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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

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 6

Endothelial jagged-2 modulates the cell-cycle status of HSPCs during regeneration.

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Endothelial jagged-2 modulates the cell-cycle status of HSPCs during reg...
(A) On day 16 after irradiation, the flow cytometric gating for KLS, CD150–CD48– short-term KLS (ST-HSCs), and CD150–CD48+ KLS multipotent progenitor cells is shown. (B) At day 16 after irradiation, the percentage of Ki67– G0 cells among KLS cells was quantified (n = 5 for each group). (C) At day 14 after irradiation, the percentage of apoptotic cells among Lin– cells, cKit+Lin– cells, KLS cells, and Sca1+Lin– cells was quantified. (D) On day 29 after 650 cGy irradiation, the percentage of Ki67– G0 cells among Lin– cells and KLS cells was quantified (n = 5 for each group). Error bars indicate the SEM. *P < 0.05, by unpaired 2-tailed t test. The numbers in the flow plots represent percentages of cells.
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