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Ferrata Storti Foundation
Haematologica 2019 Volume 104(11):2164-2177
Hematopoiesis
A Tie2-Notch1 signaling axis regulates regeneration of the endothelial bone marrow niche
Lijian Shao,1 Kilian Sottoriva,1 Karol Palasiewicz,1 Jizhou Zhang,2
James Hyun,1 Sweta S. Soni,1 Na Yoon Paik,1 Xiaopei Gao,1 Henar Cuervo,3 Asrar B. Malik,1 Jalees Rehman,1 Daniel Lucas2,4 and Kostandin V. Pajcini1
1Department of Pharmacology, The University of Illinois College of Medicine, Chicago, IL 2Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Medical Center, Cincinnati, OH; 3Department of Physiology and Biophysics, The University of Illinois College of Medicine, Chicago, IL and 4Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
ABSTRACT
Loss-of-function studies have determined that Notch signaling is essen- tial for hematopoietic and endothelial development. By deleting a sin- gle allele of the Notch1 transcriptional activation domain we generat- ed viable, post-natal mice exhibiting hypomorphic Notch signaling. These heterozygous mice, which lack only one copy of the transcriptional activa- tion domain, appear normal and have no endothelial or hematopoietic phe- notype, apart from an inherent, cell-autonomous defect in T-cell lineage development. Following chemotherapy, these hypomorphs exhibited severe pancytopenia, weight loss and morbidity. This phenotype was con- firmed in an endothelial-specific, loss-of-function Notch1 model system. Ang1, secreted by hematopoietic progenitors after damage, activated endothelial Tie2 signaling, which in turn enhanced expression of Notch lig- ands and potentiated Notch1 receptor activation. In our heterozygous, hypomorphic model system, the mutant protein that lacks the Notch1 tran- scriptional activation domain accumulated in endothelial cells and inter- fered with optimal activity of the wildtype Notch1 transcriptional complex. Failure of the hypomorphic mutant to efficiently drive transcription of key gene targets such as Hes1 and Myc prolonged apoptosis and limited regen- eration of the bone marrow niche. Thus, basal Notch1 signaling is sufficient for niche development, but robust Notch activity is required for regenera- tion of the bone marrow endothelial niche and hematopoietic recovery.
Introduction
Chemotherapy and radiotherapy are widely used in the treatment of hematopoietic malignancies but broad cytotoxicity is an undesirable feature of these treatments.1 These therapies damage multiple tissues including the bone marrow (BM) microvasculature.2-4 The regeneration of the endothelial BM vascular niche is crucial for successful reconstitution of hematopoietic cells.5,6 The interplay between the vascular and hematopoietic systems has multiple physiological and therapeutic implications. Endothelial cell (EC)-secreted growth factors such as vas- cular endothelial growth factor (VEGF)-A, enhance self-renewal and survival of hematopoietic stem cells (HSC) and mediate recovery of hematopoiesis.5,7,8 Angiopoietin-1 (Ang1) signaling9,10 via the activation of tyrosine kinase Tie2 has been proposed as the key endocrine mechanism mediating endothelial recovery and regeneration.2,11 It is unknown whether paracrine signaling plays a role in the regeneration and reassembly of the BM endothelium.
Notch receptors are evolutionarily conserved transmembrane glycoproteins. Upon paracrine activation by neighboring cells through ligand interactions and proteolytic cleavage, they activate a transcriptional apparatus.12 Notch1 and Notch4
Correspondence:
KOSTANDIN V. PAJCINI
kvp@uic.edu
Received: October 5, 2018. Accepted: March 18, 2019. Pre-published: March 28, 2019.
doi:10.3324/haematol.2018.208660
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/11/2164
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