TY - JOUR
T1 - MDS cells impair osteolineage differentiation of MSCs via extracellular vesicles to suppress normal hematopoiesis
AU - Hayashi, Yasutaka
AU - Kawabata, Kimihito C.
AU - Tanaka, Yosuke
AU - Uehara, Yasufumi
AU - Mabuchi, Yo
AU - Murakami, Koichi
AU - Nishiyama, Akira
AU - Kiryu, Shigeru
AU - Yoshioka, Yusuke
AU - Ota, Yasunori
AU - Sugiyama, Tatsuki
AU - Mikami, Keiko
AU - Tamura, Moe
AU - Fukushima, Tsuyoshi
AU - Asada, Shuhei
AU - Takeda, Reina
AU - Kunisaki, Yuya
AU - Fukuyama, Tomofusa
AU - Yokoyama, Kazuaki
AU - Uchida, Tomoyuki
AU - Hagihara, Masao
AU - Ohno, Nobuhiro
AU - Usuki, Kensuke
AU - Tojo, Arinobu
AU - Katayama, Yoshio
AU - Goyama, Susumu
AU - Arai, Fumio
AU - Tamura, Tomohiko
AU - Nagasawa, Takashi
AU - Ochiya, Takahiro
AU - Inoue, Daichi
AU - Kitamura, Toshio
N1 - Funding Information:
We thank Shiori Shikata, Akiho Tsuchiya, Hajime Kawahara, Tomoko Ando, Yukihisa Tanaka, Hiromi Yamazaki, and Miki Fukumoto for their expert technical assistance. We also thank the Flow Cytometry Core and the Mouse Core at the Institute of Medical Science , University of Tokyo , and the Foundation for Biomedical Research and Innovation at Kobe, and the MEXT Joint Usage / Research Center Program at the Advanced Medical Research Center , Yokohama City University for their help. This work was supported by AMED-PRIME ( 21gm6210022h0002 ), a Grant-in-Aid from the Ministry of Education, Science, Technology, Sports and Culture , Japan ( 15H04855 , T.K.), 20K21622 , D.I.), 20J01911 , Y.H.), 21K16258 ,Y.H.), a grant from SENSHIN Medical Research Foundation (D.I.), a grant from TERUMO LIFE SCIENCE FOUNDATION (DI), a grant from Daiwa Securities Health Foundation (DI), a grant from The MEXT Joint Research Center program , Yokohama City University (D.I.), and a grant from Nippon Shinyaku (Y.H.).
Funding Information:
We thank Shiori Shikata, Akiho Tsuchiya, Hajime Kawahara, Tomoko Ando, Yukihisa Tanaka, Hiromi Yamazaki, and Miki Fukumoto for their expert technical assistance. We also thank the Flow Cytometry Core and the Mouse Core at the Institute of Medical Science, University of Tokyo, and the Foundation for Biomedical Research and Innovation at Kobe, and the MEXT Joint Usage/Research Center Program at the Advanced Medical Research Center, Yokohama City University for their help. This work was supported by AMED-PRIME (21gm6210022h0002), a Grant-in-Aid from the Ministry of Education, Science, Technology, Sports and Culture, Japan (15H04855, T.K.), 20K21622, D.I.), 20J01911, Y.H.), 21K16258,Y.H.), a grant from SENSHIN Medical Research Foundation (D.I.), a grant from TERUMO LIFE SCIENCE FOUNDATION (DI), a grant from Daiwa Securities Health Foundation (DI), a grant from The MEXT Joint Research Center program, Yokohama City University (D.I.), and a grant from Nippon Shinyaku (Y.H.). Y.H. designed and performed most of the experiments, analyzed and interpreted the data, and wrote the manuscript. K.C.K. designed and performed the experiments and interpreted the data. Y.T. designed and performed the experiments, interpreted the data, and participated in writing the manuscript. Y.U. Y. Kunisaki, and F.A. performed single-cell qRT-PCR analyses of MSCs. T.S. and T.N. performed the qRT-PCR of CAR cells. S.K. performed the CT data analyses of MDS patients. Y.M. performed the MSC differentiation assay and single-cell RNA-seq analysis of MSCs and advised on the data interpretation. Y.Y. and T.O. performed the purification and characterization of extracellular vesicles and analysis of miRNA expression. Y.O. assisted with the analyses using pathological specimens of MDS patients. K. Murakami. A.N. and T.T. performed the single-cell RNA-seq analysis of MSCs. K. Mikami, M.T. T. Fukushima, S.A. and R.T. assisted with the experiments. T. Fukuyama provided MDS patient BM samples and the MDS patient serum sample, summarized the patient data, and advised on the data interpretation. Y. Katayama. and S.G. advised on the data interpretation. K.Y. and A.T. provided MDS patient BM samples. T.U. M.H. N.O. and K.U. provided MDS patient serum samples. D.I. and T.K. conceived the project, interpreted the data, and wrote the manuscript. The authors declare no competing interests.
Publisher Copyright:
© 2022 The Authors
PY - 2022/5/10
Y1 - 2022/5/10
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2022.110805
DO - 10.1016/j.celrep.2022.110805
M3 - Article
C2 - 35545056
AN - SCOPUS:85129691849
SN - 2211-1247
VL - 39
JO - Cell Reports
JF - Cell Reports
IS - 6
M1 - 110805
ER -