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

Abstract

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.

AHR:IKAROS Interaction Promotes Platelet Biogenesis in Response to SR1

“…The observation that CD34 + CD41 low cells harbor signs of an immature state, illustrated by low demarcation membrane system amplification and ploidy, raised the hypothesis of MK differentiation inhibition at a transcriptional level through SR1-modulated AHR. A number of hematopoietic TFs have been identified to promote or favor MK progenitor specification, MK maturation and platelet formation, including GATA-1, Friend of GATA-1 (FOG-1, ZFPM1), Fli-1, RUNX-1 and NF-E2 [7]. These TFs have also been described to promote the expression of megakaryocytic receptors [3][4][5].…”