Abstract
Extramedullary hematopoiesis (EMH) in postnatal life is a pathological process in which the differentiation of hematopoietic stem/progenitor cells (HSPCs) occurs outside the bone marrow (BM) to respond to hematopoietic emergencies. The spleen is a major site for EMH; however, the cellular and molecular nature of the stromal cell components supporting HSPC maintenance, the niche for EMH in the spleen remain poorly understood compared to the growing understanding of the BM niche at the steady-state as well as in emergency hematopoiesis. In the present study, we demonstrate that mesenchymal progenitor-like cells expressing Tlx1, an essential transcription factor for spleen organogenesis, and selectively localized in the perifollicular region of the red pulp of the spleen, are a major source of HSPC niche factors. Consistently, overexpression of Tlx1 in situ induces EMH, which is associated with mobilization of HSPC into the circulation and their recruitment into the spleen where they proliferate and differentiate. The alterations in the splenic microenvironment induced by Tlx1 overexpression in situ phenocopy lipopolysaccharide (LPS)-induced EMH, and the conditional loss of Tlx1 abolished LPS-induced splenic EMH. These findings indicate that activation of Tlx1 expression in the postnatal splenic mesenchymal cells is critical for the development of splenic EMH.
Highlights
Hematopoiesis is a highly orchestrated process that generates multi-lineage blood cells from a small pool of hematopoietic stem/progenitor cells (HSPCs) through a successive series of increasingly lineage-restricted intermediate progenitors[1]
We examined expression of mesenchymal cell markers on Venus+ tdTomato+ cells and found that they were positive for lymphotoxin receptor β (LTβR), platelet-derived growth factor receptor (PDGFR) α and β, CD105 and CD51, but were negative for leptin receptor (Fig. 1c)
We found a significant elevation in gene transcripts of hematopoietic niche factors, CXCL12 and SCF, that were highly enriched in steady-state Venus+ cells, and bone morphologic factor-4 (BMP-4) and macrophage colony-stimulating factor (M-CSF) that have been reported to participate in splenic erythropoiesis[26,27] and differentiation of monocytes[28], respectively (Fig. 4b)
Summary
Hematopoiesis is a highly orchestrated process that generates multi-lineage blood cells from a small pool of hematopoietic stem/progenitor cells (HSPCs) through a successive series of increasingly lineage-restricted intermediate progenitors[1]. Several transcription factors expressed in embryonic spleen mesenchymal cells, such as Pbx[1], WT1, Tcf[21] and Nk3.2., have been shown to be required for spleen organogenesis, as their deficiency causes spleen agenesis or hypoplasia, in association with other organ defects[19,20,21,22] Among these transcription factors, Tlx[1] is expressed in mesenchymal cells that are relatively restricted to the spleen primordium, and probably as a result, the asplenia occurs without detectable abnormalities in other organs of Tlx[1] knockout mice[23,24]. High levels of Tlx[1] expression in situ are sufficient to induce EMH and are required for the recruitment of HSPCs to the spleen in lipopolysaccharide (LPS)-induced EMH
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