Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche
Ioannis Mitroulis, Lan-Sun Chen, Rashim Pal Singh, Ioannis Kourtzelis, Matina Economopoulou, Tetsuhiro Kajikawa, Maria Troullinaki, Athanasios Ziogas, Klara Ruppova, Kavita Hosur, Tomoki Maekawa, Baomei Wang, Pallavi Subramanian, Torsten Tonn, Panayotis Verginis, Malte von Bonin, Manja Wobus, Martin Bornhäuser, Tatyana Grinenko, Marianna Di Scala, Andres Hidalgo, Ben Wielockx, George Hajishengallis, Triantafyllos Chavakis
Ioannis Mitroulis, Lan-Sun Chen, Rashim Pal Singh, Ioannis Kourtzelis, Matina Economopoulou, Tetsuhiro Kajikawa, Maria Troullinaki, Athanasios Ziogas, Klara Ruppova, Kavita Hosur, Tomoki Maekawa, Baomei Wang, Pallavi Subramanian, Torsten Tonn, Panayotis Verginis, Malte von Bonin, Manja Wobus, Martin Bornhäuser, Tatyana Grinenko, Marianna Di Scala, Andres Hidalgo, Ben Wielockx, George Hajishengallis, Triantafyllos Chavakis
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Research Article Hematology Immunology

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

Abstract

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.

Authors

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

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Figure 5

Del-1 promotes LT-HSC cell cycle progression.

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Del-1 promotes LT-HSC cell cycle progression. (A and B) Staining for Ki-...
(A and B) Staining for Ki-67 nuclear antigen and DNA content (DAPI) was performed for cell cycle analysis. G0 phase is defined as Ki-67− and 2n DNA, G1 as Ki-67+ and 2n DNA, and S-G2-M as Ki-67+ and DNA >2n. (A) Representative flow cytometry plots and (B) cell cycle analysis in LT-HSCs from 10-week-old mice (n = 8 Edil3+/+ and n = 10 Edil3–/– mice). K, thousands. (C) Representative flow cytometry plots and (D) percentage of LT-HSCs that incorporated BrdU after 3 days of BrdU administration in drinking water (n = 5 mice per group). (E) Expression of Ccnd1, Ccng1, and Ccng2 in LT-HSCs from Edil3–/– and Edil3+/+ mice (n = 11–13 mice per group). mRNA expression was normalized against 18s. (F) BrdU pulse-chase assay protocol. BrdU was administered in drinking water for 15 days. Analysis of BrdU-retaining LT-HSCs was performed on day 70 after BrdU withdrawal (n = 5 mice per group). (G) Percentage of BrdU-retaining LT-HSCs in the BM of Edil3–/– and Edil3+/+ mice (n = 5 mice per group). Data are presented as mean ± SEM. Mann-Whitney U test, *P < 0.05, **P < 0.01.