Thrombopoiesis is spatially regulated by the bone marrow vasculature

David Stegner,Katrin G Heinze,Oğuzhan Angay,Sebastian Dütting,Christian Brede,Daniela Semeniak,Andreas Beilhack,Mike Friedrich,Imke Meyer,Harald Schulze,Patrick Schmithausen,Judith M M Vaneeuwijk,Maximilian G Gorelashvili,Jürgen Pinnecker,Bernhard Nieswandt

doi:10.1038/s41467-017-00201-7

Abstract

In mammals, megakaryocytes (MKs) in the bone marrow (BM) produce blood platelets, required for hemostasis and thrombosis. MKs originate from hematopoietic stem cells and are thought to migrate from an endosteal niche towards the vascular sinusoids during their maturation. Through imaging of MKs in the intact BM, here we show that MKs can be found within the entire BM, without a bias towards bone-distant regions. By combining in vivo two-photon microscopy and in situ light-sheet fluorescence microscopy with computational simulations, we reveal surprisingly slow MK migration, limited intervascular space, and a vessel-biased MK pool. These data challenge the current thrombopoiesis model of MK migration and support a modified model, where MKs at sinusoids are replenished by sinusoidal precursors rather than cells from a distant periostic niche. As MKs do not need to migrate to reach the vessel, therapies to increase MK numbers might be sufficient to raise platelet counts.

Highlights

In mammals, megakaryocytes (MKs) in the bone marrow (BM) produce blood platelets, required for hemostasis and thrombosis
TPO supports the self-renewal of hematopoietic stem cells (HSCs) and induces transcription factors leading to the expression of proteins like CD42 (GPIb-V-IX complex) or CD41 (GPIIb) that commit HSCs to the platelet lineage[1, 2]
We provide independent lines of evidence that challenge the directed MK migration model and provide a modified model, where MKs at sinusoids are replenished by precursors originating from a sinusoidal niche rather than from a periostic niche

Summary

Introduction

Megakaryocytes (MKs) in the bone marrow (BM) produce blood platelets, required for hemostasis and thrombosis. By combining in vivo twophoton microscopy and in situ light-sheet fluorescence microscopy with computational simulations, we reveal surprisingly slow MK migration, limited intervascular space, and a vessel-biased MK pool. These data challenge the current thrombopoiesis model of MK migration and support a modified model, where MKs at sinusoids are replenished by sinusoidal precursors rather than cells from a distant periostic niche. As a result of recent developments in imaging techniques, we were able to analyze the distribution of MKs within the bone marrow by combining different in vitro and in vivo imaging techniques with computational simulations. We provide independent lines of evidence that challenge the directed MK migration model and provide a modified model, where MKs at sinusoids are replenished by precursors originating from a sinusoidal niche rather than from a periostic niche

Methods

Results

Conclusion