Single-cell level analysis of megakaryocyte growth and development

Leysi-Derilou, Younes; Duchesne, Carl; Garnier, Alain; Pineault, Nicolas

doi:10.1016/j.diff.2011.12.003

Cited by 18 publications

(21 citation statements)

References 34 publications

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“…Although endomitosis and polyploidization are undoubtedly important for MK cytoplasmic maturation, the relationship between high nuclear DNA content and efficient platelet formation is still highly debated. For example, nicotinamide, a form of vitamin B3, is commonly used to increase the ploidy of human and mouse MKs in culture (Giammona et al, 2006; Panuganti et al, 2010; Avanzi et al, 2012; Leysi-Derilou et al, 2012). Although nicotinamide does increase ploidy, its effect on platelet formation is controversial.…”

Section: Mk Maturation and Developmentmentioning

confidence: 99%

The incredible journey: From megakaryocyte development to platelet formation

Machlus

Italiano

2013

Journal of Cell Biology

661

448

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Circulating blood platelets are specialized cells that prevent bleeding and minimize blood vessel injury. Large progenitor cells in the bone marrow called megakaryocytes (MKs) are the source of platelets. MKs release platelets through a series of fascinating cell biological events. During maturation, they become polyploid and accumulate massive amounts of protein and membrane. Then, in a cytoskeletal-driven process, they extend long branching processes, designated proplatelets, into sinusoidal blood vessels where they undergo fission to release platelets. Given the need for platelets in many pathological situations, understanding how this process occurs is an active area of research with important clinical applications.

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Section: Mk Maturation and Developmentmentioning

confidence: 99%

The incredible journey: From megakaryocyte development to platelet formation

Machlus

Italiano

2013

Journal of Cell Biology

661

448

View full text Add to dashboard Cite

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“…MK cells are unique in that they dramatically increase their DNA content and volume by undergoing multiple rounds of endomitosis (DNA replication without cell division) to become polyploid (>4N) cells. Treatment of MK progenitor cells with nicotinamide (NIC) dramatically increases MK polyploidization in ex vivo cultures (Giammona et al, 2006, 2009; Leysi-Derilou et al, 2012), which is due, in part, to inhibition of sirtuin deacetylases (SIRTs). Nevertheless, the mechanism of NIC action remains unclear (Giammona et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Dynamic transcription factor activity profiles reveal key regulatory interactions during megakaryocytic and erythroid differentiation

Duncan

Shin²,

Wu³

et al. 2014

Biotech & Bioengineering

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The directed differentiation toward erythroid (E) or megakaryocytic (MK) lineages by the MK-E progenitor (MEP) could enhance the ex vivo generation of red blood cells and platelets for therapeutic transfusions. The lineage choice at the MEP bifurcation is controlled in large part by activity within the intracellular signal transduction network, the output of which determines the activity of transcription factors (TFs) and ultimately gene expression. Although many TFs have been implicated, E or MK differentiation is a complex process requiring multiple days, and the dynamics of TF activities during commitment and terminal maturation are relatively unexplored. Herein, we applied a living cell array for the large-scale, dynamic quantification of TF activities during MEP bifurcation. A panel of hematopoietic TFs (GATA-1, GATA-2, SCL/TAL1, FLI-1, NF-E2, PU.1, c-Myb) was characterized during E and MK differentiation of bipotent K562 cells. Dynamic TF activity profiles associated with differentiation towards each lineage were identified, and validated with previous reports. From these activity profiles, we show that GATA-1 is an important hub during early hemin- and PMA-induced differentiation, and reveal several characteristic TF interactions for E and MK differentiation that confirm regulatory mechanisms documented in the literature. Additionally, we highlight several novel TF interactions at various stages of E and MK differentiation. Furthermore, we investigated the mechanism by which nicotinamide (NIC) promoted terminal MK maturation using an MK-committed cell line, CHRF-288-11 (CHRF). Concomitant with its enhancement of ploidy, NIC strongly enhanced the activity of three TFs with known involvement in terminal MK maturation: FLI-1, NF-E2, and p53. Dynamic profiling of TF activity represents a novel tool to complement traditional assays focused on mRNA and protein expression levels to understand progenitor cell differentiation.

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“…Both in vivo and in culture 2N or 4N MKs form proplatelets [48][49][50], and platelet numbers are similar in mouse backgrounds with different levels of BM MK polyploidy [51]. Therefore, although some cytoskeletal (TUBB1, MYH9, RAC1, RAP1B), transmembrane (GPIIIA, GP1BA and B) and signalling proteins (LAT and SRC family kinases) known to be involved in proplatelet formation are slightly more abundant in high-ploidy MKs, this appears not to affect platelet shedding.…”

Section: Mk Dna Content: Does Ploidy Really Matter?mentioning

confidence: 99%

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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Single-cell level analysis of megakaryocyte growth and development

Cited by 18 publications

References 34 publications

The incredible journey: From megakaryocyte development to platelet formation

The incredible journey: From megakaryocyte development to platelet formation

Dynamic transcription factor activity profiles reveal key regulatory interactions during megakaryocytic and erythroid differentiation

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

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