Menatetrenone facilitates hematopoietic cell generation in a manner that is dependent on human bone marrow mesenchymal stromal/stem cells

Abstract

Vitamin K2 in the form of menatetrenone has clinical benefits for osteoporosis and cytopenia. Given the dominant role of mesenchymal-osteolineage cells in the regulation of hematopoiesis, we investigated whether menatetrenone alters the hematopoiesis-supportive capability of human bone marrow mesenchymal stromal/stem cells (BM-MSCs). Menatetrenone up-regulated fibronectin protein expression in BM-MSCs without affecting their proliferation and differentiation capabilities. In addition, menatetrenone treatment of BM-MSCs enhanced generation of the CD34+ cell population in co-cultures through acceleration of the cell cycle. This effect was associated with cell–cell interactions mediated by VLA-4 and fibronectin. This proposal was supported by cytokine array and quantitative real-time PCR analyses, in which there were no significant differences between the expression levels of hematopoiesis-associated soluble factors in naïve and menatetrenone-treated BM-MSCs. Profiling of hematopoietic cells in co-cultures with menatetrenone-treated BM-MSCs demonstrated that they included significantly more CD34+CD38+ hematopoietic progenitor cells and cells skewed toward myeloid and megakaryocytic lineages than those in co-cultures with untreated BM-MSCs. Notably, myelodysplastic syndrome-derived cells were induced to undergo apoptosis when co-cultured with BM-MSCs, and this effect was enhanced by menatetrenone. Overall, our findings indicate that pharmacological treatment with menatetrenone bestows a unique hematopoiesis-supportive capability on BM-MSCs, which may contribute to the clinical improvement of cytopenia.

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Acknowledgements

We thank Ms. Yoko Nakagawa (Kyoto University) for her excellent technical assistance.

Funding

This work was supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology in Japan (#18K08323 to Y.M., #19K17856 to S.F.), by a Japanese Society of Hematology Research Grant (to Y.M. and S.F.), and by the Takeda Science Foundation (S.F.).

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Conception and design of the study: AF, MI, SF, TM, AA, KT, AT-K, and YM. Acquisition of data: AF, MI, SF, and YM. Analysis and interpretation of data: AF, MI, SF, TM, AA, KT, AT-K, and YM. Drafting of the article: AF, MI, SF, TM, AA, KT, AT-K, and YM. All authors have approved the final article.

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Correspondence to Aya Fujishiro.

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Fujishiro, A., Iwasa, M., Fujii, S. et al. Menatetrenone facilitates hematopoietic cell generation in a manner that is dependent on human bone marrow mesenchymal stromal/stem cells. Int J Hematol (2020). https://doi.org/10.1007/s12185-020-02916-8

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Keywords

  • Menatetrenone
  • Vitamin K2
  • Hematopoiesis
  • Mesenchymal stromal/stem cell (MSC)
  • Microenvironment