Endothelial Jak3 expression enhances pro-hematopoietic angiocrine function in mice

José Gabriel Barcia Durán,Raphaël Lis,Fuqiang Geng,Shahin Rafii,Jenny Xiang,Ryan Schreiner,David Redmond,Tyler Lu,Sean Houghton

doi:10.1038/s42003-021-01846-3

José Gabriel Barcia Durán, Raphaël Lis + Show 7 more

Open Access

https://doi.org/10.1038/s42003-021-01846-3

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Abstract

Jak3 is the only non-promiscuous member of the Jak family of secondary messengers. Studies to date have focused on understanding and targeting the cell-autonomous role of Jak3 in immunity, while functional Jak3 expression outside the hematopoietic system remains largely unreported. We show that Jak3 is expressed in endothelial cells across hematopoietic and non-hematopoietic organs, with heightened expression in the bone marrow. The bone marrow niche is understood as a network of different cell types that regulate hematopoietic function. We show that the Jak3–/– bone marrow niche is deleterious for the maintenance of long-term repopulating hematopoietic stem cells (LT-HSCs) and that JAK3-overexpressing endothelial cells have increased potential to expand LT-HSCs in vitro. This work may serve to identify a novel function for a highly specific tyrosine kinase in the bone marrow vascular niche and to further characterize the LT-HSC function of sinusoidal endothelium.

Highlights

Janus kinase (Jak)[3] is the only non-promiscuous member of the Jak family of secondary messengers
We show that the Jak3–/– bone marrow niche is deleterious for the maintenance of long-term repopulating hematopoietic stem cells (LT-HSCs) and that JAK3-overexpressing endothelial cells have increased potential to expand LT-HSCs in vitro
A number of these transcripts are expressed by hematopoietic cells, but our dataset was comprised of Endothelial cells (ECs) exclusively, since surface markers restricted to the hematopoietic system such as Spn and Csfr[3] or transcription factors like Runx[1] or Gfi[1] were effectively absent from all samples

Summary

Introduction

Studies to date have focused on understanding and targeting the cell-autonomous role of Jak[3] in immunity, while functional Jak[3] expression outside the hematopoietic system remains largely unreported. We show that Jak[3] is expressed in endothelial cells across hematopoietic and non-hematopoietic organs, with heightened expression in the bone marrow. The bone marrow niche is understood as a network of different cell types that regulate hematopoietic function. We show that the Jak3–/– bone marrow niche is deleterious for the maintenance of long-term repopulating hematopoietic stem cells (LT-HSCs) and that JAK3-overexpressing endothelial cells have increased potential to expand LT-HSCs in vitro. Some of the earliest research in this field showed that radiation-induced myeloablation induces the recruitment of Mmp[9] to the membrane of bone marrow niche cells[3].

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