MDS cells impair osteolineage differentiation of MSCs via extracellular vesicles to suppress normal hematopoiesis

Yasutaka Hayashi; Kimihito C Kawabata; Yosuke Tanaka; Yasufumi Uehara; Yo Mabuchi; Koichi Murakami; Akira Nishiyama; Shigeru Kiryu; Yusuke Yoshioka; Yasunori Ota; Tatsuki Sugiyama; Keiko Mikami; Moe Tamura; Tsuyoshi Fukushima; Shuhei Asada; Reina Takeda; Yuya Kunisaki; Tomofusa Fukuyama; Kazuaki Yokoyama; Tomoyuki Uchida; Masao Hagihara; Nobuhiro Ohno; Kensuke Usuki; Arinobu Tojo; Yoshio Katayama; Susumu Goyama; Fumio Arai; Tomohiko Tamura; Takashi Nagasawa; Takahiro Ochiya; Daichi Inoue; Toshio Kitamura

doi:10.1016/j.celrep.2022.110805

MDS cells impair osteolineage differentiation of MSCs via extracellular vesicles to suppress normal hematopoiesis

Cell Rep. 2022 May 10;39(6):110805. doi: 10.1016/j.celrep.2022.110805.

Authors

Yasutaka Hayashi¹, Kimihito C Kawabata², Yosuke Tanaka³, Yasufumi Uehara⁴, Yo Mabuchi⁵, Koichi Murakami⁶, Akira Nishiyama⁷, Shigeru Kiryu⁸, Yusuke Yoshioka⁹, Yasunori Ota¹⁰, Tatsuki Sugiyama¹¹, Keiko Mikami³, Moe Tamura¹², Tsuyoshi Fukushima³, Shuhei Asada³, Reina Takeda³, Yuya Kunisaki⁴, Tomofusa Fukuyama³, Kazuaki Yokoyama¹³, Tomoyuki Uchida¹⁴, Masao Hagihara¹⁴, Nobuhiro Ohno¹⁵, Kensuke Usuki¹⁶, Arinobu Tojo¹⁷, Yoshio Katayama¹⁸, Susumu Goyama¹², Fumio Arai¹⁹, Tomohiko Tamura²⁰, Takashi Nagasawa¹¹, Takahiro Ochiya⁹, Daichi Inoue²¹, Toshio Kitamura²²

Affiliations

¹ Division of Cellular Therapy, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Minatojimaminami-machi, Chuo-ku, Kobe 650-0047, Japan.
² Division of Cellular Therapy, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; Division of Hematology/Medical Oncology, Department of Medicine, Weill-Cornell Medical College, Cornell University, NY 10021, USA.
³ Division of Cellular Therapy, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
⁴ Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka 812-8582, Japan.
⁵ Department of Biochemistry and Biophysics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
⁶ Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0043, Japan; Advanced Medical Research Center, Yokohama City University, Yokohama 236-0043, Japan.
⁷ Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0043, Japan.
⁸ Department of Radiology, International University of Health and Welfare Narita Hospital, Chiba 286-8686, Japan.
⁹ Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, Tokyo 160-0023, Japan.
¹⁰ Department of Pathology, Research Hospital, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
¹¹ Laboratory of Stem Cell Biology and Developmental Immunology, Graduate School of Frontier Biosciences and Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
¹² Division of Cellular Therapy, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo 108-8639, Japan.
¹³ Department of Hematology/Oncology, Research Hospital, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
¹⁴ Department of Hematology, Eiju General Hospital, Tokyo 110-8645, Japan.
¹⁵ Department of Hematology, Kanto Rosai Hospital, Kawasaki 211-8510, Japan.
¹⁶ Department of Hematology, NTT Medical Center Tokyo, Tokyo 141-8625, Japan.
¹⁷ Department of Hematology/Oncology, Research Hospital, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
¹⁸ Hematology, Kobe University Hospital, Kobe 650-0017, Japan.
¹⁹ Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
²⁰ Department of Biochemistry and Biophysics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0043, Japan.
²¹ Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Minatojimaminami-machi, Chuo-ku, Kobe 650-0047, Japan. Electronic address: d-inoue@fbri.org.
²² Division of Cellular Therapy, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Electronic address: kitamura@ims.u-tokyo.ac.jp.

PMID: 35545056
DOI: 10.1016/j.celrep.2022.110805

Abstract

Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells (HSCs), characterized by ineffective hematopoiesis and frequent progression to leukemia. It has long remained unresolved how MDS cells, which are less proliferative, inhibit normal hematopoiesis and eventually dominate the bone marrow space. Despite several studies implicating mesenchymal stromal or stem cells (MSCs), a principal component of the HSC niche, in the inhibition of normal hematopoiesis, the molecular mechanisms underlying this process remain unclear. Here, we demonstrate that both human and mouse MDS cells perturb bone metabolism by suppressing the osteolineage differentiation of MSCs, which impairs the ability of MSCs to support normal HSCs. Enforced MSC differentiation rescues the suppressed normal hematopoiesis in both in vivo and in vitro MDS models. Intriguingly, the suppression effect is reversible and mediated by extracellular vesicles (EVs) derived from MDS cells. These findings shed light on the novel MDS EV-MSC axis in ineffective hematopoiesis.

Keywords: CP: Cancer; CP: Stem cell research; extracellular vesicles; hematopoietic stem cells; mesenchymal stromal/stem cells; microRNAs; myelodysplastic syndrome.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Extracellular Vesicles* / metabolism
Hematopoiesis
Hematopoietic Stem Cells / metabolism
Mesenchymal Stem Cells* / metabolism
Mice
Myelodysplastic Syndromes* / metabolism