Thrombopoietin mimetic therapy alleviates radiation-induced bone marrow vascular injury in a bone marrow transplant mouse model.

Autor: Ghimire H; Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, United States., Sargur Madabushi S; Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, United States., Vercellino J; Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, United States.; Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, United States., Brooks J; Department of Radiation Oncology, Mayo Clinic, Rochester, MN, United States., Zuro D; Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States., Lim JE; Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, United States., Vishwasrao P; Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, United States., Abdelhamid AMH; Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, United States.; Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt., Strome G; Department of Radiotherapy, Universitair Ziekenhuis (UZ) Brussels, Brussels, Belgium., Eichenbaum G; Johnson and Johnson, Office of the Chief Medical Officer, New Brunswick, NJ, United States., Al Malki M; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, United States., Guha C; Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, United States.; Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, United States., Hui SK; Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, United States.
Jazyk: angličtina
Zdroj: Frontiers in oncology [Front Oncol] 2024 Oct 10; Vol. 14, pp. 1414488. Date of Electronic Publication: 2024 Oct 10 (Print Publication: 2024).
DOI: 10.3389/fonc.2024.1414488
Abstrakt: Background: There is a need for therapies that can mitigate bone marrow dysfunction and organ toxicity that occur following myeloablative injury and reduced intensity conditioning regimens used in patients undergoing bone marrow transplantation (BMT). The pathogenesis of adverse effects from BMT conditioning has been linked to injury to the vascular endothelium, bone marrow (BM), and other organs.
Objective: To evaluate the impact of the thrombopoietin mimetic drug JNJ-26366821 (TPOm) on BM vascular recovery in mice undergoing myeloablative radiation conditioning followed by BMT.
Study Design: TPOm (doses: 0 µg, 300 µg, 1000 µg per Kg body weight) was administered on Days 0 and 7 after BMT, in mice receiving a total body irradiation (TBI) conditioning regimen (5.5 Gy x 2) before congenic BMT. BM donner cell engraftment was analyzed using flow cytometry on Days 7, 14, and 30 post-BMT. The morphological and biophysical properties of the BM vasculature were evaluated by intravital multiphoton microscopy (MPM) and immunofluorescence confocal imaging. Herein, morphological properties involve microvascular density (MVD), vessel diameter, and vascular area, while biophysical properties include transfer rate (K trans ) of contrast within the BM vascular niche, as well as the fractional volume ( v ec ) of extracellular extravascular tissue (EES).
Results: No significant difference in donor chimerism was observed at days 7, 14, and 30 post-BMT, between TPOm and PBS-treated mice. TPOm intervention improved BM vasculature regeneration in transplanted mice. The MVD, K trans, and BM vasculature as well as vascular endothelial growth factor receptor-2 (VEGFR2) in the BM, showed a dose dependent improvement in mice treated with TPOm. On day 14 post-BMT, the group receiving 1000 µg/Kg TPOm showed significant shifts (p-value < 0.05) in MVD, K trans , and VEGFR2 expression from their corresponding control types (TPOm dose 0 µg) towards levels comparable to healthy controls.
Conclusion: TPOm intervention augments BM vascular structure and function, which may be important for hematopoietic recovery and bone marrow function in radiation conditioned hematopoietic stem cell transplant patients, in addition to enhancing platelet recovery.
Competing Interests: SH received honoraria from and consults for Janssen Research & Development. CG received honoraria from and consults for Janssen Research & Development. Also, CG is the Scientific advisor for focused ultrasound foundation and Co-founder of BioCovergent Health. GE participated in this work as an employee of Johnson & Johnson and its subsidiary Janssen Pharmaceuticals and stands to benefit financially from the successful development of the compound. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2024 Ghimire, Sargur Madabushi, Vercellino, Brooks, Zuro, Lim, Vishwasrao, Abdelhamid, Strome, Eichenbaum, Al Malki, Guha and Hui.)
Databáze: MEDLINE
Externí odkaz: