Id1 and Id3 Maintain Steady-State Hematopoiesis by Promoting Sinusoidal Endothelial Cell Survival and Regeneration

Abstract

Summary: Investigating mechanisms that regulate endothelial cell (EC) growth and survival is important for understanding EC homeostasis and how ECs maintain stem cell niches. We report here that targeted loss of Id genes in adult ECs results in dilated, leaky sinusoids and a pro-inflammatory state that increases in severity over time. Disruption in sinusoidal integrity leads to increased hematopoietic stem cell (HSC) proliferation, differentiation, migration, and exhaustion. Mechanistically, sinusoidal ECs (SECs) show increased apoptosis because of reduced Bcl2-family gene expression following Id gene ablation. Furthermore, Id1−/−Id3−/− SECs and upstream type H vessels show increased expression of cyclin-dependent kinase inhibitors p21 and p27 and impaired ability to proliferate, which is rescued by reducing E2-2 expression. Id1−/−Id3−/− mice do not survive sublethal irradiation because of impaired vessel regeneration and hematopoietic failure. Thus, Id genes are required for the survival and regeneration of BM SECs during homeostasis and stress to maintain HSC development. : Gadomski et al. show that Id genes are critical regulators of bone marrow endothelial cell proliferation and survival. Selective loss of Id genes in endothelial cells promotes vessel dilation, apoptosis, and increased permeability, leading to the functional decline of hematopoietic stem cells under steady-state and stress conditions. Keywords: endothelial cells, ID proteins, hematopoietic stem cells, hematopoietic microenvironment, instructive niche, transcription factors, tissue regeneration, progenitor cells, proliferation, bone marrow