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Published online June 11, 2007
doi:10.1083/jcb.200703003
The Journal of Cell Biology, Vol. 177, No. 6, 1037-1049
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Barbaro et al.
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Article

 C/EBP{delta} regulates cell cycle and self-renewal of human limbal stem cells

Vanessa Barbaro1, Anna Testa2, Enzo Di Iorio1, Fulvio Mavilio2, Graziella Pellegrini1,2, and Michele De Luca1,2

1 Epithelial Stem Cell Research Center, The Veneto Eye Bank Foundation, H. SS Giovanni and Paolo, 30100 Venice, Italy
2 Department of Biomedical Sciences, University of Modena and Reggio Emilia, 41100 Modena, Italy

Correspondence to Michele De Luca: michele.deluca{at}unimore.it

Human limbal stem cells produce transit amplifying progenitors that migrate centripetally to regenerate the corneal epithelium. Coexpression of CCAAT enhancer binding protein {delta} (C/EBP{delta}), Bmi1, and {Delta}Np63{alpha} identifies mitotically quiescent limbal stem cells, which generate holoclones in culture. Upon corneal injury, a fraction of these cells switches off C/EBP{delta} and Bmi1, proliferates, and differentiates into mature corneal cells. Forced expression of C/EBP{delta} inhibits the growth of limbal colonies and increases the cell cycle length of primary limbal cells through the activity of p27Kip1 and p57Kip2. These effects are reversible; do not alter the limbal cell proliferative capacity; and are not due to apoptosis, senescence, or differentiation. C/EBP{delta}, but not {Delta}Np63{alpha}, indefinitely promotes holoclone self-renewal and prevents clonal evolution, suggesting that self-renewal and proliferation are distinct, albeit related, processes in limbal stem cells. C/EBP{delta} is recruited to the chromatin of positively (p27Kip1 and p57Kip2) and negatively (p16INK4A and involucrin) regulated gene loci, suggesting a direct role of this transcription factor in determining limbal stem cell identity.

V. Barbaro, A. Testa, and E. Di Iorio contributed equally to this paper.

Abbreviations used in this paper: 4OHT, 4-hydroxytamoxifen; C/EBP, CCAAT enhancer binding protein; CFE, colony forming efficiency; ChIP, chromatin immunoprecipitation; ER, estrogen receptor; IRES, internal ribosomal entry site; NGFr, NGF receptor; PGK, phosphoglycerokinase; TA, transit amplifying.


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