Definitive Erythropoiesis from Pluripotent Stem Cells: Recent Advances and Perspectives

  • Selami Demirci
  • John F. Tisdale
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1107)


Derivation of functional and mature red blood cells (RBCs) with adult globin expression from renewable source such as induced pluripotent stem cells (iPSCs) is of importance from the clinical point of view. Definitive RBC generation can only be succeeded through production of true hematopoietic stem cells (HSCs). There has been a great effort to obtain definitive engraftable HSCs from iPSCs but the results were mostly unsatisfactory due to low, short-term and linage-biased engraftment in mouse models. Moreover, ex vivo differentiation approaches ended up with RBCs with mostly embryonic and fetal globin expression. To establish reliable, standardized and effective laboratory protocols, we need to expand our knowledge about developmental hematopoiesis/erythropoiesis and identify critical regulatory signaling pathways and transcription factors. Once we meet these challenges, we could establish differentiation protocols for massive RBC production for transfusion purposes in the clinical setting, performing drug screening and disease modeling in ex vivo conditions, and investigating the embryological cascade of erythropoiesis. More interestingly, with the introduction of relatively efficient and facile genome editing tools, genetic correction for inherited RBC disorders such as sickle cell disease (SCD) would become possible through iPSCs that can subsequently generate definitive HSCs, which then give rise to definitive RBCs producing β-globin after transplantation.


Embryonic stem cells Erythrocytes Hemogenic endothelium β-Globin 





Bone morphogenetic proteins


Bone marrow transplantation


Embryoid bodies


Endothelial-to-hematopoietic transition


Erythromyeloid progenitors


Definitive erythrocytes


Primitive erythrocytes


Embryonic stem cells


Fibroblast growth factor 2


Fms-like tyrosine kinase 3


Human leukocyte antigen


Hematopoietic stem cells




Induced pluripotent stem cells


Red blood cells


Sickle cell disease


Stem cell factor




Vascular endothelial growth factor


Conflicts of Interest

The authors have no commercial, proprietary, or financial interest in the products described in this article.


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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Molecular and Clinical Hematology BranchNational Heart Lung and Blood Institutes (NHLBI)BethesdaUSA

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