NRF2-mediated Notch pathway activation enhances hematopoietic reconstitution following myelosuppressive radiation
Jung-Hyun Kim, Rajesh K. Thimmulappa, Vineet Kumar, Wanchang Cui, Sarvesh Kumar, Ponvijay Kombairaju, Hao Zhang, Joseph Margolick, William Matsui, Thomas Macvittie, Sanjay V. Malhotra, Shyam Biswal
Jung-Hyun Kim, Rajesh K. Thimmulappa, Vineet Kumar, Wanchang Cui, Sarvesh Kumar, Ponvijay Kombairaju, Hao Zhang, Joseph Margolick, William Matsui, Thomas Macvittie, Sanjay V. Malhotra, Shyam Biswal
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Research Article

NRF2-mediated Notch pathway activation enhances hematopoietic reconstitution following myelosuppressive radiation

Abstract

A nuclear disaster may result in exposure to potentially lethal doses of ionizing radiation (IR). Hematopoietic acute radiation syndrome (H-ARS) is characterized by severe myelosuppression, which increases the risk of infection, bleeding, and mortality. Here, we determined that activation of nuclear factor erythroid-2–related factor 2 (NRF2) signaling enhances hematopoietic stem progenitor cell (HSPC) function and mitigates IR-induced myelosuppression and mortality. Augmenting NRF2 signaling in mice, either by genetic deletion of the NRF2 inhibitor Keap1 or by pharmacological NRF2 activation with 2-trifluoromethyl-2′-methoxychalone (TMC), enhanced hematopoietic reconstitution following bone marrow transplantation (BMT). Strikingly, even 24 hours after lethal IR exposure, oral administration of TMC mitigated myelosuppression and mortality in mice. Furthermore, TMC administration to irradiated transgenic Notch reporter mice revealed activation of Notch signaling in HSPCs and enhanced HSPC expansion by increasing Jagged1 expression in BM stromal cells. Administration of a Notch inhibitor ablated the effects of TMC on hematopoietic reconstitution. Taken together, we identified a mechanism by which NRF2-mediated Notch signaling improves HSPC function and myelosuppression following IR exposure. Our data indicate that targeting this pathway may provide a countermeasure against the damaging effects of IR exposure.

Authors

Jung-Hyun Kim, Rajesh K. Thimmulappa, Vineet Kumar, Wanchang Cui, Sarvesh Kumar, Ponvijay Kombairaju, Hao Zhang, Joseph Margolick, William Matsui, Thomas Macvittie, Sanjay V. Malhotra, Shyam Biswal

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Figure 5

Administration of NRF2 activator TMC mitigates TBI-induced myelosuppression in mice.

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Administration of NRF2 activator TMC mitigates TBI-induced myelosuppress...
Mice exposed to 6.9 Gy TBI were administered 6 doses of vehicle or TMC (once every 48 hours), beginning 24 hours after TBI. At each time period indicated, a cohort of mice (n = 5–8) were sacrificed and PB was isolated. (A and B) Differential blood cell counts (wbc, rbc, neutrophils, platelets [Plt], and hematocrit [Hct]) in TMC- or vehicle-administered mice at the indicated time period (A) and on day 23 after TBI (B). *P < 0.05; **P < 0.01; ***P < 0.001. Data are representative of two independent experiments. (C) Image of blood samples isolated from TMC- or vehicle-treated mice on day 23 following TBI. (D) H&E-stained bones of TMC- or vehicle-administered mice on day 23 after TBI. Scale bars: 1 mm. (E) Analysis and image of bacterial CFU in PB of TMC- or vehicle-administered mice on days 18–23 after TBI (n = 16–25). **P < 0.001 compared with vehicle-treated mice.