title: Distinct gene expression program dynamics during erythropoiesis from human induced pluripotent stem cells compared with adult and cord blood progenitors.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors: Radcliffe Department of Medicine, University of Oxford, Headington, Oxford, OX3 9DU, UK.|National Health Service Blood and Transplant, John Radcliffe Hospital, Headington, Oxford, OX3 9BQ, UK.
authors: Alison T
authors: AT
authors: Merryweather-Clarke
authors: Radcliffe Department of Medicine, University of Oxford, Headington, Oxford, OX3 9DU, UK.|National Health Service Blood and Transplant, John Radcliffe Hospital, Headington, Oxford, OX3 9BQ, UK.
authors: Alex J
authors: AJ
authors: Tipping
authors: Radcliffe Department of Medicine, University of Oxford, Headington, Oxford, OX3 9DU, UK. abigail.lamikanra@ndcls.ox.ac.uk.|National Health Service Blood and Transplant, John Radcliffe Hospital, Headington, Oxford, OX3 9BQ, UK. abigail.lamikanra@ndcls.ox.ac.uk.
authors: Abigail A
authors: AA
authors: Lamikanra
authors: Department of Electronic and Computer Engineering, Brunel University London, Middlesex, UB8 3PH, UK.
authors: Rui
authors: R
authors: Fa
authors: Department of Electronic and Computer Engineering, Brunel University London, Middlesex, UB8 3PH, UK.
authors: Basel
authors: B
authors: Abu-Jamous
authors: Radcliffe Department of Medicine, University of Oxford, Headington, Oxford, OX3 9DU, UK.|National Health Service Blood and Transplant, John Radcliffe Hospital, Headington, Oxford, OX3 9BQ, UK.
authors: Hoi Pat
authors: HP
authors: Tsang
authors: Radcliffe Department of Medicine, University of Oxford, Headington, Oxford, OX3 9DU, UK.|National Health Service Blood and Transplant, John Radcliffe Hospital, Headington, Oxford, OX3 9BQ, UK.
authors: Lee
authors: L
authors: Carpenter
authors: MRC Weatherall Institute of Molecular Medicine, University of Oxford, Headington, OX3 9DU, Oxford, UK.
authors: Kathryn J H
authors: KJ
authors: Robson
authors: Department of Electronic and Computer Engineering, Brunel University London, Middlesex, UB8 3PH, UK.|Distinguished Visiting Professor, The Key Laboratory of Embedded Systems and Service Computing, College of Electronic and Information Engineering, Tongji University, Shanghai, People's Republic of China.
authors: Asoke K
authors: AK
authors: Nandi
authors: Radcliffe Department of Medicine, University of Oxford, Headington, Oxford, OX3 9DU, UK. david.roberts@ndcls.ox.ac.uk.|National Health Service Blood and Transplant, John Radcliffe Hospital, Headington, Oxford, OX3 9BQ, UK. david.roberts@ndcls.ox.ac.uk.
authors: David J
authors: DJ
authors: Roberts
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D016000:Cluster Analysis; D004900:Erythroblasts / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis / Q000235:genetics*; D005312:Fetal Blood / Q000166:cytology*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D059467:Transcriptome
keywords: Erythropoiesis; SMART and Bi-CoPaM; Transcriptome; hiPSC