Clodronate-liposomes aggravate irradiation-induced myelosuppression by promoting myeloid differentiation

Abstract

Purpose

Clodronate-liposomes (Clod-Lip) is an effective candidate drug for treating chronic myelomonocytic leukemia, autoimmune hemolytic anemia and immune thrombocytopenic purpura in mice experiments. But its role in hematopoietic recovery after acute myelosuppression is still unknown. We aim to explore the function and underlining mechanisms of Clod-Lip on hematopoietic reconstitution after sublethal dose irradiation in mice.

Materials and methods

Mice at 8-10 weeks received a total-body sublethal dose γ-irradiation (TBI) and injected with Clod-Lip or PBS-Liposomes (PBS-Lip) every 4 days after TBI. The survival rate of each group was recorded. Flow cytometry was used to analyze changes in hematopoietic stem cells and their progenies in bone marrow. ELISA and RT-qPCR were used for the analysis of hematopoietic regulatory factors. Regarding IL-1β inhibition, 25 mg/kg diacerein or an equal volume of DMSO was intraperitoneally injected into mice every day after TBI.

Results

In sublethal dose-irradiated mice, Clod-Lip reduced the survival rate, the total number of bone marrow and hematopoietic stem cells, delayed peripheral blood recovery of red blood cells and platelets. However, it could increase the number of CMP, MEP and myeloid cells, which suggested that Clod-Lip could induce HSC to myeloid differentiation in vivo. We further verified that Clod-Lip may induce myeloid differentiation by bone marrow microenvironmental factor IL-1β.

Conclusions

In summary, this study suggested that Clod-Lip may aggravate inhibitor effect of hematopoietic function and promote myeloid differentiation in myelosuppression mice model.

Keywords:

• Clodronate-liposomes
• hematopoiesis
• γ-radiation
• IL-1β
• myeloid

Disclosure statement

All authors have no dispute of interest to disclose.

Data availability statement

The data and materials used to support the findings in this study are included in the article.

Additional information

Funding

This study was supported by National Natural Science Foundation of China [Grant numbers 81700178, 31872795, and 81570096]; Natural Science Foundation of Jiangsu Province under Grant [number BK20170259]; Jiangsu Province’s Key Provincial Talents Program under Grant [number ZDRCA2016054]; Major Basic Research Project of the Natural Science Foundation of the Jiangsu Higher Education Institutions [number 17KJA320008]; China Postdoctoral Science Foundation Grant [number 2018M632380]; Jiangsu Provincial Key Research and Development Program under Grant [number BE2018637]; and Jiangsu Postdoctoral Science Foundation under Grant [number 1701064B].

Notes on contributors

Wen Ju

Wen Ju is an associate professor in the Department of hematology, Xuzhou medical University. Her research interests are in the area of bone marrow microenvironment and hematopoietic recovery. She performed the experiments, analyzed data and wrote the manuscript.

Wenyi Lu

Wenyi Lu is a postgraduate in the Department of hematology, Xuzhou medical University. Her research interests are in the area of radiation injuries and hematopoietic recovery. She performed the experiments and analyzed data.

Yurong Bao

Yurong Bao is a postgraduate in the Department of hematology, Xuzhou medical University. Her research interests are in the area of bone marrow macrophage and hematopoietic recovery. She performed the experiments and analyzed data.

Tiantian Sun

Tiantian Sun is a postgraduate in the Department of hematology, Xuzhou medical University. Her research interests are in the area of bone marrow macrophage and hematopoietic recovery. She performed the experiments and analyzed data.

Seyram Yao Adzraku

Seyram Yao Adzraku is a postgraduate in the Department of hematology, Xuzhou medical University. His research interests are in the area of hematopoietic recovery after irradiation. She performed the experiments and analyzed data.

Chunling Fu

Chunling Fu is an associate professor in the Department of hematology, Xuzhou medical University. Her research interests are in the area of hematopoietic recovery and MPN. She performed the experiments and analyzed data.

Kunming Qi

Kunming Qi works in the Department of hematology, Xuzhou medical University. His research interests are in the area of leukemia and hematopoietic recovery. He performed the experiments and analyzed data.

Xi Zhang

Xi Zhang is a professor at the Medical Center of Hematology, Xinqiao Hospital, Third Military Medical University, He specializes in bone marrow microenvironment and hematopoietic recovery. He analyzed data and provided fruitful discussion.

Zhenyu Li

Zhenyu Li is a professor in the Department of hematology, Xuzhou medical University. His research interests are in the area of leukemia and hematopoietic recovery. He analyzed data and provided fruitful discussion.

Kailin Xu

Kailin Xu is a professor in the Department of hematology, Xuzhou medical University. His research interests are in the area of leukemia and hematopoietic recovery. He designed the study, analyzed data and wrote the manuscript.

Jianlin Qiao

Jianlin Qiao is a professor in the Department of hematology, Xuzhou medical University. He is good at platelet and hematopoietic recovery. He designed the study, analyzed data and wrote the manuscript.

Lingyu Zeng

Lingyu Zeng is a professor in the Department of hematology, Xuzhou medical University. She works in the area of bone marrow microenvironment and hematopoietic recovery. She designed the study, analyzed data and wrote the manuscript.