Foundation for Biomedical Innovation Research and Innovation at Kobe (FBRI, President: Dr. Tasuku Honjo) is pleased to announce that Yasutaka Hayashi (Research Fellow of the Japan Society for the Promotion of Science (SPD), Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, FBRI), Dr. Daichi Inoue, (Professor, Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, FBRI), Dr. Toshio Kitamura (Director, Institute of Biomedical Research and Innovation, FBRI) and their research team have elucidated a novel mechanism by which extracellular vesicles (EVs)(*1) released from malignant cells impair osteolineage differentiation of bone marrow mesenchymal stem/stromal cells (MSCs)(*2) in myelodysplastic syndrome (MDS) (*3), leading to the suppression of normal hematopoiesis.
Myelodysplastic syndrome (MDS) is a clonal hematological malignancy that arises from aberrant Hematopoietic stem cells (HSCs)(*4) with somatic mutations and are characterized by disturbed differentiation, peripheral-blood cytopenia, and predisposition to acute myeloid leukemia (AML). It has long remained unresolved how MDS cells, which are less proliferative, inhibit normal hematopoiesis and eventually dominate the bone marrow space.
In the present work, our team examined how MDS cells perturb bone metabolism by suppressing the osteolineage differentiation of MSCs, which impairs the ability of MSCs to support normal HSCs. Our integrated biological analyses demonstrated that microRNAs (miRNAs)(*5) contained in EVs secreted from MDS cells play an essential role in perturbing the osteolineage differentiation of MSCs to suppress the niche function for normal hematopoiesis. Moreover, the forced osteolineage differentiation of MSCs restored the ability of MSCs to support normal hematopoiesis. Intriguingly, the suppression effect was reversible and enforced MSC differentiation rescued the suppressed normal hematopoiesis. These findings suggest that restoration of the HSC-supportive ability of MSCs will be a potential therapeutic option to recover normal hematopoiesis in MDS.
This research was published in Cell Reports on Tuesday, May 10, 2022, at 11:00 a.m. ET.
1. Normal hematopoiesis is indirectly and profoundly impaired in MDS.
2. MDS cells inhibit osteolineage differentiation of MSCs via MDS-derived EVs, leading to bone marrow failure due to less supportive niche function.
3. Osteogenic differentiation of MSCs contributes to the recovery of hematopoiesis.
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１ Research Paper
Yasutaka Hayashi1,2, Kimihito C. Kawabata1,3, Yosuke Tanaka1, Yasufumi Uehara4,5, Yo Mabuchi6, Koichi Murakami7,8, Akira Nishiyama7, Shigeru Kiryu9, Yusuke Yoshioka10 Yasunori Ota11, Tatsuki Sugiyama12, Keiko Mikami1, Moe Tamura1,13, Tsuyoshi Fukushima1, Shuhei Asada1, Reina Takeda1, Yuya Kunisaki4,5, Tomofusa Fukuyama1, Kazuaki Yokoyama14, Tomoyuki Uchida15, Masao Hagihara15, Nobuhiro Ohno16, Kensuke Usuki17, Arinobu Tojo14,18, Yoshio Katayama19, Susumu Goyama1,13, Fumio Arai4, Tomohiko Tamura6,7, Takashi Nagasawa12, Takahiro Ochiya10, Daichi Inoue2*, Toshio Kitamura1*
- 1Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- 2Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan
- 3Division of Hematology/Medical Oncology, Department of Medicine, Weill-Cornell Medical College, Cornell University, NY, USA
- 4Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- 5Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan
- 6Department of Biochemistry and Biophysics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
- 7Department of Immunology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan
- 8Advanced Medical Research Center, Yokohama City University, Kanagawa, Japan
- 9Department of Radiology, International University of Health and Welfare Narita Hospital, Chiba, Japan
- 10Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
- 11Department of Pathology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- 12Laboratory 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, Japan
- 13Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
- 14Department of Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- 15Department of Hematology, Eiju General Hospital, Tokyo, Japan
- 16Department of Hematology, Kanto Rosai Hospital, Kanagawa, Japan
- 17Department of Hematology, NTT Medical Center Tokyo, Tokyo, Japan
- 18Tokyo Medical and Dental University, Tokyo, Japan
- 19Hematology, Kobe University Hospital, Kobe, Japan
- *Correspondence: DI, TK
- Title of original:
- MDS cells impair osteolineage differentiation of MSCs via extracellular vesicles to suppress normal hematopoiesis
- Journal: Cell Reports
- DOI: https://doi.org/10.1016/j.celrep.2022.110805
- *1. Extracellular vesicles: Nanoparticles about 100 nm in size with lipid bilayer structure. They carry functional molecules such as miRNA and work as a mediator of intercellular communications.
- *2. Mesenchymal Stem/Stromal Cells: One of the tissue stem cells, which have self-renewal and multi-differentiative potential, reside in mesenchymal tissue. They differentiate into osteoblast, chondrocyte, adipocyte, and so on.
- *3. Myelodysplastic Syndrome: A group of hematological malignancies with a poor prognosis that arises from aberrant HSCs with somatic mutations characterized by disturbed differentiation and peripheral-blood cytopenia.
- *4. Hematopoietic Stem Cells: Tissue stem cells of the hematopoietic system mainly reside in bone marrow, which produces all types of blood cells, including red blood cells, white blood cells, and platelets.
- *5 MicroRNAs: Small single-strand RNA molecules containing about 22 nucleotides. MicroRNAs are known to recognize complementary sequences in the 3' UTR of target mRNAs and suppress gene expression by translational repression or mRNA degradation.
Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, the Foundation for Biomedical Research and Innovation at KobeURL:https://www.fbri-kobe.org/english/laboratory/research5