1995 ). In fact, gene expression pro-grams activated by cell-surface receptorsimpinging on Rho proteins rely on thenuclearintegrationofmechanismssensingcytoskeletal changes with activation of MAPK cascades ( Bar-Sagi and Hall, 2000;Posern and Treisman, 2006; Olson andNordheim, 2010 ). Thus, we can speculatethat if epithelial stem cells attach to theECM but are restricted from subsequentspreading by constraints imposed by thesurface geometry, only partial deploymentof the integrin-initiated signaling networkmayresult,andhenceleadtotheuncoordi-nated activation of Rho GTPases, MAPKs,andcytoskeletalcomponents.Thiscombi-nation of signals may result in the initiationof cell differentiation programs, causingcells to exit the cell cycle permanently andthus the stem cell pool. Althoughthe relevance ofthesemecha-nisms to in vivo stem cell maintenanceremains to be elucidated, it is known thatsignaling events that mediate the interac-tion between the basement membraneand the basal epidermal stem cells arerequired to maintain their stem-like state.For example, stem cells lacking the smallGTPase Rac1 fail to undergo shapechanges and migrate on the provisionalECM at the wound edge ( Castilho et al.,2010 ). In addition, the mutant cells differ-entiate and thus exit from the stem cellpool, resulting in defective wound closure( Castilhoetal.,2010 ).Wecanhypothesizethat the requirement for the integration of proliferative cues with mechanosensingpathways in order to communicate thecondition of the niche may serve as a fail-safe mechanism that triggers differenti-ating gene programs when stem cellssense aberrant biophysical conditions( Figure 1 ). The depletion of epithelial stemcells by promoting their differentiation inresponse to extrinsic or intrinsic cellularstress pathways may also act as a pro-tective mechanism against oncogenicperturbation of this particularly vulnerableself-renewing cell population ( Castilhoet al., 2009 ). Alternatively, this emergingtendencyofstemcellstoundergodifferen-tiation under stress conditions may alsocontribute to pathological events, such asacceleratedtissueagingorreducedtissueregeneration. On the other hand, failure toactivate differentiation pathways maycontribute to psoriasis and other skin hy-perproliferative conditions. Hence, themolecular dissection of the underlyingmechanisms that exist in the epidermalstemcellnichemayprovidenewmoleculartargetsfor pharmacologicalinterventioninmultiple diseases characterized by defec-tive stem cell differentiation, includingcancer, orby accelerated stem cell deple-tion, which leadsto loss of tissue regener-ative capacity and premature aging.
,227–238.Castilho, R.M., Squarize, C.H., Chodosh, L.A., Wil-liams, B.O., and Gutkind, J.S. (2009). Cell StemCell
, 279–289.Castilho, R.M., Squarize, C.H., Leelahavanichkul,K., Zheng, Y., Bugge, T., and Gutkind, J.S.(2010). PLoS ONE
, e10503.Connelly, J.T., Gautrot, J.E., Trappmann, B., Tan,D.W., Donati, G., Huck, W.T., and Watt, F.M.(2010). Nat. Cell Biol.
, 711–718.Coso, O.A., Chiariello, M., Yu, J.C., Teramoto, H.,Crespo, P., Xu, N., Miki, T., and Gutkind, J.S.(1995). Cell
, 1137–1146.Ezhkova, E., Pasolli, H.A., Parker, J.S., Stokes, N.,Su, I.H., Hannon, G., Tarakhovsky, A., and Fuchs,E. (2009). Cell
, 1122–1135.Geiger, B., Spatz, J.P., and Bershadsky, A.D.(2009). Nat. Rev. Mol. Cell Biol.
, 21–33.Olson, E.N., and Nordheim, A. (2010). Nat. Rev.Mol. Cell Biol.
, 353–365.Posern, G., and Treisman, R. (2006). Trends CellBiol.
, 588–596.Samuel, M.S., and Olson, M.F. (2010). Cell StemCell
, this issue, 135–136.
Differential DNA Damage Responsein Stem and Progenitor Cells
and Irving L. Weissman
Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
Harvard Stem Cell Institute, Boston, MA 02115, USA
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
Immune Disease Institute, Boston, MA 02115, USA
Program in Cellular and Molecular Medicine, Children’s Hospital Boston, Boston, MA 02115, USA *Correspondence:firstname.lastname@example.orgDOI 10.1016/j.stem.2010.07.006
Thelonglifespanoftissue-speciﬁcstemcellssuggeststhattheymayresponddifferentlytoDNAdamagethandownstream cells. In this issue of
Cell Stem Cell
Nearly 50 years after Till and McCullochdiscovered clonal myeloerythroid cellsin the pursuit of developing assays forhematopoietic cell radiation sensitivity( Till and McCulloch, 1961 ), the mecha-nisms and the meaning of hematopoieticstem cell (HSC) radiosensitivity arebeginning to be unraveled. In contrastto somatic cells that are frequently
Cell Stem Cell
, August 6, 2010
2010 Elsevier Inc.
Cell Stem Cell