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 4

Del-1 in recipient BM promotes the recovery of myelopoiesis.

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Del-1 in recipient BM promotes the recovery of myelopoiesis. Lethally ir...
Lethally irradiated Edil3+/+ or Edil3–/– mice (CD45.2) were transplanted with CD45.1+ BM cells, as described in Methods. (A) Representative flow cytometry plots and (B) number of donor-derived LSK cells (CD45.1+) in the BM of recipient Edil3+/+ or Edil3–/– mice (CD45.2+) at 6 weeks after transplantation (n = 10 mice per group). (C) Representative flow cytometry plots and numbers of donor-derived (D) LT-HSCs, (E) ST-HSCs, and (F) MPPs in the BM of recipient Edil3+/+ or Edil3–/– mice at 6 weeks after transplantation (n = 10 mice per group). (G) Relative abundance of the indicated cell populations (LT-HSCs, ST-HSCs, and MPPs) in the total LSK population is shown (CD48+CD150+ LSK cells were not considered). (H) Representative flow cytometry plots of cells gated on LK (see FACS plot in A); (I) donor-derived CMP and (J) donor-derived GMP cell numbers in the BM of recipient Edil3+/+ or Edil3–/– mice at 6 weeks after transplantation (n = 10 mice per group). Donor-derived (K) Gr1hiCD11b+ granulocytes, (L) Gr1intCD11b+ myeloid cells, and (M) CD19+ B cells in the BM of recipient Edil3+/+ or Edil3–/– mice at 6 weeks after transplantation (n = 10 mice per group). Data are presented as mean ± SEM. Mann-Whitney U test, *P < 0.05, **P < 0.01, ***P < 0.001.