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STEM CELL BIOLOGY

The GPI-anchored protein CD109 protects hematopoietic progenitor cells from undergoing erythroid differentiation induced by TGF-β

Leukemia volume 36, pages 847–855 (2022)Cite this article

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Abstract

Although a glycosylphosphatidylinositol-anchored protein (GPI-AP) CD109 serves as a TGF-β co-receptor and inhibits TGF-β signaling in keratinocytes, the role of CD109 on hematopoietic stem progenitor cells (HSPCs) remains unknown. We studied the effect of CD109 knockout (KO) or knockdown (KD) on TF-1, a myeloid leukemia cell line that expresses CD109, and primary human HSPCs. CD109-KO or KD TF-1 cells underwent erythroid differentiation in the presence of TGF-β. CD109 was more abundantly expressed in hematopoietic stem cells (HSCs) than in multipotent progenitors and HSPCs of human bone marrow (BM) and cord blood but was not detected in mouse HSCs. Erythroid differentiation was induced by TGF-β to a greater extent in CD109-KD cord blood or iPS cell-derived megakaryocyte–erythrocyte progenitor cells (MEPs) than in wild-type MEPs. When we analyzed the phenotype of peripheral blood MEPs of patients with paroxysmal nocturnal hemoglobinuria who had both GPI(+) and GPI(−) CD34+ cells, the CD36 expression was more evident in CD109− MEPs than CD109+ MEPs. In summary, CD109 suppresses TGF-β signaling in HSPCs, and the lack of CD109 may increase the sensitivity of PIGA-mutated HSPCs to TGF-β, thus leading to the preferential commitment of erythroid progenitor cells to mature red blood cells in immune-mediated BM failure.

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Fig. 1: Erythroid differentiation of TF-1 cells induced by TGF-β and GPI-AP depletion.
Fig. 2: Effect of transient CD109 KD by siRNA on the erythroid differentiation of TF-1 cells and UCB HSPCs.
Fig. 3: Effect of transient CD109 KD on the erythroid differentiation of iPSC-derived HSPCs.
Fig. 4: Erythroid differentiation of CD109+ and CD109− HSPCs from patients with PNH.

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Acknowledgements

This work was supported by MEXT KAKENHI (Grant-in-Aid for Scientific Research (B), Grant Number: 24390243) to SN, MEXT KAKENHI (Grant-in-Aid for Young Scientists (B), Grant Number: 26860363) to TK, MEXT KAKENHI (Grant-in-Aid for Young Scientists, Grant Number: 17K16184 and 19K17823) to KH, MEXT KAKENHI (Grant-in-Aid for Scientific Research (C), Grant Number: 18K08318) to HY. We are grateful to the following doctors providing us with technical advice: Prof. Toshio Kitamura (The institute of Medial Sciences, The University of Tokyo, Japan) and Shinji Mii (Nagoya University). We thank the patients and donors and their physicians for contributing to this study and the Advanced Preventive Medical Sciences Research Center, Kanazawa University for the use of facilities. MT is a Ph.D. candidate at Kanazawa University, and this work is submitted in partial fulfillment of the requirements for the Ph.D.

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Author notes

  1. These authors contributed equally: Mikoto Tanabe, Kohei Hosokawa, Mai Anh Thi Nguyen.

Authors and Affiliations

  1. Department of Hematology, Faculty of Medicine, Institute of Medical Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan

    Mikoto Tanabe, Kohei Hosokawa, Mai Anh Thi Nguyen, Noriharu Nakagawa, Kana Maruyama, Noriaki Tsuji, Ryota Urushihara & Shinji Nakao

  2. Pediatric Department, University of Medicine and Pharmacy at HCMC, Ho Chi Minh City, Vietnam

    Mai Anh Thi Nguyen

  3. Department of Clinical Laboratory Sciences, Kanazawa University Graduate School, Kanazawa, Japan

    Luis Espinoza & Takamasa Katagiri

  4. Department of Internal Medicine, Division of Hematology, Faculty of Medicine, Sohag University, Sohag, Egypt

    Mahmoud I. Elbadry

  5. Department of Respiratory Medicine, Kanazawa University, Kanazawa, Japan

    Md Mohiuddin

  6. Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan

    Masanori Ono & Hiroshi Fujiwara

  7. Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

    Kazuhisa Chonabayashi & Yoshinori Yoshida

  8. Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Kazuhisa Chonabayashi

  9. Division of Transfusion Medicine, Kanazawa University Hospital, Kanazawa, Japan

    Hirohito Yamazaki

  10. Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Japan

    Atsushi Hirao

  11. WPI Nano Life Science Institute, Kanazawa University, Kanazawa, Japan

    Atsushi Hirao

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Contributions

MT, KH, NN, NT, RU, HY, and SN collected clinical data and blood and BM samples. MT, KH, MATN, NN, LE, MIE, and MM, performed most of the in vitro experiments. KM, TK, and AH, performed in vivo experiments. MO and HF collected cord blood samples. KC and YY generated induced pluripotent stem cells. MT, KH, and SN designed the research and wrote the paper. All authors critically reviewed the paper and checked the final version. MT, KH, and MATN contributed equally to this work.

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Correspondence to Shinji Nakao.

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Tanabe, M., Hosokawa, K., Nguyen, M.A.T. et al. The GPI-anchored protein CD109 protects hematopoietic progenitor cells from undergoing erythroid differentiation induced by TGF-β. Leukemia 36, 847–855 (2022). https://doi.org/10.1038/s41375-021-01463-3

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