Red blood cell generation from human induced pluripotent stem cells: perspectives for transfusion medicine

Lapillonne, Hélène; Kobari, Ladan; Mazurier, Christelle; Tropel, Philippe; Giarratana, Marie‐Catherine; Zanella-Cléon, Isabelle; Kiger, Laurent; Wattenhofer‐Donzé, Marie; Puccio, Hélène; Hebert, Nicolas; Francina, Alain; Andreu, G.; Viville, Stéphane; Douay, Luc

doi:10.3324/haematol.2010.023556

Cited by 211 publications

(271 citation statements)

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“…6,13,14 Our previous studies have demonstrated the possibility of generating enucleated erythrocytes containing functional fetal hemoglobin (HbF) from normal hiPSC. 5,15 We now report for the first time in a normal and a pathological erythropoietic differentiation models that hiPSC are intrinsically able to mature into adult hemoglobin synthesizing cells.…”

Section: Introductionmentioning

confidence: 99%

“…cells which can indefinitely self-renew in vitro while maintaining their ability to differentiate into cells of all three germ layers. This technology provides a powerful new tool to investigate tissue differentiation [3][4][5][6][7][8] and to model genetic diseases in order to explore their physiopathology, providing new concepts of treatment. 9,10 It also opens the way to the production of patient-specific cells for cell therapy.…”

Section: Introductionmentioning

confidence: 99%

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Human induced pluripotent stem cells can reach complete terminal maturation: in vivo and in vitro evidence in the erythropoietic differentiation model

et al. 2012

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The online version of this article has a Supplementary Appendix. BackgroundHuman induced pluripotent stem cells offer perspectives for cell therapy and research models for diseases. We applied this approach to the normal and pathological erythroid differentiation model by establishing induced pluripotent stem cells from normal and homozygous sickle cell disease donors. Design and MethodsWe addressed the question as to whether these cells can reach complete erythroid terminal maturation notably with a complete switch from fetal to adult hemoglobin. Sickle cell disease induced pluripotent stem cells were differentiated in vitro into red blood cells and characterized for their terminal maturation in terms of hemoglobin content, oxygen transport capacity, deformability, sickling and adherence. Nucleated erythroblast populations generated from normal and pathological induced pluripotent stem cells were then injected into non-obese diabetic severe combined immunodeficiency mice to follow the in vivo hemoglobin maturation. ResultsWe observed that in vitro erythroid differentiation results in predominance of fetal hemoglobin which rescues the functionality of red blood cells in the pathological model of sickle cell disease. We observed, in vivo, the switch from fetal to adult hemoglobin after infusion of nucleated erythroid precursors derived from either normal or pathological induced pluripotent stem cells into mice. ConclusionsThese results demonstrate that human induced pluripotent stem cells: i) can achieve complete terminal erythroid maturation, in vitro in terms of nucleus expulsion and in vivo in terms of hemoglobin maturation; and ii) open the way to generation of functionally corrected red blood cells from sickle cell disease induced pluripotent stem cells, without any genetic modification or drug treatment. ABSTRACT© F e r r a t a S t o r t i F o u n d a t i o n

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human induced pluripotent stem cells can reach complete terminal maturation: in vivo and in vitro evidence in the erythropoietic differentiation model

et al. 2012

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“…Both human embryonic stem cells [27] and, more recently, pluripotent stem lines (derived from human fetal cells and adult fibroblasts) [28] are being investigated as potential sources.…”

Section: Production Of Blood and Platelets From Hsc Lines: A Replacemmentioning

confidence: 99%

Concise Review: Expanding Roles for Hematopoietic Cellular Therapy and the Blood Transfusion Services

Hodby

Pamphilon

2011

Stem Cells

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Hematopoietic stem cells (HSCs) have remained at the forefront of stem cell research for the past 50 years, since the therapeutic potential of bone marrow transplantation was realized. Uniquely, among stem and progenitor cells, research progress has been made in parallel between the laboratory benchtop and hospital bedside during this period. Integral to this work has been the role of the transfusion medicine services in the collection, storage, and processing of HSCs. The next decade promises to bring further developments: with new fields of cellular therapies, stem cell vaccination, and stem cell drug testing opening up. This article summarizes exciting areas of research concerning the behavior and potential clinical applications of HSCs. For the purposes of clarity, we describe in turn the trafficking and transfer of HSCs; ex vivo expansion of HSC units from different sources; and finally, applications of specifically selected subsets of hematopoietic cells and their progeny.

