lee et al / Biomaterials 116 (2017) 10e20 between SSC and fibroblast morphologies means that biochemical regulation controlling the SSC and fibroblast phenotypes is subtle even though the phenotypical differences are large Failure to control these small differences in culture likely results in the fibroblastic over-growth typically seen in vitro. An, as yet, unmet need remains to develop methods that will enhance SSC self-renewal (population expansion without loss of multipotency) [10,11], while preventing spontaneous differentiation of SSCs to fibroblasts when propagated in cell culture
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