Commitment of stem cells to different lineages is regulated by many cues in the local
tissue microenvironment. Here we demonstrate that cell shape regulates commitment
of human mesenchymal stem cells (hMSCs) to adipocyte or osteoblast fate. hMSCs allowed
to adhere, flatten, and spread underwent osteogenesis, while unspread, round cells
became adipocytes. Cell shape regulated the switch in lineage commitment by modulating
endogenous RhoA activity. Expressing dominant-negative RhoA committed hMSCs to become
adipocytes, while constitutively active RhoA caused osteogenesis. However, the RhoA-mediated
adipogenesis or osteogenesis was conditional on a round or spread shape, respectively,
while constitutive activation of the RhoA effector, ROCK, induced osteogenesis independent
of cell shape. This RhoA-ROCK commitment signal required actin-myosin-generated tension.
These studies demonstrate that mechanical cues experienced in developmental and adult
contexts, embodied by cell shape, cytoskeletal tension, and RhoA signaling, are integral
to the commitment of stem cell fate.