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Intramedullary megakaryocytes internalize released platelet factor 4 and store it in alpha granules

M P Lambert1,2, R Meng3, L Xiao2

  • 1Department of Pediatrics Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Journal of Thrombosis and Haemostasis : JTH
|August 11, 2015
PubMed
Abstract

Insights

Platelet factor 4 (PF4) has a complex life cycle within bone marrow, influencing blood cell production. This study defines its source and intramedullary behavior, revealing implications for megakaryopoiesis and stem cell replication.

Area of Science:

  • Hematology
  • Cell Biology
  • Molecular Biology

Background:

  • Megakaryocytes (MKs) store and release platelet factor 4 (PF4) from alpha granules.
  • PF4 negatively regulates megakaryopoiesis and hematopoietic stem cell (HSC) replication in vivo.
  • A regulated source of free intramedullary PF4 is suggested by these observations.

Purpose of the Study:

  • To define the source of free intramedullary PF4.
  • To elucidate the intramedullary life cycle of PF4.

Main Methods:

  • In vitro studies using murine and human bone marrow-derived cells during megakaryopoiesis.
  • Confocal microscopy and enzyme-linked immunosorbent assay (ELISA) were employed.
  • In vivo immunohistochemistry examined free PF4 in murine bone marrow before and after radiation injury, and in settings of megakaryocytopenia and thrombocytopenia.

Main Results:

  • Murine megakaryocytes internalize exogenous PF4, which colocalizes with endogenous PF4 in alpha granules and is releasable upon thrombin stimulation.
  • Free PF4 is detected in bone marrow, increasing with radiation injury and decreasing with megakaryocytopenia.
  • PF4 internalization is partially dependent on low-density lipoprotein receptor-related protein 1 (LRP1), implicating it in PF4's paracrine effects.

Conclusions:

  • PF4 exhibits a complex intramedullary life cycle.
  • This cycle has significant implications for megakaryopoiesis and HSC replication.
  • These effects are distinct from other alpha granule proteins studied.
Keywords:
diphtheria toxinlow density lipoprotein receptor-related protein-1megakaryocytesplatelet factor 4radiation injurythrombocytopenia

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