Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment.
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.
McBeath
Rowena
R
The Cellular and Molecular Medicine Program, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Pirone
Dana M
DM
Nelson
Celeste M
CM
Bhadriraju
Kiran
K
Chen
Christopher S
CS
D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism; D017667:Adipocytes / Q000201:enzymology / Q000648:ultrastructure; D002450:Cell Communication / Q000235:genetics; D002452:Cell Count; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics*; D048429:Cell Size / Q000235:genetics; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008648:Mesoderm / Q000201:enzymology / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D009218:Myosins / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000201:enzymology / Q000648:ultrastructure; D010012:Osteogenesis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism* / Q000648:ultrastructure; D013314:Stress, Mechanical; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000172:deficiency* / Q000235:genetics
D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D009218:Myosins; D020742:rhoA GTP-Binding Protein