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NORMAL HEMATOPOIESIS

MiR-9-1 controls osteoblastic regulation of lymphopoiesis

Leukemia volume 37, pages 2261–2275 (2023)Cite this article

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Abstract

The highly conserved MicroRNA-9 (miR-9) family consists of three members. We discovered that miR-9-1 deletion reduced mature miR-9 expression, causing 43% of the mice to display smaller size and postweaning lethality. MiR-9-1-deficient mice with growth defects experienced severe lymphopenia, but other blood cells were unaffected. The lymphopenia wasn’t due to defects in hematopoietic progenitors, as mutant bone marrow (BM) cells underwent normal lymphopoiesis after transplantation into wild-type recipients. Additionally, miR-9-1-deficient mice exhibited impaired osteoblastic bone formation, as mutant mesenchymal stem cells (MSCs) failed to differentiate into osteoblastic cells (OBs). RNA sequencing revealed reduced expression of master transcription factors for osteoblastic differentiation, Runt-related transcription factor 2 (Runx2) and Osterix (Osx), and genes related to collagen formation, extracellular matrix organization, and cell adhesion, in miR-9-1-deficient MSCs. Follistatin (Fst), an antagonist of bone morphogenetic proteins (BMPs), was found to be a direct target of miR-9-1. Its deficiency led to the up-regulation of Fst, inhibiting BMP signaling in MSCs, and reducing IL-7 and IGF-1. Thus, miR-9-1 controls osteoblastic regulation of lymphopoiesis by targeting the Fst/BMP/Smad signaling axis.

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Fig. 1: Deficiency of miR-9-1 reduces overall mature miR-9 expression and causes growth defect and white blood cell reduction with incomplete penetrance.
Fig. 2: Lack of miR-9-1 impairs lymphopoiesis.
Fig. 3: MiR-9-1 deficiency reduces hematopoietic progenitors, especially CLPs.
Fig. 4: Restored the hematopoietic progenitor populations and lymphopoiesis of miR-9-1-deficient BM cells after transplantation.
Fig. 5: MiR-9-1 is required for osteoblastic differentiation.
Fig. 6: MiR-9-1 regulates the expression of the genes associated with osteoblastic differentiation and function in MSCs.
Fig. 7: MiR-9-5p directly targets Fst to regulate BMP signaling in MSCs.

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Data availability

Sequencing data have been deposited in the GEO repository under the Accession number GSE239376.

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Acknowledgements

The authors acknowledge Robert Burns and Shikan Zheng for their assistance with the analysis of the high-throughput sequence data. This work is supported in part by NIH grants AI079087 (D.W.), HL130724 (D.W.), and HL148120 (R.W.). Y.Z. (Yongwei Zheng) is supported by The Elizabeth Elser Doolit - the Postdoctoral Fellowship. Y.Z. (Yongguang Zhang) receives a stipend from Fujian Normal University, China.

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Authors and Affiliations

  1. Versiti Blood Research Institute, Milwaukee, WI, 53213, USA

    Yongguang Zhang, Yongwei Zheng, Yuhong Chen, Mei Yu, Karen-Sue Carlson, Renren Wen & Demin Wang

  2. Biomedical Research Center of South China, Fujian Normal University, Fujian, 350117, China

    Yongguang Zhang, Danfeng Lin, Dongya Cui & Miaohui Huang

  3. Department of Orthopedics, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 205006, China

    Xinlin Su

  4. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Yong Sun & Yabing Chen

  5. Research Department, Birmingham Veterans Affairs Medical Center, Birmingham, AL, 35294, USA

    Yong Sun & Yabing Chen

  6. Division of Hematology and Oncology, Department of Medicine, Department of Biochemistry and Molecular Biology, the University of Florida, Gainesville, FL, 32610, USA

    Zhijian Qian

  7. Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Karen-Sue Carlson

  8. Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Renren Wen & Demin Wang

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YZ (Yongguang Zhang) contributed to the experimental design, performed the experiments, analyzed the results and wrote the draft of the manuscript. DL, YC, YZ (Yongwei Zheng), MY, DC, MH, XS, and YS performed some experiments. YC, ZQ, and KSC provided intellectual input and critically read the manuscript. RW provided intellectual input, analyzed the results and wrote the manuscript. DW conceived and supervised the study, analyzed the results and wrote the manuscript.

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Zhang, Y., Lin, D., Zheng, Y. et al. MiR-9-1 controls osteoblastic regulation of lymphopoiesis. Leukemia 37, 2261–2275 (2023). https://doi.org/10.1038/s41375-023-02014-8

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