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

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 UchidaMasao Hagihara, Nobuhiro Ohno, Kensuke Usuki, Arinobu Tojo, Yoshio Katayama, Susumu Goyama, Fumio Arai, Tomohiko Tamura, Takashi Nagasawa, Takahiro Ochiya, Daichi Inoue, Toshio Kitamura

Research output: Contribution to journal › Article › peer-review

10 Citations (Scopus)

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.

Original language	English
Article number	110805
Journal	Cell Reports
Volume	39
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2022.110805
Publication status	Published - 10-05-2022
Externally published	Yes

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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10.1016/j.celrep.2022.110805

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Hayashi, Y., Kawabata, K. C., Tanaka, Y., Uehara, Y., Mabuchi, Y., Murakami, K., Nishiyama, A., Kiryu, S., Yoshioka, Y., Ota, Y., Sugiyama, T., Mikami, K., Tamura, M., Fukushima, T., Asada, S., Takeda, R., Kunisaki, Y., Fukuyama, T., Yokoyama, K., ... Kitamura, T. (2022). MDS cells impair osteolineage differentiation of MSCs via extracellular vesicles to suppress normal hematopoiesis. Cell Reports, 39(6), Article 110805. https://doi.org/10.1016/j.celrep.2022.110805

@article{c230449e3e7049d4a50f429a3cba01a6,

title = "MDS cells impair osteolineage differentiation of MSCs via extracellular vesicles to suppress normal hematopoiesis",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = may,

day = "10",

doi = "10.1016/j.celrep.2022.110805",

language = "English",

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Hayashi, Y, Kawabata, KC, Tanaka, Y, Uehara, Y, Mabuchi, Y, Murakami, K, Nishiyama, A, Kiryu, S, Yoshioka, Y, Ota, Y, Sugiyama, T, Mikami, K, Tamura, M, Fukushima, T, Asada, S, Takeda, R, Kunisaki, Y, Fukuyama, T, Yokoyama, K, Uchida, T, Hagihara, M, Ohno, N, Usuki, K, Tojo, A, Katayama, Y, Goyama, S, Arai, F, Tamura, T, Nagasawa, T, Ochiya, T, Inoue, D & Kitamura, T 2022, 'MDS cells impair osteolineage differentiation of MSCs via extracellular vesicles to suppress normal hematopoiesis', Cell Reports, vol. 39, no. 6, 110805. https://doi.org/10.1016/j.celrep.2022.110805

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

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 -

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

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