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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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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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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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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DOI: https://doi.org/10.1038/s41375-021-01463-3
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