期刊
CELL CYCLE
卷 14, 期 8, 页码 1197-1206出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15384101.2015.1013667
关键词
corneal endothelium; contact inhibition; E2F2; JAK1; LIF; proliferation; p16(INK4a); STAT3
类别
资金
- National Eye Institute, National Institutes of Health [R43 EY 022502-01, R44 EY 022502-02]
- TissueTech, Miami, FL
Human corneal endothelial cells (HCECs) responsible for corneal transparency have limited proliferative capacity in vivo because of contact-inhibition. This feature has hampered the ability to engineer HCECs for transplantation. Previously we have reported an in vitro model of HCECs in which contact inhibition was re-established at Day 21, even though cell junction and cell matrix interaction were not perturbed during isolation. Herein, we observe that such HCEC monolayers continue to expand and retain a normal phenotype for 2 more weeks if cultured in a leukemia inhibitory factor (LIF)-containing serum-free medium. Such expansion is accompanied initially by upregulation of Cyclin E2 colocalized with nuclear translocation of phosphorylated retinoblastoma tumor suppressor (p-Rb) at Day 21 followed by a delay in contact inhibition through activation of LIF-Janus kinase1 (JAK1)-signal transducer and activator of transcription 3 (STAT3) signaling at Day 35. The LIF-JAK1-STAT3 signaling is coupled with upregulation of E2F2 colocalized with nuclear p-Rb and with concomitant downregulation of p16(INK4a), of which upregulation is linked to senescence. Hence, activation of LIF-JAK1-STAT3 signaling to delay contact inhibition can be used as another strategy to facilitate engineering of HCEC grafts to solve the unmet global shortage of corneal grafts.
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