Redifferentiation of adult human β cells expanded in vitro by inhibition of the WNT pathway

Ayelet Lenz*, Ginat Toren-Haritan, Shimon Efrat

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


In vitro expansion of adult human islet b cells is an attractive solution for the shortage of tissue for cell replacement therapy of type 1 diabetes. Using a lineage tracing approach we have demonstrated that β-cell-derived (BCD) cells rapidly dedifferentiate in culture and can proliferate for up to 16 population doublings. Dedifferentiation is associated with changes resembling epithelial-mesenchymal transition (EMT). The WNT pathway has been shown to induce EMT and plays key roles in regulating replication and differentiation in many cell types. Here we show that BCD cell dedifferentiation is associated with β-catenin translocation into the nucleus and activation of the WNT pathway. Inhibition of β-catenin expression in expanded BCD cells using short hairpin RNA resulted in growth arrest, mesenchymal-epithelial transition, and redifferentiation, as judged by activation of β-cell gene expression. Furthermore, inhibition of β-catenin expression synergized with redifferentiation induced by a combination of soluble factors, as judged by an increase in the number of Cpeptide- positive cells. Simultaneous inhibition of the WNT and NOTCH pathways also resulted in a synergistic effect on redifferentiation. These findings, which were reproducible in cells derived from multiple human donors, suggest that inhibition of the WNT pathway may contribute to a therapeutically applicable way for generation of functional insulinproducing cells following ex-vivo expansion.

Original languageEnglish
Article numbere112914
JournalPLoS ONE
Issue number11
StatePublished - 13 Nov 2014


FundersFunder number
Israel Science Foundation244/09
Juvenile Diabetes Research Foundation United States of America31-2008-413


    Dive into the research topics of 'Redifferentiation of adult human β cells expanded in vitro by inhibition of the WNT pathway'. Together they form a unique fingerprint.

    Cite this