Inra Christopher N, Zhou Bo O, Acar Melih, Murphy Malea M, Richardson James, Zhao Zhiyu, Morrison Sean J
Department of Pediatrics and Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Nature. 2015 Nov 26;527(7579):466-471. doi: 10.1038/nature15530. Epub 2015 Nov 16.
Haematopoietic stresses mobilize haematopoietic stem cells (HSCs) from the bone marrow to the spleen and induce extramedullary haematopoiesis (EMH). However, the cellular nature of the EMH niche is unknown. Here we assessed the sources of the key niche factors, SCF (also known as KITL) and CXCL12, in the mouse spleen after EMH induction by myeloablation, blood loss, or pregnancy. In each case, Scf was expressed by endothelial cells and Tcf21(+) stromal cells, primarily around sinusoids in the red pulp, while Cxcl12 was expressed by a subset of Tcf21(+) stromal cells. EMH induction markedly expanded the Scf-expressing endothelial cells and stromal cells by inducing proliferation. Most splenic HSCs were adjacent to Tcf21(+) stromal cells in red pulp. Conditional deletion of Scf from spleen endothelial cells, or of Scf or Cxcl12 from Tcf21+ stromal cells, severely reduced spleen EMH and reduced blood cell counts without affecting bone marrow haematopoiesis. Endothelial cells and Tcf21(+) stromal cells thus create a perisinusoidal EMH niche in the spleen, which is necessary for the physiological response to diverse haematopoietic stresses.
造血应激促使造血干细胞（HSCs）从骨髓迁移至脾脏，并诱导髓外造血（EMH）。然而，EMH微环境的细胞本质尚不清楚。在此，我们评估了通过骨髓消融、失血或妊娠诱导EMH后，小鼠脾脏中关键微环境因子干细胞因子（SCF，也称为KITL）和CXC趋化因子配体12（CXCL12）的来源。在每种情况下，Scf由内皮细胞和Tcf21(+)基质细胞表达，主要在红髓的血窦周围，而Cxcl12由一部分Tcf21(+)基质细胞表达。EMH诱导通过诱导增殖显著扩大了表达Scf的内皮细胞和基质细胞。大多数脾HSCs与红髓中的Tcf21(+)基质细胞相邻。条件性敲除脾脏内皮细胞中的Scf，或Tcf21+基质细胞中的Scf或Cxcl12，会严重减少脾脏EMH并降低血细胞计数，而不影响骨髓造血。因此，内皮细胞和Tcf21(+)基质细胞在脾脏中形成了一个血窦周围的EMH微环境，这是对多种造血应激生理反应所必需的。
