Niche-induced extramedullary hematopoiesis in the spleen is regulated by the transcription factor Tlx1

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.

Targeting the Spleen as an Alternative Site for Hematopoiesis

“…The dynamic role of the spleen in provisioning emergency hematopoiesis appears to rely on the rapid expansion of perivascular reticular cells that support HSCs . One possibility yet to be investigated is that mesenchymal stem and progenitor cells reside in spleen and quickly differentiate to expand stromal cells that form the niche.…”

“…It has long been known that Hox11 (or Tlx1) expressed by splenic stromal cells is an essential transcription factor for spleen organogenesis . Overexpression of Tlx1 is sufficient to induce EMH in the absence of any other physiological stressor . When Tlx1 conditional knockout mice were investigated it was concluded that Tlx1‐expressing stromal cells are required for recruitment of HSCs into the spleen following EMH, and that those cells are a component of HSC niches in the spleen .…”

“…Overexpression of Tlx1 is sufficient to induce EMH in the absence of any other physiological stressor . When Tlx1 conditional knockout mice were investigated it was concluded that Tlx1‐expressing stromal cells are required for recruitment of HSCs into the spleen following EMH, and that those cells are a component of HSC niches in the spleen . Tlx1‐expressing cells also resemble bone marrow niche elements through the expression of PDGFRa/b, CD51, and CD105 and production of CXCL12 and SCF .…”

“…When Tlx1 conditional knockout mice were investigated it was concluded that Tlx1‐expressing stromal cells are required for recruitment of HSCs into the spleen following EMH, and that those cells are a component of HSC niches in the spleen . Tlx1‐expressing cells also resemble bone marrow niche elements through the expression of PDGFRa/b, CD51, and CD105 and production of CXCL12 and SCF . An unanswered question is whether mobilization treatments (like G‐CSF) impact splenic niches as well as bone marrow niches such that the spleen contributes to the supply of HSCs into peripheral blood.…”

“…There are no osteoblasts in the spleen, and hence, HSC niches in the spleen portend to be distinct in comparison with the bone marrow. Recent studies have identified a role for both endothelial and mesenchymal cells in formation of HSC niches supporting EMH …”