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

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 8

Jagged-2 supplied by ECs and hematopoietic cells maintains HSC number.

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Jagged-2 supplied by ECs and hematopoietic cells maintains HSC number. (...
(A) Summary of mRNA expression of Notch ligands Jag1, Jag2, Dll1, Dll3, and Dll4 in HSPCs. Data are from the published RNA sequencing data of SP-KLS-CD150+ cells (29). VE-cadherin-Cre mice (30) were crossed with Jag2fl/fl mice to delete exons 1 and 2 of the Jag2 gene from ECs and hematopoietic cells. (B and C) After crossing of VE-cadherin-Cre mice with Rosa26CAG<stop>tdtomato mice, the deletion efficiency of VE-cadherin-Cre in ECs (B) and hematopoietic cells within the BM (C) was quantified. (D–F) The platelets (D), WBC (E), and RBC (F) were monitored after sublethal irradiation with 650 cGy at the indicated time points. (G) The survival curve of Jag2fl/fl or Jag2KO mice was plotted. (H and I) Competitive repopulating assay was carried out using BMMNCs from Jag2fl/fl or Jag2KO mice (n = 7 for each group). For B and C, n = 3 biological replicates for each group. For D–G, n = 5 for Jag2fl/fl, n = 4 for Jag2KO mice. For I, n = 7 each for Jag2fl/fl and Jag2KO mice. Error bars indicate SEM. For D–F, at each individual time point, the difference between Jag2fl/fl and Jag2KO mice was compared using a 2-tailed t test. The resulting P value is shown. For D–F and J, the overall differences of the 2 curves were also compared using 2-way ANOVA, and the P values of the observed variance based on the genotype are as follows: for D, P = 0.0025; for E, P < 0.0001; for F, P = 0.0373; for I, P = 0.0016. *P < 0.05; **P < 0.01 (**P value was determined by 2-way ANOVA).