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Aldehyde dehydrogenase 1 activity in the developing human pancreas modulates retinoic acid signalling in mediating islet differentiation and survival

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Abstract

Aims/hypothesis

Aldehyde dehydrogenase 1 (ALDH1), a human stem-cell marker, is an enzyme responsible for converting retinaldehydes to retinoic acids (RAs) to modulate cell differentiation. However, data on expression levels and functional roles of ALDH1 during human fetal pancreatic development are limited. The focus of this study was to characterise ALDH1 expression patterns and to determine its functional role in islet cell differentiation.

Methods

The presence of ALDH1 in the human fetal pancreas (8–22 weeks) was characterised by microarray, quantitative RT-PCR, western blotting and immunohistological approaches. Isolated human fetal islet-epithelial cell clusters were treated with ALDH1 inhibitors, retinoic acid receptor (RAR) agonists and ALDH1A1 small interfering (si)RNA.

Results

In the developing human pancreatic cells, high ALDH1 activity frequently co-localised with key stem-cell markers as well as endocrine transcription factors. A high level of ALDH1 was expressed in newly differentiated insulin+ cells and this decreased as development progressed. Pharmacological inhibition of ALDH1 activity in human fetal islet-epithelial cell clusters resulted in reduced endocrine cell differentiation and increased cell apoptosis, and was reversed with co-treatment of RAR/RXR agonists. Furthermore, siRNA knockdown of ALDH1A1 significantly decreased RAR expression and induced cell apoptosis via suppression of the phosphoinositide 3-kinase (PI3K) pathway and activation of caspase signals.

Conclusions/interpretation

Our findings indicate that ALDH1+ cells represent a pool of endocrine precursors in the developing human pancreas and that ALDH1 activity is required during endocrine cell differentiation. Inhibition of ALDH1-mediated retinoid signalling impairs human fetal islet cell differentiation and survival.

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Abbreviations

ALDH:

Aldehyde dehydrogenase

ATRA:

All-trans retinoic acid

CDA:

Canadian Diabetes Association

cRNA:

Complementary RNA

DEAB:

Diethylaminobenzaldehyde

NGN3:

Neurogenin 3

NKX2.2:

NK2 homeobox 2

NKX6.1:

NK6 homeobox 1

PAX6:

Paired box 6

PDX1:

Pancreatic and duodenal homeobox 1

PI3K:

Phosphoinositide 3-kinase

RA:

Retinoic acid

RAR:

Retinoic acid receptor

RXR:

Retinoid X receptor

si:

small interfering

TTNPB:

4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl] benzoic acid

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Funding

This work was supported by grants from the Canadian Diabetes Association (CDA). ZCF is a recipient of a CDA Doctoral Student Research Award. DAH is supported by a Heart and Stroke Foundation of Canada New Investigator Salary Award.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

JL, ZCF, FS-HY and MR-MW contributed to the acquisition of data and manuscript drafting. JL, ZCF, AO, GFF, CGG, DAH and RW contributed to data analysis and interpretation. AO, GFF, CGG, DAH and RW also contributed to manuscript drafting. GFF provided study materials. RW contributed to the conception and design of the study. All authors gave final approval of the manuscript version to be published.

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Authors and Affiliations

  1. Children’s Health Research Institute, Western University, 800 Commissioners Road East, London, ON, Canada, N6C 2V5

    Jinming Li, Zhi C. Feng, Frances S.-H. Yeung, Melanie R.-M. Wong, Amanda Oakie & Rennian Wang

  2. Department of Physiology & Pharmacology, Western University, London, ON, Canada

    Jinming Li, Zhi C. Feng, Amanda Oakie, David A. Hess & Rennian Wang

  3. Department of Obstetrics and Gynecology, Western University, London, ON, Canada

    George F. Fellows

  4. Department of Pediatrics, McGill University, Montreal, QC, Canada

    Cynthia G. Goodyer

  5. Robarts Research Institute, Western University, London, ON, Canada

    David A. Hess

  6. Department of Medicine, Western University, London, ON, Canada

    Rennian Wang

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  1. Jinming Li
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  2. Zhi C. Feng
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Correspondence to Rennian Wang.

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Li, J., Feng, Z.C., Yeung, F.SH. et al. Aldehyde dehydrogenase 1 activity in the developing human pancreas modulates retinoic acid signalling in mediating islet differentiation and survival. Diabetologia 57, 754–764 (2014). https://doi.org/10.1007/s00125-013-3147-y

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  • DOI: https://doi.org/10.1007/s00125-013-3147-y

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