Megakaryocytic IGF1 Coordinates Activation and Ferroptosis to Safeguard Hematopoietic Stem Cell Regeneration After Radiation Injury

Overview

Journal Cell Commun Signal

Publisher Biomed Central

Specialties Biochemistry
Cell Biology

Date 2024 May 27

PMID 38802843

Authors

Weinian Liao

Xinliang Chen

Shuzhen Zhang

Jun Chen

Chaonan Liu

Kuan Yu

Yimin Zhang

Mo Chen

Fang Chen

Mingqiang Shen

Binghui Lu

Songling Han

Song Wang

Junping Wang

Changhong Du

Affiliations

Soon will be listed here.

Abstract

Background: Hematopoietic stem cell (HSC) regeneration underlies hematopoietic recovery from myelosuppression, which is a life-threatening side effect of cytotoxicity. HSC niche is profoundly disrupted after myelosuppressive injury, while if and how the niche is reshaped and regulates HSC regeneration are poorly understood.

Methods: A mouse model of radiation injury-induced myelosuppression was built by exposing mice to a sublethal dose of ionizing radiation. The dynamic changes in the number, distribution and functionality of HSCs and megakaryocytes were determined by flow cytometry, immunofluorescence, colony assay and bone marrow transplantation, in combination with transcriptomic analysis. The communication between HSCs and megakaryocytes was determined using a coculture system and adoptive transfer. The signaling mechanism was investigated both in vivo and in vitro, and was consolidated using megakaryocyte-specific knockout mice and transgenic mice.

Results: Megakaryocytes become a predominant component of HSC niche and localize closer to HSCs after radiation injury. Meanwhile, transient insulin-like growth factor 1 (IGF1) hypersecretion is predominantly provoked in megakaryocytes after radiation injury, whereas HSCs regenerate paralleling megakaryocytic IGF1 hypersecretion. Mechanistically, HSCs are particularly susceptible to megakaryocytic IGF1 hypersecretion, and mTOR downstream of IGF1 signaling not only promotes activation including proliferation and mitochondrial oxidative metabolism of HSCs, but also inhibits ferritinophagy to restrict HSC ferroptosis. Consequently, the delicate coordination between proliferation, mitochondrial oxidative metabolism and ferroptosis ensures functional HSC expansion after radiation injury. Importantly, punctual IGF1 administration simultaneously promotes HSC regeneration and hematopoietic recovery after radiation injury, representing a superior therapeutic approach for myelosuppression.

Conclusions: Our study identifies megakaryocytes as a last line of defense against myelosuppressive injury and megakaryocytic IGF1 as a novel niche signal safeguarding HSC regeneration.

Citing Articles

Advances in the Regulation of Hematopoietic Homeostasis by Programmed Cell Death Under Radiation Conditions.

Shu M, Zhang J, Huang H, Chen Y, Shi Y, Zeng H Stem Cell Rev Rep. 2025; .

PMID: 40056317 DOI: 10.1007/s12015-025-10863-2.

Insights into ionizing radiation-induced bone marrow hematopoietic stem cell injury.

Zhang Y, Chen X, Wang X, Chen J, Du C, Wang J Stem Cell Res Ther. 2024; 15(1):222.

PMID: 39039566 PMC: 11265359. DOI: 10.1186/s13287-024-03853-7.

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