Inductive interactions mediated by interplay of asymmetric signalling underlie development of adult haematopoietic stem cells.

Céline Souilhol,Antoniana Batsivari,Samir Taoudi,Javier G Lendinez,Stanislav Rybtsov,Suling Zhao,Alexander Medvinsky,David Hills,Lucia Morgado-Palacin,Christèle Gonneau,Heather Wilson,Jennifer Antonchuk

doi:10.1038/ncomms10784

Abstract

During embryonic development, adult haematopoietic stem cells (HSCs) emerge preferentially in the ventral domain of the aorta in the aorta–gonad–mesonephros (AGM) region. Several signalling pathways such as Notch, Wnt, Shh and RA are implicated in this process, yet how these interact to regulate the emergence of HSCs has not previously been described in mammals. Using a combination of ex vivo and in vivo approaches, we report here that stage-specific reciprocal dorso–ventral inductive interactions and lateral input from the urogenital ridges are required to drive HSC development in the aorta. Our study strongly suggests that these inductive interactions in the AGM region are mediated by the interplay between spatially polarized signalling pathways. Specifically, Shh produced in the dorsal region of the AGM, stem cell factor in the ventral and lateral regions, and BMP inhibitory signals in the ventral tissue are integral parts of the regulatory system involved in the development of HSCs.

Highlights

During embryonic development, adult haematopoietic stem cells (HSCs) emerge preferentially in the ventral domain of the aorta in the aorta–gonad–mesonephros (AGM) region
As dHSCs mature from pre-HSCs, we investigated whether the emergence of dHSC predominantly in the AoV6 is a result of asymmetric distribution of pre-HSCs
We investigated the spatial distribution of pre-HSCs type I and pre-HSCs type II in E10.5–E11.5 embryos using the OP9 co-culture system supplemented with Il3 þ stem cell factor (SCF) þ Flt[3], which allows pre-HSCs to mature into dHSC that become detectable by long-term repopulation assay as described previously[16]

Summary

Introduction

Adult haematopoietic stem cells (HSCs) emerge preferentially in the ventral domain of the aorta in the aorta–gonad–mesonephros (AGM) region. Several signalling pathways such as Notch, Wnt, Shh and RA are implicated in this process, yet how these interact to regulate the emergence of HSCs has not previously been described in mammals. An important property of adult (definitive) haematopoietic stem cells (dHSCs) is that they are capable of long-term reconstitution of the haematopoietic system upon transplantation into irradiated recipients In the mouse, such cells develop by embryonic stages E10–E11 in the aorta–gonad– mesonephros (AGM) region[1,2,3,4]. Subaortic BMP4 and Shh/Indian Hedgehog derived from gut were proposed to be responsible for HSC development[36,37]

Methods

Results

Conclusion