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Transgenic expression of a canonical Wnt inhibitor, kallistatin, is associated with decreased circulating CD19+ B lymphocytes in the peripheral blood

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Abstract

Members of the family of serine proteinase inhibitors, such as kallistatin, have been shown to inhibit canonical Wnt-TCF/LEF-β-catenin signaling via their interactions with the Wnt co-receptor LRP6. Yet the effects of transgenic overexpression of anti-Wnt serpins on hematopoiesis and lymphopoiesis are not well known. We studied the effects of human kallistatin (SERPINA4) on Wnt reporter activity in various cell types throughout the hematopoietic system and associated impacts on circulating white blood cell profiles. Transgenic overexpression of kallistatin suppressed Wnt-TCF/LEF-β-catenin signaling in bone marrow, as demonstrated using a Wnt reporter mouse. Further, kallistatin overexpression and treatment were associated with reduced Wnt-TCF/LEF-β-catenin activity in CD34+ c-kit+ bone marrow cells and CD19+ B lymphocytes, with reduced levels of these populations in bone marrow and peripheral circulation, respectively. The presence of CD3+CD4+, CD3+CD8+, and CD3− NK1.1+ T lymphocytes were not significantly affected. Our data suggest that overexpression of kallistatin interferes with lymphopoiesis, ultimately impacting the level of circulating CD19+ B lymphocytes.

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Authors and Affiliations

  1. Department of Cell Biology, University of Oklahoma Health Sciences Center, BSEB 328B, 941 Stanton L. Young Blvd, Oklahoma City, OK, 73104-5020, USA

    Jeffrey D. McBride, William L. Berry, Ralf Janknecht & Jian-xing Ma

  2. Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Jeffrey D. McBride, Xiaochen Liu, Rui Cheng, Kelu Zhou & Jian-xing Ma

  3. Department of Dermatology, Miller School of Medicine, University of Miami, Miami, USA

    Jeffrey D. McBride & Evangelos V. Badiavas

  4. Interdisciplinary Stem Cell Institute, University of Miami, Miami, USA

    Jeffrey D. McBride & Evangelos V. Badiavas

  5. Department of Biochemistry and Molecular Biology, University of Miami, Miami, USA

    Xiaochen Liu

Authors
  1. Jeffrey D. McBride
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  2. Xiaochen Liu
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  8. Jian-xing Ma
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Corresponding author

Correspondence to Jian-xing Ma.

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Funding information

This study was supported by NIH Grants EY012231, EY018659, EY019309 and GM104934 and a Grant from Oklahoma Center for the Advancement of Science and Technology (OCAST), HR13-076.

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Authors have no conflict of interests to disclose.

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12185_2017_2205_MOESM1_ESM.tiff

Supplemental Figure S1. No differences in c-myc and ThPOK expression among T lymphocytes of WT and KS-TG mice. (A) c-myc expression as quantified by real time qPCR in CD3+CD4+ and CD3+CD8+ T lymphocytes from WT and KS-TG mice (triplicate). (B) ThPOK gene expression in CD3+CD4+ cells from WT and KS-TG mice (triplicate). Gapdh was used as housekeeping gene for normalization; ns = not significant (TIFF 651 kb)

12185_2017_2205_MOESM2_ESM.tiff

Supplemental Figure S2. Total peripheral blood cells collected from various populations among WT and KS-TG mice. (A) total leukocytes. (B) total lymphocytes. (C) total CD19+ cells. (D) total CD3+ cells. (E) total CD3+CD4+ cells. (F) total CD3+CD8+ cells. N = 5/group. **p < 0.01. ns = not significant (TIFF 1321 kb)

12185_2017_2205_MOESM3_ESM.tiff

Supplemental Figure S3. Gross and histologic appearance of fixed lymph nodes from WT and KS-TG mice. (A) WT and KS-TG mice lymph nodes, from left to right, columns represent WT male, WT female, KS-TG male, and KS-TG female (n = 5/group shown). (B) sizes of lymph nodes dissected from cervical region in each group (n = 5/group). (C-D) representative H&E sections of lymph nodes from WT and KS-TG mice, as labeled; (C) scale bar 500 um. (D) higher magnification, scale bar 100 um (TIFF 31526 kb)

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McBride, J.D., Liu, X., Berry, W.L. et al. Transgenic expression of a canonical Wnt inhibitor, kallistatin, is associated with decreased circulating CD19+ B lymphocytes in the peripheral blood. Int J Hematol 105, 748–757 (2017). https://doi.org/10.1007/s12185-017-2205-5

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  • DOI: https://doi.org/10.1007/s12185-017-2205-5

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