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“…17 The demonstration that ex-vivo expanded red cells protect mice from lethal bleeding 14 has suggested that red cells generated ex-vivo from induced pluripotent cells may represent alternative products for autologous transfusion in humans. 15 The data from Ji et al 11 however, indicate that erythrocytes expanded from HDAC inhibitor-treated induced pluripotent cells may not be suitable for transfusion because they may fail to enucleate.…”

Section: Recent Advances In Translational Research On Histone Deacetymentioning

confidence: 99%

Erythroblast enucleation

Migliaccio¹

2010

Haematologica

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E rythrocytes, commonly called red cells, are the cellular elements of blood that perform the unique function of ensuring proper oxygen delivery to the tissues. 1 The average blood volume for an adult is 5 liters (55-75 mL/Kg of body weight) and the blood contains approximately 10 9 red cells per milliliter. Red cells do not normally contain a nucleus and are unable to proliferate. They have a limited life-span (~120 days in humans) and are replenished by the constant generation of new cells from hematopoietic stem/progenitor cell compartments. The process of erythropoiesis includes two phases: a first commitment/proliferation phase in which stem/progenitor cells are induced by extrinsic (growth factors) and intrinsic (transcription factors) factors to expand and to activate the differentiation programs and a second maturation phase in which the first morphologically recognizable erythroid cell (the pro-erythroblast) becomes unable to proliferate and undergoes cytoplasmic and nuclear alterations. Cytoplasmic maturation includes loss of mitochondria, reduction of ribosome numbers and reorganization of the microfilament structure and is mediated by the autophagic program, a proteosome-dependent pathway of proteolysis developed by eukaryotic cells to survive starvation (but which may lead to death).2 Nuclear changes involve chromosome condensation and loss of cytoplasmic-nuclear junctions in preparation for enucleation and may represent an extreme case of asymmetric division (Figure 1). The enucleation processThe earliest recognizable erythroid cell, the pro-erythroblast, undergoes four or five mitotic divisions which generate, in sequence, basophilic, polychromatophilic and orthochromatic erythroblasts ( Figure 2A). The morphological differences between these cells reflect progressive accumulation of hemoglobin (and other erythroid-specific proteins) and decrease in nuclear size and activity.1 The nucleus becomes dense, because of chromosome condensation, is isolated from the cytoplasm by a ring of cytoplasmic membranes and moves to one side of the cell. 3 The orthochromatic erythroblast is then partitioned into two daughter structures, the reticulocyte, containing most of the cytoplasm, and the pyrenocyte, containing the condensed nucleus encased in a thin cytoplasmic layer. This partitioning is called nuclear extrusion or enucleation and is favored by interaction between the erythroblasts and the macrophage within the erythroid niche, an anatomical structure first identified by Bessis in 1958 4 (Figure 1). Since most of the pyrenocytes are engulfed and degraded by the macrophage, 3 their recognition as bona fide cells occurred when they were discovered in the blood of embryos (which contains limited numbers of macrophages) where they are released during the enucleation process of primitive mammalian erythroblasts. 5Enucleated erythrocytes are present in the blood of all mammals, suggesting that enucleation provides an evolutionary advantage. Studies in lower eukaryotes (budding yeast and Drosophila) are clarifyi...

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Red blood cell generation from human induced pluripotent stem cells: perspectives for transfusion medicine

Cited by 211 publications

References 24 publications

Human induced pluripotent stem cells can reach complete terminal maturation: in vivo and in vitro evidence in the erythropoietic differentiation model

Human induced pluripotent stem cells can reach complete terminal maturation: in vivo and in vitro evidence in the erythropoietic differentiation model

Concise Review: Expanding Roles for Hematopoietic Cellular Therapy and the Blood Transfusion Services

Erythroblast enucleation

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