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 6

Del-1 deficiency enhances long-term reconstitution capacity and lineage bias of LT-HSCs.

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Del-1 deficiency enhances long-term reconstitution capacity and lineage ...
(A) Competitive repopulation assay: BM cells from either Edil3–/– or Edil3+/+ mice (CD45.2+; donor) and CD45.1+ BM cells as competitors were transplanted into B6.SJL recipient mice (CD45.1+). (B) Representative flow cytometry plots of donor-derived chimerism in the peripheral blood of recipient mice at week 16 after transplantation and (C) number of R.U. per femur of Edil3–/– or Edil3+/+ donor mice (n = 10 recipients per group). (D) Representative flow cytometry plots and (E) percentage of donor-derived (CD45.2+) Gr1+CD11b+ myeloid cells in the blood of recipient mice. (F) Frequency of donor-derived cells in the BM of recipient mice at 16 weeks after transplantation (n = 10 recipients per group). (G) Representative flow cytometry plots and (H) percentage of donor-derived (CD45.2+) Gr1+CD11b+ myeloid cells in the BM of recipient mice (n = 10 recipients per group). (I) Representative flow cytometry plots and (J) percentage of donor-derived CD19+ B cells in the BM of recipient mice at 16 weeks after transplantation (n = 10 recipients per group). Data are presented as mean ± SEM. Mann-Whitney U test, *P < 0.05, **P < 0.01, ***P < 0.001.