Endothelial jagged-2 sustains hematopoietic stem and progenitor reconstitution after myelosuppression
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
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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Research Article Hematology Vascular biology

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

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 4

Endothelial jagged-2 ensures proper HSPC recovery after myelosuppression.

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Endothelial jagged-2 ensures proper HSPC recovery after myelosuppression...
(A) Jag2fl/fl or Jag2ECKO mice were subjected to weekly 5-fluorouracil (5-FU) injections at the dose of 150 mg/kg. Kaplan-Meier survival curve was generated after monitoring of the survival rate of the mice. n = 12 for Jag2fl/fl, n = 9 for Jag2ECKO mice. (B) Jag2fl/fl or Jag2ECKO mice were subjected to sublethal irradiation at 650 cGy, and their survival rate was monitored. This experiment was performed 4 times. Each time, n = 4 mice were used for each genotype. The data are combined and shown in B. (C–H) To monitor the kinetics of hematopoiesis regeneration following irradiation, the quantification of KLS cells and LT-HSCs at day 10 (C and D) (n = 4 for each genotype), day 16 (E and F) (n = 5 for each group), and day 29 (G and H) (n = 5 for each group) after sublethal irradiation is further shown. Error bars indicate the SEM. *P < 0.05 and **P < 0.01, by unpaired 2-tailed t test.