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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Suttie JW. Vitamin K-dependent carboxylase. Annu Rev Biochem. 1985;54:459–77. https://doi.org/10.1146/annurev.bi.54.070185.002331.
Shitaki S, Tsugawa N, Okano T. Recent advances in vitamin K-dependent Gla-containing proteins and vitamin K nutrition. Osteoporos Sarcopenia. 2015;1:22–38. https://doi.org/10.1016/j.afos.2015.07.009.
Su S, He N, Men P, Song C, Zhai S. The efficacy and safety of menatetrenone in the management of osteoporosis: a systematic review and meta-analysis of randomized controlled trials. Osteoporos Int. 2019;30:1175–86. https://doi.org/10.1007/s00198-019-04853-7.
Takami A, Nakao S, Ontachi Y, Yamauchi H, Matsuda T. Successful therapy of myelodysplastic syndrome with menatetrenone, a vitamin K2 analog. Int J Hematol. 1999;69:24–6.
Miyazawa K, Nishimaki J, Ohyashiki K, Enomoto S, Kuriya S, Fukuda R, et al. Vitamin K2 therapy for myelodysplastic syndromes (MDS) and post-MDS acute myeloid leukemia: information through a questionnaire survey of multi-center pilot studies in Japan. Leukemia. 2000;14:1156–7. https://doi.org/10.1038/sj.leu.2401790.
Takami A, Asakura H, Nakao S. Menatetrenone, a vitamin K2 analog, ameliorates cytopenia in patients with refractory anemia of myelodysplastic syndrome. Ann Hematol. 2002;81:16–9. https://doi.org/10.1007/s00277-001-0391-x.
Akiyama N, Miyazawa K, Kanda Y, Tohyama K, Omine M, Mitani K, et al. Multicenter phase II trial of vitamin K(2) monotherapy and vitamin K(2) plus 1alpha-hydroxyvitamin D(3) combination therapy for low-risk myelodysplastic syndromes. Leuk Res. 2010;34:1151–7. https://doi.org/10.1016/j.leukres.2010.04.006.
Yaguchi M, Miyazawa K, Katagiri T, Nishimaki J, Kizaki M, Tohyama K, et al. Vitamin K2 and its derivatives induce apoptosis in leukemia cells and enhance the effect of all-trans retinoic acid. Leukemia. 1997;11:779–87. https://doi.org/10.1038/sj.leu.2400667.
Nishimaki J, Miyazawa K, Yaguchi M, Katagiri T, Kawanishi Y, Toyama K, et al. Vitamin K2 induces apoptosis of a novel cell lines established from a patient with myelodysplastic syndrome in blastic transformation. Leukemia. 1999;13:1399–405.
Morrison SJ, Scadden DT. The bone marrow niche for haematopoietic stem cells. Nature. 2014;505:327–34. https://doi.org/10.1038/nature12984.
Wei Q, Frenette PS. Niches for hematopoietic stem cells and their progeny. Immunity. 2018;48:632–48. https://doi.org/10.1016/j.immuni.2018.03.024.
Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, Takubo K, et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell. 2004;118:149–61. https://doi.org/10.1016/j.cell.2004.07.004.
Sato M, Asada N, Kawano Y, Wakahashi K, Minagawa K, Kawano H, et al. Osteocytes regulate primary lymphoid organs and fat metabolism. Cell Metab. 2013;18:749–58. https://doi.org/10.1016/j.cmet.2013.09.014.
Fulzele K, Krause DS, Panaroni C, Saini V, Barry KJ, Liu X, et al. Myelopoiesis is regulated by osteocytes through Gsalpha-dependent signaling. Blood. 2013;121:930–9. https://doi.org/10.1182/blood-2012-06-437160.
Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003;425:841–6. https://doi.org/10.1038/nature02040.
Paredes-Gamero EJ, Barbosa CM, Ferreira AT. Calcium signaling as a regulator of hematopoiesis. Front Biosci (Elite Ed). 2012;4:1375–84.
Yao H, Miura Y, Yoshioka S, Miura M, Hayashi Y, Tamura A, et al. Parathyroid hormone enhances hematopoietic expansion via upregulation of cadherin-11 in bone marrow mesenchymal stromal cells. Stem Cells. 2014;32:2245–55. https://doi.org/10.1002/stem.1701.
Sugino N, Miura Y, Yao H, Iwasa M, Fujishiro A, Fujii S, et al. Early osteoinductive human bone marrow mesenchymal stromal/stem cells support an enhanced hematopoietic cell expansion with altered chemotaxis- and adhesion-related gene expression profiles. Biochem Biophys Res Commun. 2016;469:823–9. https://doi.org/10.1016/j.bbrc.2015.12.061.
Fujishiro A, Miura Y, Iwasa M, Fujii S, Sugino N, Andoh A, et al. Effects of acute exposure to low-dose radiation on the characteristics of human bone marrow mesenchymal stromal/stem cells. Inflamm Regen. 2017;37:19. https://doi.org/10.1186/s41232-017-0049-2.
Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini FC, Krause DS, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315–7. https://doi.org/10.1080/14653240600855905.
Miura Y. Human bone marrow mesenchymal stromal/stem cells: current clinical applications and potential for hematology. Int J Hematol. 2016;103:122–8. https://doi.org/10.1007/s12185-015-1920-z.
Giarratana MC, Kobari L, Lapillonne H, Chalmers D, Kiger L, Cynober T, et al. Ex vivo generation of fully mature human red blood cells from hematopoietic stem cells. Nat Biotechnol. 2005;23:69–74. https://doi.org/10.1038/nbt1047.
Boehm D, Murphy WG, Al-Rubeai M. The potential of human peripheral blood derived CD34 + cells for ex vivo red blood cell production. J Biotechnol. 2009;144:127–34. https://doi.org/10.1016/j.jbiotec.2009.08.017.
Li B, Ding L, Yang C, Kang B, Liu L, Story MD, et al. Characterization of transcription factor networks involved in umbilical cord blood CD34 + stem cells-derived erythropoiesis. PLoS One. 2014;9:e107133. https://doi.org/10.1371/journal.pone.0107133.
Matsuoka A, Tochigi A, Kishimoto M, Nakahara T, Kondo T, Tsujioka T, et al. Lenalidomide induces cell death in an MDS-derived cell line with deletion of chromosome 5q by inhibition of cytokinesis. Leukemia. 2010;24:748–55. https://doi.org/10.1038/leu.2009.296.
Drexler HG, Dirks WG, Macleod RA. Many are called MDS cell lines: one is chosen. Leuk Res. 2009;33:1011–6. https://doi.org/10.1016/j.leukres.2009.03.005.
Klamer S, Voermans C. The role of novel and known extracellular matrix and adhesion molecules in the homeostatic and regenerative bone marrow microenvironment. Cell Adhes Migr. 2014;8:563–77. https://doi.org/10.4161/19336918.2014.968501.
Williams DA, Rios M, Stephens C, Patel VP. Fibronectin and VLA-4 in haematopoietic stem cell-microenvironment interactions. Nature. 1991;352:438–41.
Okamoto T, Okada M, Yamada S, Takatsuka H, Wada H, Tamura A, et al. Good response to cyclosporine therapy in patients with myelodysplastic syndromes having the HLA-DRB1*1501 allele. Leukemia. 2000;14:344–6. https://doi.org/10.1038/sj.leu.2401665.
Hellstrom-Lindberg E, Ahlgren T, Beguin Y, Carlsson M, Carneskog J, Dahl IM, et al. Treatment of anemia in myelodysplastic syndromes with granulocyte colony-stimulating factor plus erythropoietin: results from a randomized phase II study and long-term follow-up of 71 patients. Blood. 1998;92:68–75.
Raza A, Reeves JA, Feldman EJ, Dewald GW, Bennett JM, Deeg HJ, et al. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood. 2008;111:86–93. https://doi.org/10.1182/blood-2007-01-068833.
Nilsson-Ehle H, Birgegard G, Samuelsson J, Antunovic P, Astermark J, Garelius H, et al. Quality of life, physical function and MRI T2* in elderly low-risk MDS patients treated to a haemoglobin level of ≥ 120 g/L with darbepoetin alfa ± filgrastim or erythrocyte transfusions. Eur J Haematol. 2011;87:244–52. https://doi.org/10.1111/j.1600-0609.2011.01654.x.
Tefferi A, Vardiman JM. Myelodysplastic syndromes. N Engl J Med. 2009;361:1872–85. https://doi.org/10.1056/NEJMra0902908.
Tefferi A. Myelodysplastic syndromes–many new drugs, little therapeutic progress. Mayo Clin Proc. 2010;85:1042–5.
Interview form of Glakay®. (https://medical.eisai.jp/content/000000488.pdf). Accessed 5 May 2020.
Klopp AH, Gupta A, Spaeth E, Andreeff M, Marini F 3rd. Concise review: dissecting a discrepancy in the literature: do mesenchymal stem cells support or suppress tumor growth? Stem Cells. 2011;29:11–9. https://doi.org/10.1002/stem.559.
Qiao L, Xu ZL, Zhao TJ, Ye LH, Zhang XD. Dkk-1 secreted by mesenchymal stem cells inhibits growth of breast cancer cells via depression of Wnt signalling. Cancer Lett. 2008;269:67–77. https://doi.org/10.1016/j.canlet.2008.04.032.
Li L, Tian H, Yue W, Zhu F, Li S, Li W. Human mesenchymal stem cells play a dual role on tumor cell growth in vitro and in vivo. J Cell Physiol. 2011;226:1860–7. https://doi.org/10.1002/jcp.22511.
Kidd S, Caldwell L, Dietrich M, Samudio I, Spaeth EL, Watson K, et al. Mesenchymal stromal cells alone or expressing interferon-β suppress pancreatic tumors in vivo, an effect countered by anti-inflammatory treatment. Cytotherapy. 2010;12:615–25. https://doi.org/10.3109/14653241003631815.
Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007;449:557–63. https://doi.org/10.1038/nature06188.
Yu JM, Jun ES, Bae YC, Jung JS. Mesenchymal stem cells derived from human adipose tissues favor tumor cell growth in vivo. Stem Cells Dev. 2008;17:463–73. https://doi.org/10.1089/scd.2007.0181.
Lin G, Yang R, Banie L, Wang G, Ning H, Li L, et al. Effects of transplantation of adipose tissue-derived stem cells on prostate tumor. Prostate. 2010;70:1066–73. https://doi.org/10.1002/pros.21140.
Yulyana Y, Ho IA, Sia KC, Newman JP, Toh XY, Endaya BB, et al. Paracrine factors of human fetal MSCs inhibit liver cancer growth through reduced activation of IGF-1R/PI3K/Akt signaling. Mol Ther. 2015;23:746–56. https://doi.org/10.1038/mt.2015.13.
Wu YL, Li HY, Zhao XP, Jiao JY, Tang DX, Yan LJ, et al. Mesenchymal stem cell-derived CCN2 promotes the proliferation, migration and invasion of human tongue squamous cell carcinoma cells. Cancer Sci. 2017;108:897–909. https://doi.org/10.1111/cas.13202.
Lee MW, Ryu S, Kim DS, Lee JW, Sung KW, Koo HH, Yoo KH. Mesenchymal stem cells in suppression or progression of hematologic malignancy: current status and challenges. Leukemia. 2019;33:597–611. https://doi.org/10.1038/s41375-018-0373-9.
Iwasa M, Miura Y, Fujishiro A, Fujii S, Sugino N, Yoshioka S, et al. Bortezomib interferes with adhesion of B cell precursor acute lymphoblastic leukemia cells through SPARC up-regulation in human bone marrow mesenchymal stromal/stem cells. Int J Hematol. 2017;105:587–97. https://doi.org/10.1007/s12185-016-2169-x.
Yoshioka S, Miura Y, Yao H, Satake S, Hayashi Y, Tamura A, et al. CCAAT/enhancer-binding protein β expressed by bone marrow mesenchymal stromal cells regulates early B-cell lymphopoiesis. Stem Cells. 2014;32:730–40. https://doi.org/10.1002/stem.1555.
Aanei CM, Eloae FZ, Flandrin-Gresta P, Tavernier E, Carasevici E, Guyotat D, et al. Focal adhesion protein abnormalities in myelodysplastic mesenchymal stromal cells. Exp Cell Res. 2011;317:2616–29. https://doi.org/10.1016/j.yexcr.2011.08.007.
Roversi FM, Lopes MR, Machado-Neto JA, Longhini AL, Duarte Ada S, Baratti MO, et al. Serine protease inhibitor kunitz-type 2 is downregulated in myelodysplastic syndromes and modulates cell-cell adhesion. Stem Cells Dev. 2014;23:1109–20. https://doi.org/10.1089/scd.2013.0441.
Wu Y, Aanei CM, Kesr S, Picot T, Guyotat D, Campos Catafal L. Impaired expression of focal adhesion kinase in mesenchymal stromal cells from low-risk myelodysplastic syndrome patients. Front Oncol. 2017;7:164. https://doi.org/10.3389/fonc.2017.00164.
Corradi G, Baldazzi C, Očadlíková D, Marconi G, Parisi S, Testoni N, et al. Mesenchymal stromal cells from myelodysplastic and acute myeloid leukemia patients display in vitro reduced proliferative potential and similar capacity to support leukemia cell survival. Stem Cell Res Ther. 2018;9:271. https://doi.org/10.1186/s13287-018-1013-z.
Matthes TW, Meyer G, Samii K, Beris P. Increased apoptosis in acquired sideroblastic anaemia. Br J Haematol. 2000;111:843–52.
Zhao ZG, Xu W, Yu HP, Fang BL, Wu SH, Li F, et al. Functional characteristics of mesenchymal stem cells derived from bone marrow of patients with myelodysplastic syndromes. Cancer Lett. 2012;317:136–43. https://doi.org/10.1016/j.canlet.2011.08.030.
Geyh S, Oz S, Cadeddu RP, Fröbel J, Brückner B, Kündgen A, et al. Insufficient stromal support in MDS results from molecular and functional deficits of mesenchymal stromal cells. Leukemia. 2013;27:1841–51. https://doi.org/10.1038/leu.2013.193.
Verma D, Kumar R, Pereira RS, Karantanou C, Zanetti C, Minciacchi VR, et al. Vitamin K antagonism impairs the bone marrow microenvironment and hematopoiesis. Blood. 2019;134:227–38. https://doi.org/10.1182/blood.2018874214.
We thank Ms. Yoko Nakagawa (Kyoto University) for her excellent technical assistance.
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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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
- Vitamin K2
- Mesenchymal stromal/stem cell (MSC)