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

doi:10.1172/JCI92571

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 ScalaAndres Hidalgo, Ben Wielockx, George Hajishengallis, Triantafyllos Chavakis

The Hull York Medical School

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	3624-3639
Number of pages	16
Journal	Journal of Clinical Investigation
Volume	127
Issue number	10
DOIs	https://doi.org/10.1172/JCI92571
Publication status	Published - 2 Oct 2017

Bibliographical note

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Keywords

Animals
Carrier Proteins/genetics
Chemokine CXCL12/genetics
Endothelial Cells/metabolism
Hematopoietic Stem Cells/metabolism
Humans
Integrin beta3/genetics
Intercellular Signaling Peptides and Proteins
Mice
Mice, Knockout
Myelopoiesis
Stem Cell Niche
Stress, Physiological

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10.1172/JCI92571

92571.2-20170920113146-covered-253bed37ca4c1ab43d105aefdf7b5536
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Ioannis Kourtzelis
- ioannis.kourtzelisyork.acuk
- The Hull York Medical School - Lecturer
Person: Academic

Cite this

Mitroulis, I., Chen, L.-S., Singh, R. P., Kourtzelis, I., Economopoulou, M., Kajikawa, T., Troullinaki, M., Ziogas, A., Ruppova, K., Hosur, K., Maekawa, T., Wang, B., Subramanian, P., Tonn, T., Verginis, P., von Bonin, M., Wobus, M., Bornhäuser, M., Grinenko, T., ... Chavakis, T. (2017). Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche. Journal of Clinical Investigation, 127(10), 3624-3639. https://doi.org/10.1172/JCI92571

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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.",

keywords = "Animals, Carrier Proteins/genetics, Chemokine CXCL12/genetics, Endothelial Cells/metabolism, Hematopoietic Stem Cells/metabolism, Humans, Integrin beta3/genetics, Intercellular Signaling Peptides and Proteins, Mice, Mice, Knockout, Myelopoiesis, Stem Cell Niche, Stress, Physiological",

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

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Mitroulis, I, Chen, L-S, Singh, RP, Kourtzelis, I, Economopoulou, M, Kajikawa, T, Troullinaki, M, Ziogas, A, Ruppova, K, Hosur, K, Maekawa, T, Wang, B, Subramanian, P, Tonn, T, Verginis, P, von Bonin, M, Wobus, M, Bornhäuser, M, Grinenko, T, Di Scala, M, Hidalgo, A, Wielockx, B, Hajishengallis, G & Chavakis, T 2017, 'Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche', Journal of Clinical Investigation, vol. 127, no. 10, pp. 3624-3639. https://doi.org/10.1172/JCI92571

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T1 - Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche

AU - Mitroulis, Ioannis

AU - Chen, Lan-Sun

AU - Singh, Rashim Pal

AU - Kourtzelis, Ioannis

AU - Economopoulou, Matina

AU - Kajikawa, Tetsuhiro

AU - Troullinaki, Maria

AU - Ziogas, Athanasios

AU - Ruppova, Klara

AU - Hosur, Kavita

AU - Maekawa, Tomoki

AU - Wang, Baomei

AU - Subramanian, Pallavi

AU - Tonn, Torsten

AU - Verginis, Panayotis

AU - von Bonin, Malte

AU - Wobus, Manja

AU - Bornhäuser, Martin

AU - Grinenko, Tatyana

AU - Di Scala, Marianna

AU - Hidalgo, Andres

AU - Wielockx, Ben

AU - Hajishengallis, George

AU - Chavakis, Triantafyllos

N1 - Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details

PY - 2017/10/2

Y1 - 2017/10/2

N2 - 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.

AB - 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.

KW - Animals

KW - Carrier Proteins/genetics

KW - Chemokine CXCL12/genetics

KW - Endothelial Cells/metabolism

KW - Hematopoietic Stem Cells/metabolism

KW - Humans

KW - Integrin beta3/genetics

KW - Intercellular Signaling Peptides and Proteins

KW - Mice

KW - Mice, Knockout

KW - Myelopoiesis

KW - Stem Cell Niche

KW - Stress, Physiological

U2 - 10.1172/JCI92571

DO - 10.1172/JCI92571

M3 - Article

C2 - 28846069

SN - 0021-9738

VL - 127

SP - 3624

EP - 3639

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 10

ER -

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

Abstract

Bibliographical note

Keywords

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Ioannis Kourtzelis

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