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Endothelial jagged-2 sustains hematopoietic stem and progenitor reconstitution after myelosuppression
Peipei Guo, … , Jason M. Butler, Shahin Rafii
Peipei Guo, … , Jason M. Butler, Shahin Rafii
Published October 23, 2017
Citation Information: J Clin Invest. 2017;127(12):4242-4256. https://doi.org/10.1172/JCI92309.
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Research Article Hematology Vascular biology Article has an altmetric score of 26

Endothelial jagged-2 sustains hematopoietic stem and progenitor reconstitution after myelosuppression

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Abstract

Angiocrine factors, such as Notch ligands, supplied by the specialized endothelial cells (ECs) within the bone marrow and splenic vascular niche play an essential role in modulating the physiology of adult hematopoietic stem and progenitor cells (HSPCs). However, the relative contribution of various Notch ligands, specifically jagged-2, to the homeostasis of HSPCs is unknown. Here, we show that under steady state, jagged-2 is differentially expressed in tissue-specific vascular beds, but its expression is induced in hematopoietic vascular niches after myelosuppressive injury. We used mice with EC-specific deletion of the gene encoding jagged-2 (Jag2) to demonstrate that while EC-derived jagged-2 was dispensable for maintaining the capacity of HSPCs to repopulate under steady-state conditions, by activating Notch2 it did contribute to the recovery of HSPCs in response to myelosuppressive conditions. Engraftment and/or expansion of HSPCs was dependent on the expression of endothelial-derived jagged-2 following myeloablation. Additionally, jagged-2 expressed in bone marrow ECs regulated HSPC cell cycle and quiescence during regeneration. Endothelial-deployed jagged-2 triggered Notch2/Hey1, while tempering Notch2/Hes1 signaling in HSPCs. Collectively, these data demonstrate that EC-derived jagged-2 activates Notch2 signaling in HSPCs to promote hematopoietic recovery and has potential as a therapeutic target to accelerate balanced hematopoietic reconstitution after myelosuppression.

Authors

Peipei Guo, Michael G. Poulos, Brisa Palikuqi, Chaitanya R. Badwe, Raphael Lis, Balvir Kunar, Bi-Sen Ding, Sina Y. Rabbany, Koji Shido, Jason M. Butler, Shahin Rafii

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Figure 1

Jagged-2 is dynamically expressed in BMECs.

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Jagged-2 is dynamically expressed in BMECs.
(A) The expression level of ...
(A) The expression level of Jag2 mRNA in different mouse whole organs (n = 3). The mRNA expression is calculated using GAPDH as internal control. (B) The FPKM (fragments per kilobase of exon per million fragments mapped) value for Jag2 mRNA in primary ECs from various organs. The number of dots indicates the number of biological replicates. (C) Representative flow cytometric plots for the gating of CD31+CD45– BMECs and CD31–CD45– non-BMECs (n = 4). (D) Histogram of jagged-2 expression on BMECs and non-BMECs. (E) qPCR quantification of Jag2 mRNA from sorted BMECs (n = 3) and non-BMECs (n = 5). The RNA expression level is calculated using GAPDH as internal control. (F–H) Representative flow plots for jagged-2 expression in BMECs and non-BMECs (n = 4) under homeostatic conditions. (I–K) Jagged-2 expression within BMECs and non-BMECs at 2 weeks after 650 cGy sublethal irradiation (n = 5). (L) Comparison of percentage of jagged-2+ cells among BMECs under steady state and during regeneration after myeloablative injuries. Error bars indicate the SEM. *P < 0.05, **P < 0.01, and ****P < 0.0001, by 2-tailed unpaired t test. The numbers in the flow plots represent percentages of cells.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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