Distinct gene expression program dynamics during erythropoiesis from human induced pluripotent stem cells compared with adult and cord blood progenitors

Alison T. Merryweather-Clarke, Alex J. Tipping, Abigail A. Lamikanra*, Rui Fa, Basel Abu-Jamous, Hoi Pat Tsang, Lee Carpenter, Kathryn J.H. Robson, Asoke K. Nandi, David J. Roberts

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

Background: Human-induced pluripotent stem cells (hiPSCs) are a potentially invaluable resource for regenerative medicine, including the in vitro manufacture of blood products. HiPSC-derived red blood cells are an attractive therapeutic option in hematology, yet exhibit unexplained proliferation and enucleation defects that presently preclude such applications. We hypothesised that substantial differential regulation of gene expression during erythroid development accounts for these important differences between hiPSC-derived cells and those from adult or cord-blood progenitors. We thus cultured erythroblasts from each source for transcriptomic analysis to investigate differential gene expression underlying these functional defects. Results: Our high resolution transcriptional view of definitive erythropoiesis captures the regulation of genes relevant to cell-cycle control and confers statistical power to deploy novel bioinformatics methods. Whilst the dynamics of erythroid program elaboration from adult and cord blood progenitors were very similar, the emerging erythroid transcriptome in hiPSCs revealed radically different program elaboration compared to adult and cord blood cells. We explored the function of differentially expressed genes in hiPSC-specific clusters defined by our novel tunable clustering algorithms (SMART and Bi-CoPaM). HiPSCs show reduced expression of c-KIT and key erythroid transcription factors SOX6, MYB and BCL11A, strong HBZ-induction, and aberrant expression of genes involved in protein degradation, lysosomal clearance and cell-cycle regulation. Conclusions: Together, these data suggest that hiPSC-derived cells may be specified to a primitive erythroid fate, and implies that definitive specification may more accurately reflect adult development. We have therefore identified, for the first time, distinct gene expression dynamics during erythroblast differentiation from hiPSCs which may cause reduced proliferation and enucleation of hiPSC-derived erythroid cells. The data suggest several mechanistic defects which may partially explain the observed aberrant erythroid differentiation from hiPSCs.

Original languageEnglish
Article number817
JournalBMC Genomics
Volume17
Issue number1
DOIs
Publication statusPublished - 21 Oct 2016
Externally publishedYes

Bibliographical note

Funding Information:
We thank Isabel Diez-Sevilla, Phillip Morgan and Alexander Portus for technical assistance; Kevin Clark and Paul Sopp for performing FACsorts. The project (Ref. NIHR-RP-PG-0310-1004) is supported by National Institute for Health Research (NIHR), UK and research in NHSBT Oxford is also supported by research funding from NHS Blood and Transplant (UK). This work was also partly supported by the National Science Foundation of China grant number 61520106006. Funding for open access charge: NIHR.

Publisher Copyright:
© 2016 The Author(s).

Keywords

  • Erythropoiesis
  • HiPSC
  • SMART and Bi-CoPaM
  • Transcriptome

Fingerprint

Dive into the research topics of 'Distinct gene expression program dynamics during erythropoiesis from human induced pluripotent stem cells compared with adult and cord blood progenitors'. Together they form a unique fingerprint.

Cite this