Endothelial Jagged-1 Is necessary for homeostatic and regenerative hematopoiesis

Michael G. Poulos; Peipei Guo; Natalie M. Kofler; Sandra Pinho; Michael C. Gutkin; Anastasia Tikhonova; Iannis Aifantis; Paul S. Frenette; Jan Kitajewski; Shahin Rafii; Jason M. Butler

doi:10.1016/j.celrep.2013.07.048

Endothelial Jagged-1 Is necessary for homeostatic and regenerative hematopoiesis

Michael G. Poulos, Peipei Guo, Natalie M. Kofler, Sandra Pinho, Michael C. Gutkin, Anastasia Tikhonova, Iannis Aifantis, Paul S. Frenette, Jan Kitajewski, Shahin Rafii, Jason M. Butler

Medicine

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

195 Scopus citations

Abstract

The bone marrow (BM) microenvironment is composed of multiple niche cells that, by producing paracrine factors, maintain and regenerate the hematopoietic stem cell (HSC) pool (Morrison and Spradling, 2008). We have previously demonstrated that endothelial cells support the proper regeneration of the hematopoietic system following myeloablation (Butler etal., 2010; Hooper etal., 2009; Kobayashi etal., 2010). Here, we demonstrate that expression of the angiocrine factor Jagged-1, supplied by the BM vascular niche, regulates homeostatic and regenerative hematopoiesis through a Notch-dependent mechanism. Conditional deletion of Jagged-1 in endothelial cells (Jag1^(ECKO) mice) results in a profound decrease in hematopoiesis and premature exhaustion of the adult HSC pool, whereas quantification and functional assays demonstrate that loss of Jagged-1 does not perturb vascular or mesenchymal compartments. Taken together, these data demonstrate that the instructive function of endothelial-specific Jagged-1 is required to support the self-renewal and regenerative capacity of HSCs in the adult BM vascular niche

Original language	English (US)
Pages (from-to)	1022-1034
Number of pages	13
Journal	Cell Reports
Volume	4
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2013.07.048
State	Published - May 12 2013

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2013.07.048

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@article{49688c0b0a0e46f6a0ecb5ca88fbc4c3,

title = "Endothelial Jagged-1 Is necessary for homeostatic and regenerative hematopoiesis",

abstract = "The bone marrow (BM) microenvironment is composed of multiple niche cells that, by producing paracrine factors, maintain and regenerate the hematopoietic stem cell (HSC) pool (Morrison and Spradling, 2008). We have previously demonstrated that endothelial cells support the proper regeneration of the hematopoietic system following myeloablation (Butler etal., 2010; Hooper etal., 2009; Kobayashi etal., 2010). Here, we demonstrate that expression of the angiocrine factor Jagged-1, supplied by the BM vascular niche, regulates homeostatic and regenerative hematopoiesis through a Notch-dependent mechanism. Conditional deletion of Jagged-1 in endothelial cells (Jag1(ECKO) mice) results in a profound decrease in hematopoiesis and premature exhaustion of the adult HSC pool, whereas quantification and functional assays demonstrate that loss of Jagged-1 does not perturb vascular or mesenchymal compartments. Taken together, these data demonstrate that the instructive function of endothelial-specific Jagged-1 is required to support the self-renewal and regenerative capacity of HSCs in the adult BM vascular niche",

author = "Poulos, {Michael G.} and Peipei Guo and Kofler, {Natalie M.} and Sandra Pinho and Gutkin, {Michael C.} and Anastasia Tikhonova and Iannis Aifantis and Frenette, {Paul S.} and Jan Kitajewski and Shahin Rafii and Butler, {Jason M.}",

note = "Funding Information: We would like to thank Kathleen Loomes and Klaus Kaestner for generating and Dr. Jon Epstein for sending us the Jag1 fl/fl mice. This work was supported by the Tri-Institutional Stem Cell Initiative (M.G.P. and J.M.B.), the National Institutes of Health (S.R., J.M.B, P.S.F., S.P., N.M.K., and J.K.), Ansary Stem Cell Institute (S.R. and J.M.B), the Howard Hughes Medical Institute (S.R. and I.A.), Empire State Stem Cell Board and New York State Department of Health grants (NYSTEM, C024180, C026438, C026878) (S.R.); NHLBI R01s HL097797 and DK095039 (S.R.); Qatar National Priorities Research Foundation NPRP08-663-3-140 and Qatar foundation BioMedical Research Program (BMRP) (S.R.). ",

year = "2013",

month = may,

day = "12",

doi = "10.1016/j.celrep.2013.07.048",

language = "English (US)",

volume = "4",

pages = "1022--1034",

journal = "Cell Reports",

issn = "2211-1247",

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T1 - Endothelial Jagged-1 Is necessary for homeostatic and regenerative hematopoiesis

AU - Poulos, Michael G.

