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Stem cell biology

Mesenchymal PGD2 activates an ILC2-Treg axis to promote proliferation of normal and malignant HSPCs

Leukemia volume 34, pages 3028–3041 (2020)Cite this article

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Abstract

Cyclooxygenase (COX)-dependent production of prostaglandins (PGs) is known to play important roles in tumorigenesis. PGD2 has recently emerged as a key regulator of tumor- and inflammation-associated functions. Here we show that mesenchymal stromal cells (MSCs) from patients with acute myeloid leukemia (AML) or normal MSCs overexpressing COX2 promote proliferation of co-cultured hematopoietic stem and progenitor cells (HSPCs), which can be prevented by treatment with COX2 knockdown or TM30089, a specific antagonist of the PGD2 receptor CRTH2. Mechanistically, we demonstrate that PGD2-CRTH2 signaling acts directly on type 2 innate lymphoid cells (ILC2s), potentiating their expansion and driving them to produce Interleukin-5 (IL-5) and IL-13. Furthermore, IL-5 but not IL-13 expands CD4+CD25+IL5Rα+ T regulatory cells (Tregs) and promotes HSPC proliferation. Disruption of the PGD2-activated ILC2-Treg axis by specifically blocking the PGD2 receptor CRTH2 or IL-5 impedes proliferation of normal and malignant HSPCs. Conversely, co-transfer of CD4+CD25+IL5Rα+ Tregs promotes malignant HSPC proliferation and accelerates leukemia development in xenotransplanted mice. Collectively, these results indicate that the mesenchymal source of PGD2 promotes proliferation of normal and malignant HSPCs through activation of the ILC2-Treg axis. These findings also suggest that this novel PGD2-activated ILC2-Treg axis may be a valuable therapeutic target for cancer and inflammation-associated diseases.

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Fig. 1: Mesenchymal COX2 promote proliferation of co-cultured HSPCs.
Fig. 2: CRTH2/DP2 mediates the effect of mesenchymal PGD2 in HSPC expansion.
Fig. 3: Activation of mesenchymal PGD2-CRTH2/ILC2 axis overproduces IL-5, which promotes HSPC expansion.
Fig. 4: Mesenchymal PGD2-activated ILC2s-induced IL-5 expands CD4+CD25+IL5Rα+ Tregs, which promote HSPC expansion.
Fig. 5: Mesenchymal PGD2-expanded CD4+CD25+ Tregs produce IL-10, which promotes co-cultured HSPC expansion.
Fig. 6: Mesenchymal PGD2-activated ILC2-Treg axis promotes proliferation of normal HSPCs.
Fig. 7: Mesenchymal PGD2-activated ILC2-Treg axis promotes proliferation of malignant HSPCs.
Fig. 8: Mesenchymal PGD2 activates an ILC2-Treg axis to promote proliferation of normal and malignant HSPCs.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by NIH/NHLBI grant (R01HL151390), NIH Tumor Microenvironment Center of Biomedical Excellence Award (P20GM121322), West Virginia University (WVU) Health Science Center (HSC) and School of Pharmacy (SOP) startup funds, a Leukemia Research Foundation (LRF) Award, and an American Cancer Society (ACS) Institutional Research Grant. We thank the BioSpecimen Processing Core at West Virginia University Cancer Center for the bone marrow samples used in this study.

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  1. Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, 26506, USA

    Limei Wu, Qiqi Lin, Zhilin Ma, Fabliha Ahmed Chowdhury, Md Habibul Hasan Mazumder & Wei Du

  2. Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, China

    Qiqi Lin & Zhilin Ma

  3. Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program, West Virginia University Cancer Institute, Morgantown, WV, 26506, USA

    Wei Du

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LW performed the research and analyzed the data; QL, ZM, FAC, MHHM performed some of the research, assist data analysis. WD designed the research, analyzed the data, and wrote the paper.

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Wu, L., Lin, Q., Ma, Z. et al. Mesenchymal PGD2 activates an ILC2-Treg axis to promote proliferation of normal and malignant HSPCs. Leukemia 34, 3028–3041 (2020). https://doi.org/10.1038/s41375-020-0843-8

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