Apelin ⁺ Endothelial Niche Cells Control Hematopoiesis and Mediate Vascular Regeneration after Myeloablative Injury

Summary

Radiotherapy and chemotherapy disrupt bone vasculature, but the underlying causes and mechanisms enabling vessel regeneration after bone marrow (BM) transplantation remain poorly understood. Here, we show that loss of hematopoietic cells per se, in response to irradiation and other treatments, triggers vessel dilation, permeability, and endothelial cell (EC) proliferation. We further identify a small subpopulation of Apelin-expressing (Apln ⁺) ECs, representing 0.003% of BM cells, that is critical for physiological homeostasis and transplant-induced BM regeneration. Genetic ablation of Apln ⁺ ECs or Apln-CreER-mediated deletion of Kitl and Vegfr2 disrupt hematopoietic stem cell (HSC) maintenance and contributions to regeneration. Consistently, the fraction of Apln ⁺ ECs increases substantially after irradiation and promotes normalization of the bone vasculature in response to VEGF-A, which is provided by transplanted hematopoietic stem and progenitor cells (HSPCs). Together, these findings reveal critical functional roles for HSPCs in maintaining vascular integrity and for Apln ⁺ ECs in hematopoiesis, suggesting potential targets for improving BM transplantation.

Graphical Abstract

Highlights

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  Loss of hematopoietic cells phenocopies irradiation-induced vascular defects

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  Identification and characterization of Apln ⁺ ECs in adult BM

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  Apln ⁺ ECs regulate HSC maintenance and steady-state hematopoiesis

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  Apln ⁺ ECs expand, respond to HSPCs, and drive post-transplantation recovery

Abstract

Chen and colleagues identify an Apln ⁺ subpopulation of bone marrow endothelial cells (ECs), which are distinct from other sinusoidal ECs. Apln ⁺ ECs regulate HSC maintenance, hematopoiesis, hematopoietic reconstitution, and vascular regeneration after irradiation. Crosstalk between Apln ⁺ ECs and donor-cell-derived VEGF-A can be manipulated to improve bone marrow transplantation efficiency.