Emergence of patterned stem cell differentiation within multicellular structures

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 gra-dients of mechanical forces can also drive patterning of lin-eages. In the presence of soluble factors permitting osteogenic and adipogenic differentiation, human mesenchymal stem cells at the edge of multicellular islands differentiate into the osteo-genic lineage, whereas those in the center became adipocytes. Interestingly, changing the shape of the multicellular sheet modulated the locations of osteogenic versus adipogenic differ-entiation. Measuring traction forces revealed gradients of stress that preceded and mirrored the patterns of differentia-tion, where regions of high stress resulted in osteogenesis, whereas stem cells in regions of low stress differentiated to adipocytes. Inhibiting cytoskeletal tension suppressed the rela-tive degree of osteogenesis versus adipogenesis, and this spatial patterning of differentiation was also present in three-dimen-sional 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; 26:2921–2927 Disclosure of potential conflicts of interest is found at the end of this article