Matrix Gla protein maintains normal and malignant hematopoietic progenitor cells by interacting with bone morphogenetic protein-4

Kana Kuronuma; Aya Yokoi; Tomoya Fukuoka; Muneaki Miyata; Akio Maekawa; Satowa Tanaka; Leo Matsubara; Chie Goto; Miki Matsuo; Hao-Wei Han; Mai Tsuruta; Haruka Murata; Hikari Okamoto; Natsumi Hasegawa; Shigetaka Asano; Mitsuhiro Ito

doi:10.1016/j.heliyon.2020.e03743

Matrix Gla protein maintains normal and malignant hematopoietic progenitor cells by interacting with bone morphogenetic protein-4

Heliyon. 2020 Apr 12;6(4):e03743. doi: 10.1016/j.heliyon.2020.e03743. eCollection 2020 Apr.

Authors

Kana Kuronuma¹, Aya Yokoi¹, Tomoya Fukuoka¹, Muneaki Miyata², Akio Maekawa¹, Satowa Tanaka¹, Leo Matsubara¹, Chie Goto¹, Miki Matsuo¹, Hao-Wei Han³, Mai Tsuruta¹, Haruka Murata¹, Hikari Okamoto¹, Natsumi Hasegawa¹, Shigetaka Asano³, Mitsuhiro Ito^{1

3}

Affiliations

¹ Laboratory of Hematology, Division of Medical Biophysics, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Suma-ku, Kobe 654-0142, Japan.
² Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, CREST, Japan Science and Technology Agency, 1-5-6 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan.
³ Research Organization for Nano & Life Innovation, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 159-8555, Japan.

Abstract

Matrix Gla protein (MGP), a modulator of the BMP-SMAD signals, inhibits arterial calcification in a Glu γ-carboxylation dependent manner but the role of MGP highly expressed in a subset of bone marrow (BM) mesenchymal stem/stromal cells is unknown. Here we provide evidence that MGP might be a niche factor for both normal and malignant myelopoiesis. When mouse BM hematopoietic cells were cocultured with mitomycin C-treated BM stromal cells in the presence of anti-MGP antibody, growth of hematopoietic cells was reduced by half, and maintenance of long-term culture-initiating cells (LTC-ICs) was profoundly attenuated. Antibody-mediated blockage of MGP also inhibited growth (by a fifth) and cobblestone formation (by half) of stroma-dependent MB-1 myeloblastoma cells. MGP was undetectable in normal hematopoietic cells but was expressed in various mesenchymal cells and was aberrantly high in MB-1 cells. MGP and bone morphogenetic protein (BMP)-4 were co-induced in stromal cells cocultured with both normal hematopoietic cells and MB-1 myeloblastoma cells in an oscillating several days-periodic manner. BMP-2 was also induced in stromal cells cocultured with normal hematopoietic cells but was barely expressed when cocultured with MB-1 cells. GST-pulldown and luciferase reporter assays showed that uncarboxylated MGP interacted with BMP-4 and that anti-MGP antibody abolished this interaction. LDN-193189, a selective BMP signaling inhibitor, inhibited growth and cobblestone formation of MB-1 cells. The addition of warfarin, a selective inhibitor of vitamin K-dependent Glu γ-carboxylation, did not affect MB-1 cell growth, suggesting that uncarboxylated MGP has a biological effect in niche. These results indicate that MGP may maintain normal and malignant hematopoietic progenitor cells, possibly by modulating BMP signals independently of Glu γ-carboxylation. Aberrant MGP by leukemic cells and selective induction of BMP-4 relative to BMP-2 in stromal cells might specify malignant niche.

Keywords: BMP-2; Biochemistry; Biomolecules; Bone morphogenetic protein-4 (BMP-4); Cancer research; Cell biology; Hematological system; Hematopoietic niche; Matrix Gla protein (MGP); Mediator transcriptional coregulatory complex; Molecular biology; Molecular dynamics; Oncology; Physiology; Stem cells research.