Diabetologia

, Volume 57, Issue 4, pp 754–764

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

  • Jinming Li
  • Zhi C. Feng
  • Frances S.-H. Yeung
  • Melanie R.-M. Wong
  • Amanda Oakie
  • George F. Fellows
  • Cynthia G. Goodyer
  • David A. Hess
  • Rennian Wang
Article

DOI: 10.1007/s00125-013-3147-y

Cite this article as:
Li, J., Feng, Z.C., Yeung, F.S. et al. Diabetologia (2014) 57: 754. doi:10.1007/s00125-013-3147-y

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.

Keywords

Aldehyde dehydrogenase 1Human fetal pancreasPancreatic endocrine cell differentiationRetinoic acid signalling

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

Supplementary material

125_2013_3147_MOESM1_ESM.pdf (80 kb)
ESM Methods(PDF 80 kb)
125_2013_3147_MOESM2_ESM.pdf (16 mb)
ESM Fig. 1(PDF 16345 kb)
125_2013_3147_MOESM3_ESM.pdf (141 kb)
ESM Fig. 2(PDF 140 kb)
125_2013_3147_MOESM4_ESM.pdf (71 kb)
ESM Fig. 3(PDF 70 kb)
125_2013_3147_MOESM5_ESM.pdf (70 kb)
ESM Table 1(PDF 69 kb)
125_2013_3147_MOESM6_ESM.pdf (88 kb)
ESM Table 2(PDF 88 kb)
125_2013_3147_MOESM7_ESM.pdf (92 kb)
ESM Table 3(PDF 91 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Jinming Li
    • 1
    • 2
  • Zhi C. Feng
    • 1
    • 2
  • Frances S.-H. Yeung
    • 1
  • Melanie R.-M. Wong
    • 1
  • Amanda Oakie
    • 1
    • 2
  • George F. Fellows
    • 3
  • Cynthia G. Goodyer
    • 4
  • David A. Hess
    • 2
    • 5
  • Rennian Wang
    • 1
    • 2
    • 6
  1. 1.Children’s Health Research InstituteWestern UniversityLondonCanada
  2. 2.Department of Physiology & PharmacologyWestern UniversityLondonCanada
  3. 3.Department of Obstetrics and GynecologyWestern UniversityLondonCanada
  4. 4.Department of PediatricsMcGill UniversityMontrealCanada
  5. 5.Robarts Research InstituteWestern UniversityLondonCanada
  6. 6.Department of MedicineWestern UniversityLondonCanada