AU - Guo, Peipei

AU - Kofler, Natalie M.

AU - Pinho, Sandra

AU - Gutkin, Michael C.

AU - Tikhonova, Anastasia

AU - Aifantis, Iannis

AU - Frenette, Paul S.

AU - Kitajewski, Jan

AU - Rafii, Shahin

AU - Butler, Jason M.

N1 - Funding Information: We would like to thank Kathleen Loomes and Klaus Kaestner for generating and Dr. Jon Epstein for sending us the Jag1 fl/fl mice. This work was supported by the Tri-Institutional Stem Cell Initiative (M.G.P. and J.M.B.), the National Institutes of Health (S.R., J.M.B, P.S.F., S.P., N.M.K., and J.K.), Ansary Stem Cell Institute (S.R. and J.M.B), the Howard Hughes Medical Institute (S.R. and I.A.), Empire State Stem Cell Board and New York State Department of Health grants (NYSTEM, C024180, C026438, C026878) (S.R.); NHLBI R01s HL097797 and DK095039 (S.R.); Qatar National Priorities Research Foundation NPRP08-663-3-140 and Qatar foundation BioMedical Research Program (BMRP) (S.R.).

PY - 2013/5/12

Y1 - 2013/5/12

N2 - The bone marrow (BM) microenvironment is composed of multiple niche cells that, by producing paracrine factors, maintain and regenerate the hematopoietic stem cell (HSC) pool (Morrison and Spradling, 2008). We have previously demonstrated that endothelial cells support the proper regeneration of the hematopoietic system following myeloablation (Butler etal., 2010; Hooper etal., 2009; Kobayashi etal., 2010). Here, we demonstrate that expression of the angiocrine factor Jagged-1, supplied by the BM vascular niche, regulates homeostatic and regenerative hematopoiesis through a Notch-dependent mechanism. Conditional deletion of Jagged-1 in endothelial cells (Jag1(ECKO) mice) results in a profound decrease in hematopoiesis and premature exhaustion of the adult HSC pool, whereas quantification and functional assays demonstrate that loss of Jagged-1 does not perturb vascular or mesenchymal compartments. Taken together, these data demonstrate that the instructive function of endothelial-specific Jagged-1 is required to support the self-renewal and regenerative capacity of HSCs in the adult BM vascular niche

AB - The bone marrow (BM) microenvironment is composed of multiple niche cells that, by producing paracrine factors, maintain and regenerate the hematopoietic stem cell (HSC) pool (Morrison and Spradling, 2008). We have previously demonstrated that endothelial cells support the proper regeneration of the hematopoietic system following myeloablation (Butler etal., 2010; Hooper etal., 2009; Kobayashi etal., 2010). Here, we demonstrate that expression of the angiocrine factor Jagged-1, supplied by the BM vascular niche, regulates homeostatic and regenerative hematopoiesis through a Notch-dependent mechanism. Conditional deletion of Jagged-1 in endothelial cells (Jag1(ECKO) mice) results in a profound decrease in hematopoiesis and premature exhaustion of the adult HSC pool, whereas quantification and functional assays demonstrate that loss of Jagged-1 does not perturb vascular or mesenchymal compartments. Taken together, these data demonstrate that the instructive function of endothelial-specific Jagged-1 is required to support the self-renewal and regenerative capacity of HSCs in the adult BM vascular niche

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U2 - 10.1016/j.celrep.2013.07.048

DO - 10.1016/j.celrep.2013.07.048

M3 - Article

C2 - 24012753

AN - SCOPUS:84884157062

SN - 2211-1247

VL - 4

SP - 1022

EP - 1034

JO - Cell Reports

JF - Cell Reports

IS - 5

ER -

Endothelial Jagged-1 Is necessary for homeostatic and regenerative hematopoiesis

Abstract

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