Tie2+ Bone Marrow Endothelial Cells Regulate Hematopoietic Stem Cell Regeneration Following Radiation Injury

Abstract

Hematopoietic stem cells (HSCs) reside in proximity to bone marrow endothelial cells (BM ECs) and maintenance of the HSC pool is dependent upon EC-mediated c-kit signaling. Here, we utilized genetic models to determine if radioprotection of BM ECs could facilitate hematopoietic regeneration following radiation-induced myelosuppression. We developed mice bearing deletion of the pro-apoptotic proteins, BAK and BAX, in Tie2+ endothelial cells (ECs) and HSCs (Tie2Bak/BaxFl/− mice) and compared their hematopoietic recovery following total body irradiation (TBI) with mice which retained Bax in Tie2+ cells. Mice bearing deletion of Bak and Bax in Tie2+ cells demonstrated protection of BM HSCs, preserved BM vasculature and 100% survival following lethal dose TBI. In contrast, mice that retained Bax expression in Tie2+ cells demonstrated depletion of BM HSCs, disrupted BM vasculature and 10% survival post-TBI. In a complementary study, VEcadherinBak/BaxFl/− mice, which lack Bak and Bax in VEcadherin+ ECs, also demonstrated increased recovery of BM stem/progenitor cells following TBI compared to mice which retained Bax in VEcadherin+ ECs. Importantly, chimeric mice which lacked Bak and Bax in HSCs but retained Bak and Bax in BM ECs displayed significantly decreased HSC content and survival following TBI compared to mice lacking Bak and Bax in both HSCs and BM ECs. These data suggest that the hematopoietic response to ionizing radiation is dependent upon HSC-autonomous responses but is regulated by BM EC-mediated mechanisms. Therefore, BM ECs may be therapeutically targeted as a means to augment hematopoietic reconstitution following myelosuppression.

Hematopoietic stem cell niche maintenance during homeostasis and regeneration

“…A recent investigation further highlighted the regulatory effects of endothelial cells on HSC regeneration after radiation injury123. In mice, deletion of the proapoptotic genes Bak and Bax in Tie2-expressing HSCs and endothelial cells prevented their depletion after irradiation and resulted in radioprotection of HSCs123.…”

“…In mice, deletion of the proapoptotic genes Bak and Bax in Tie2-expressing HSCs and endothelial cells prevented their depletion after irradiation and resulted in radioprotection of HSCs123. Deletion of Bak and Bax in VE-cadherin–Cre mice, which only targets a small subset of HSCs, led to an increase in 15-day survival but resulted in no statistical difference in 30-day survival compared to VE-cadherin–Cre+ Bakflox/+; or Baxflox/+ and VE-cadherin–Cre− mice123. These results indicate that the hematopoietic response to radiation is mediated by HSC-autonomous effects as well as endothelial cell–mediated mechanisms123.…”

Pleiotrophin mediates hematopoietic regeneration via activation of RAS

“…Radiation causes toxicity to hematopoietic stem cells (HSCs) through the generation of ROS, induction of DNA strand breaks and apoptosis, and damage to the BM microenvironment (2)(3)(4). Despite an understanding of mechanisms through which ionizing radiation causes hematopoietic toxicity, few effective mitigators of radiation-induced hematopoietic injury have been developed (5)(6)(7)(8)(9).…”

“…We and others have shown that BM-derived endothelial cells regulate the response of HSCs to genotoxic stressors such as ionizing radiation (3,4,16,21). However, the precise mechanisms through which BM niche cells promote HSC regeneration after injury remain poorly understood.…”

Nice Neighborhood: Emerging Concepts of the Stem Cell Niche

“…Further, VEGFR2 expressing sinusoidal endothelial cells have been shown to be necessary for hematopoietic stem and progenitor cell engraftment post irradiation (Hooper et al, 2009). Protection of bone marrow vascular endothelium improves survival and regeneration of hematopoiesis after radiation (Doan et al, 2013), while addition of endothelial progenitors to a stem cell graft enhanced engraftment efficiency (Salter et al, 2009). These studies demonstrate the participation of endothelium in regulating stem and progenitor cells, though how they may alter that regulation to reflect tissue or organismal state has not been experimentally examined.…”