Abstract

Platelets, the tiny anucleate cells responsible for stopping bleeding through thrombosis, are derived from hematopoietic stem cells through a series of differentiation steps. Thrombocytopenia, characterized by abnormally low blood platelet counts, may arise from cancer therapies, trauma, sepsis, as well as blood disorders, and could become a life-threatening problem. Platelet transfusion is the most effective strategy to treat thrombocytopenia, however, the source of platelets is in great shortage. Therefore, in vitro generation of platelets has become an important topic and numerous attempts have been made toward generating platelets from different types of cells, including hematopoietic stem cells, pluripotent stem cells, fibroblast cells, and adipose-derived cells. In this review, we will detail the efforts made to produce, in the in vitro culture, platelets from these different cell types. Importantly, as transfusion medicine requires a huge number of platelets, we will highlight some studies on producing platelets on a large scale. Although new methods of gene manipulation, new culture conditions, new cytokines and chemical compounds have been introduced in platelet generation research since the first study of hematopoietic stem cell-derived platelets nearly 30 years ago, limited success has been achieved in obtaining truly mature and functional platelets in vitro, indicating the studies of platelets fall behind those of other blood cell types. This is possibly because megakaryocytes, which produce platelets, are very rare in blood and marrow. We have previously developed a platform to identify new extrinsic and intronic regulators for megakaryocytic lineage development, and in this review, we will also cover our effort on that. In summary, stem cell-based differentiation is a promising way of generating large-scale platelets to meet clinical needs, and continuous study of the cellular development of platelets will greatly facilitate this.

Highlights

  • Platelets, small and anucleate cells in the blood, are multifunctional and implicated in many pathophysiological processes, including hemostasis, thrombosis, vessel constriction and repair, and inflammations during host defense and tumor growth/metastasis (Harrison, 2005)

  • There is no detailed analysis of the production of each progenitor population (CMPs, EPs, and megakaryocyte progenitors (MkPs)) during the differentiation process, which led to the incomplete establishment of the differentiation path from Hematopoietic stem cells (HSCs) to platelets

  • We found inhibition of histone deacetylase (HDAC) activity could promote the differentiation of HSCs into MkPs and platelets, possibly through regulating some of the 9 newly identified transcription factors (TFs): gene expression analysis showed GSX2, MXD3, HOXC6, and HES7 were significantly up-regulated while PCGF2, FOXB1, and MZF1 were moderately up-regulated after HDAC inhibition

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Summary

INTRODUCTION

Small and anucleate cells in the blood, are multifunctional and implicated in many pathophysiological processes, including hemostasis, thrombosis, vessel constriction and repair, and inflammations during host defense and tumor growth/metastasis (Harrison, 2005). The ability to regenerate platelets in vitro would address the urgent and unmet needs of platelet supply in clinics and provide a promising way to solve the life-threatening bleeding problem in different diseases These methods have significant advantages over the current donor-dependent program, in terms of variations between donors, number of cells that could be obtained, risk of bacteria and virus contamination, cell viability, and storage, etc. They tested the functions of megakaryocyte growth and development factor (MGDF, commonly known as thrombopoietin, TPO), the ligand for Mpl, either alone or in various combinations with stem cell factor (SCF), interleukin-3 (IL-3), and IL-6 They found both TPO alone and its combination with these three cytokines accelerated MK differentiation, while TPO alone was able to promote platelet production by 10-fold, highlighting the critical role of TPO in MK differentiation, maturation, and platelet generation (Norol et al, 1998). IL-6, IL-9, ACF, FL, APEL, BMP-4, VEGF, bFGF hiPSC-hPSC- TPO, IL-1β, SCF, GATA1, MK

29.9 MKs per MKs produced
Findings
DISCUSSION
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