Redifferentiation of expanded human islet β cells by inhibition of ARX

Orr Friedman-Mazursky, Ran Elkon, Shimon Efrat*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Ex-vivo expansion of adult human islet β cells has been evaluated for generation of abundant insulin-producing cells for transplantation; however, lineage-tracing has demonstrated that this process results in β-cell dedifferentiation. Redifferentiation of β-cell-derived (BCD) cells can be achieved using a combination of soluble factors termed Redifferentiation Cocktail (RC); however, this treatment leads to redifferentiation of only a fraction of BCD cells. This study aimed at improving redifferentiation efficiency by affecting the balance of islet progenitor-cell transcription factors activated by RC treatment. Specifically, RC treatment induces the transcription factors PAX4 and ARX, which play key roles in directing pancreas endocrine progenitor cells into the β/δ or α/PP developmental pathways, respectively. Misactivation of ARX in RC-treated BCD cells may inhibit their redifferentiation into β cells. Blocking ARX expression by shRNA elevated insulin mRNA levels 12.8-fold, and more than doubled the number of insulin-positive BCD cells. ARX inhibition in expanded α-cell-derived cells treated with RC did not cause their transdifferentiation into insulin-producing cells. The combination of RC and ARX shRNA treatment may facilitate the generation of abundant insulin-producing cells for transplantation into patients with type 1 diabetes.

Original languageEnglish
Article number20698
JournalScientific Reports
Volume6
DOIs
StatePublished - 9 Feb 2016

Funding

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

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