Emergence of Patterned Stem Cell Differentiation Within Multicellular Structures

Abstract

The ability of stem cells to differentiate into specified lineages in the appropriate locations is vital to morphogenesis and adult tissue regeneration. Although soluble signals are important regulators of patterned differentiation, here we show that gradients of mechanical forces can also drive patterning of lineages. In the presence of soluble factors permitting osteogenic and adipogenic differentiation, human mesenchymal stem cells at the edge of multicellular islands differentiate into the osteogenic lineage, whereas those in the center became adipocytes. Interestingly, changing the shape of the multicellular sheet modulated the locations of osteogenic versus adipogenic differentiation. Measuring traction forces revealed gradients of stress that preceded and mirrored the patterns of differentiation, where regions of high stress resulted in osteogenesis, whereas stem cells in regions of low stress differentiated to adipocytes. Inhibiting cytoskeletal tension suppressed the relative degree of osteogenesis versus adipogenesis, and this spatial patterning of differentiation was also present in three-dimensional multicellular clusters. These findings demonstrate a role for mechanical forces in linking multicellular organization to spatial differentials of cell differentiation, and they represent an important guiding principle in tissue patterning that could be exploited in stem cell-based therapies. STEM CELLS 2008;

Stiffening hydrogels to probe short- and long-term cellular responses to dynamic mechanics

“…4d). These results confirm previous studies, in which the ability of a cell to generate tension and spread on two-dimensional substrates leads to osteogenic differentiation, whereas rounded cells primarily undergo adipogenic differentiation [40][41][42][43] . However, there has been no previous work to investigate hMSC differentiation responses to changing substrate stiffness.…”

Surface Curvature Differentially Regulates Stem Cell Migration and Differentiation via Altered Attachment Morphology and Nuclear Deformation

“…Numerous studies have shown that the mechanical properties of the cell's microenvironment, such as the substrate stiffness, have a fundamental effect on hMSC cell fate and function and impact tissue regeneration 6, 7, 8, 9. Recently, evidence is rising that the geometrical properties of the cell's environment also play an important role as regulators of cell behavior 10, 11, 12, 13, 14, 15, 16, 17, 18, 19. Using geometric features, such as pore geometry, as a cue to direct tissue regeneration is compelling since it may allow a biomaterial to steer cell function purely by its shape and hereby contribute to tissue regeneration.…”

Stem cell fate dictated solely by altered nanotube dimension

“…Recent studies related to the effect of nanotopography on cellular behavior indicated that osteoblast adhesion and functionality was enhanced by 30% when cultured on a nanograined Al 2 O 3 and TiO 2 substrate (4-6) compared with those cultured on a micrograined surface, and nanostructures such as TiO 2 nanotubes with Ͻ100-nm spacing showed superior characteristics in bone mineral synthesis (5). However, most of the previous studies on nanostructures and cell responses have mainly used oriented, patterned, or semiordered polymer arrays (7)(8)(9) and alumina/ polymer hybrid patterned arrays (10).…”