Large-scale production of megakaryocytes from human pluripotent stem cells by chemically defined forward programming

Moreau, Thomas; Evans, Amanda; Vasquez, Louella; Tijssen, Marloes R.; Yan, Yan; Trotter, Matthew; Howard, Daniel J.; Colzani, Maria; Arumugam, Meera; Wu, Wing Han; Dalby, Amanda; Lampela, Riina; Bouet, Guénaëlle; Hobbs, Catherine M.; Pask, Dean C.; Payne, Holly; Ponomaryov, Tatyana; Brill, Alexander; Soranzo, Nicole; Ouwehand, Willem H.; Pedersen, Roger A.; Ghevaert, Cédric

doi:10.1038/ncomms11208

Cited by 204 publications

(271 citation statements)

References 67 publications

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“…More recently, the combinatorial expression of TAL1 with GATA2 was found to induce a haemogenic endothelial phenotype biased towards erythro-MK differentiation from hPSCs [237]. Proceeding from a methodically curated list of candidate genes, we found that the minimal combination of GATA1, FLI1 and TAL1 results in the highly efficient production of MKs from an array of hPSC lines in chemically-defined serum-free conditions and with minimum cytokine input [238]. None of these three TFs by itself or a combination of two could efficiently induce forward programming and impose MK identity to hPSCs.…”

Section: Mks and Platelets From Human Pluripotent Stem Cellsmentioning

confidence: 90%

Transcriptional Regulation of Platelet Formation: Harnessing the Complexity for Efficient Platelet Production In Vitro

Tijssen

Moreau

Ghevaert

2016

Molecular and Cellular Biology of Platelet Formation

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It is now common knowledge that specific repertoires of transcription factors (TFs) determine a cell's protein content and thereby its phenotype. The expression of a given TF is not necessarily cell specific, and many TFs play a pivotal role in several different cell types. For example, TAL1, FLI1, RUNX1, ERG and GATA2 are important regulators of stem cells, but also play a vital role in megakaryopoiesis. Although the megakaryocyte (MK) and its closest relative, the red blood cell, share key TFs like GATA1 and NFE2, the bifurcation between the two lineages has been associated with pairs of TFs that act as a toggle switch (such as FLI1 and KLF1). This chapter will summarise the current knowledge of key transcriptional regulators of MK differentiation and how some of these TFs, despite being expressed in several cell types, can impose MK cell identity. Since the discovery of TPO in 1994, our knowledge of MK biology and differentiation has increased exponentially, but we still lack a deep understanding of what triggers the transition from MK growth and maturation to proplatelet formation. We describe how some well-known TFs control the expression of proteins that play a pivotal role in the dramatic cytoplasmic and cytoskeletal events that accompany proplatelet formation. Finally, we show how TFs can be harnessed in a powerful way to produce MKs and, potentially, platelets in vitro for future clinical applications.

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Section: Mks and Platelets From Human Pluripotent Stem Cellsmentioning

confidence: 90%

Transcriptional Regulation of Platelet Formation: Harnessing the Complexity for Efficient Platelet Production In Vitro

Tijssen

Moreau

Ghevaert

2016

Molecular and Cellular Biology of Platelet Formation

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“…Moreau et al [65] described the generation of high yields of MKs by chemical forward programming (fop) of hPSCs based on the overexpression of GATA1, FLI1 and TAL1. FopMKs tolerated cryopreservation, and PLTs appeared to be functional as revealed by spreading on fibrinogen as well as in vivo thrombi formation.…”

Section: Pluripotent Stem Cellsmentioning

confidence: 99%

Towards the Manufacture of Megakaryocytes and Platelets for Clinical Application

Baigger¹,

Blasczyk²,

Figueiredo³

2017

Transfus Med Hemother

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Platelet transfusions are used in standard clinical practice to prevent hemorrhage in patients suffering from thrombocytopenia or platelet dysfunctions. Recently, a constant rise on the demand of platelets for transfusion has been registered. This may be associated with several factors including demographic changes, population aging as well as incidence and prevalence of hematological diseases. In addition, platelet-regenerative properties have been started to be exploited in different areas such as tissue remodeling and anti-cancer therapies. These new applications are also expected to increase the future demand on platelets. Thus, in vitro generated platelets may constitute a highly desirable alternative to meet the rising demand on platelets. Several factors have been considered in the road trip of producing in vitro megakaryocytes and platelets for clinical application. From selection of the cell source, differentiation protocols and culture conditions to the design of optimal bioreactors, several strategies have been proposed to maximize production yields while preserving functionality. This review summarizes new advances in megakaryocyte and platelet differentiation and their production upscaling.

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“…Alternatively, and although initial studies have used ibroblasts [61][62][63], UCB may be reprogrammed to induced pluripotent stem (iPS) cells [64], which can then be diferentiated into diferent cell lineages, e.g., to generate red blood cells and platelets. As these end cells lack nuclei, they may allay certain safety concerns with respect to iPS cells and tumorigenicity (provided that enucleated cells can survive transplantation).…”

Section: Other Uses Of Ucbmentioning

confidence: 99%

Umbilical Cord Blood Hematopoietic Stem and Progenitor Cell Expansion for Therapeutic Use

Watt¹,

Hua²

2017

Umbilical Cord Blood Banking for Clinical Application and Regenerative Medicine

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Hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for severe hematological malignancies and other severe disorders of the blood, immune system, and bone marrow. It is the most successful regenerative therapy to date, with 2013 marking the one millionth HSCT and the 25th anniversary of the irst umbilical cord blood (UCB) HSCT. UCB has most often been used for allogeneic HSCT when a matched bone marrow or peripheral blood donor is unavailable. Recently, novel genome editing technologies to correct inherited gene disorders or to modulate biomarkers/ receptors on HSC and the potential use of HSCT for a variety of other nonmalignant conditions have led to a surge of interest in autologous HSCT, with the HSC source depending on the condition to be treated. UCB HSCs may be used to generate red blood cells, granulocytes, or platelets ex vivo for transfusion into diicult-to-transfuse patients. Alternatively, UCB may be reprogrammed to induced pluripotent stem cells or used to generate cell lines, which can then be diferentiated into diferent cell lineages for transfusion or used as diagnostic reagents. Disadvantages of UCB are its restricted cell numbers and delayed hematological engraftment. Here, UCB HSC expansion/ manipulation ex vivo and clinical applications are addressed.

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Large-scale production of megakaryocytes from human pluripotent stem cells by chemically defined forward programming

Cited by 204 publications

References 67 publications

Transcriptional Regulation of Platelet Formation: Harnessing the Complexity for Efficient Platelet Production In Vitro

Transcriptional Regulation of Platelet Formation: Harnessing the Complexity for Efficient Platelet Production In Vitro

Towards the Manufacture of Megakaryocytes and Platelets for Clinical Application

Umbilical Cord Blood Hematopoietic Stem and Progenitor Cell Expansion for Therapeutic Use

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