Menatetrenone facilitates hematopoietic cell generation in a manner that is dependent on human bone marrow mesenchymal s
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ORIGINAL ARTICLE
Menatetrenone facilitates hematopoietic cell generation in a manner that is dependent on human bone marrow mesenchymal stromal/ stem cells Aya Fujishiro1,2 · Masaki Iwasa1,2 · Sumie Fujii1,3 · Taira Maekawa1 · Akira Andoh2 · Kaoru Tohyama4 · Akifumi Takaori‑Kondo3 · Yasuo Miura1,3 Received: 28 January 2020 / Revised: 6 June 2020 / Accepted: 11 June 2020 © Japanese Society of Hematology 2020
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 C D34+ 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 C D34+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. Keywords Menatetrenone · Vitamin K2 · Hematopoiesis · Mesenchymal stromal/stem cell (MSC) · Microenvironment
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12185-020-02916-8) contains supplementary material, which is available to authorized users. * Aya Fujishiro [email protected]‑med.ac.jp 1
Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo‑ku, Kyoto 606‑8507, Japan
2
Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Setatsukinowacho, Otsu, Shiga 520‑2192, Japan
3
Department of Hematology and Oncology, Kyoto University Graduate School for Medicine, 54 Kawaharacho, Shogoin, Sakyo‑ku, Kyoto 606‑8507, Japan
4
Department of Laboratory Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701‑0192, Japan
Vitamin K is required for post-transcr iptional γ-carboxylation of vitamin K-depend
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