Journal Article

Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche

Tonn, Torsten, Chavakis, Triantafyllos, Verginis, Panayotis, Hajishengallis, George, von Bonin, Malte, Ziogas, Athanasios, Bornhäuser, Martin, Troullinaki, Maria, Kourtzelis, Ioannis, Wielockx, Ben, Ruppova, Klara, Hidalgo, Andres, Kajikawa, Tetsuhiro, Subramanian, Pallavi, Mitroulis, Ioannis, Singh, Rashim Pal, Economopoulou, Matina, Maekawa, Tomoki, Grinenko, Tatyana, Hosur, Kavita, Di Scala, Marianna, Wang, Baomei, Chen, Lan-Sun, Wobus, Manja

2017

Overview

Hematopoietic stem cells (HSCs) remain mostly quiescent under steady-state conditions but switch to a proliferative state following hematopoietic stress, e.g., bone marrow (BM) injury, transplantation, or systemic infection and inflammation. The homeostatic balance between quiescence, self-renewal, and differentiation of HSCs is strongly dependent on their interactions with cells that constitute a specialized microanatomical environment in the BM known as the HSC niche. Here, we identified the secreted extracellular matrix protein Del-1 as a component and regulator of the HSC niche. Specifically, we found that Del-1 was expressed by several cellular components of the HSC niche, including arteriolar endothelial cells, CXCL12-abundant reticular (CAR) cells, and cells of the osteoblastic lineage. Del-1 promoted critical functions of the HSC niche, as it regulated long-term HSC (LT-HSC) proliferation and differentiation toward the myeloid lineage. Del-1 deficiency in mice resulted in reduced LT-HSC proliferation and infringed preferentially upon myelopoiesis under both steady-state and stressful conditions, such as hematopoietic cell transplantation and G-CSF- or inflammation-induced stress myelopoiesis. Del-1-induced HSC proliferation and myeloid lineage commitment were mediated by β3 integrin on hematopoietic progenitors. This hitherto unknown Del-1 function in the HSC niche represents a juxtacrine homeostatic adaptation of the hematopoietic system in stress myelopoiesis.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Biomedical research / Bone marrow / Bone marrow transplantation / Breast cancer / Carrier Proteins - genetics / Carrier Proteins - secretion / Cell cycle / Cell self-renewal / Chemokine CXCL12 - genetics / Chemokine CXCL12 - metabolism / CXCL12 protein / Disseminated infection / Endothelial cells / Endothelial Cells - metabolism / Extracellular matrix / Granulocyte colony-stimulating factor / Health aspects / Hematopoietic stem cells / Hematopoietic Stem Cells - metabolism / Humans / Inflammation / Integrin beta3 - genetics / Integrin beta3 - metabolism / Leukemia / Matrix protein / Mice / Mice, Knockout / Myelopoiesis / Neutropenia / Osteoblasts / Proteins / Rodents / Stem Cell Niche / Stem cell transplantation / Stem cells / Stress, Physiological / Transplantation / Transplants & implants