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Thrombopoietin metabolically primes hematopoietic stem cells to megakaryocyte-lineage differentiation

Thrombopoietin metabolically primes hematopoietic stem cells to megakaryocyte-lineage differentiation
Thrombopoietin metabolically primes hematopoietic stem cells to megakaryocyte-lineage differentiation

During acute myelosuppression or thrombocytopenia, bone marrow (BM) hematopoietic cells respond rapidly to replenish peripheral blood platelets. While the cytokine thrombopoietin (Thpo) both regulates platelet production and maintains HSC potential, whether Thpo controls megakaryocyte (Mk)-lineage differentiation of HSCs is unclear. Here, we show that Thpo rapidly upregulates mitochondrial activity in HSCs, an activity accompanied by differentiation to an Mk lineage. Moreover, in unperturbed hematopoiesis, HSCs with high mitochondrial activity exhibit Mk-lineage differentiation in vitro and myeloid lineage-biased reconstitution in vivo. Furthermore, Thpo skewed HSCs to express the tetraspanin CD9, a pattern correlated with mitochondrial activity. Mitochondria-active HSCs are resistant to apoptosis and oxidative stress upon Thpo stimulation. Thpo-regulated mitochondrial activity associated with mitochondrial translocation of STAT3 phosphorylated at serine 727. Overall, we report an important role for Thpo in regulating rapid Mk-lineage commitment. Thpo-dependent changes in mitochondrial metabolism prime HSCs to undergo direct differentiation to an Mk lineage. Nakamura-Ishizu et al. show that Thpo rapidly upregulates HSC mitochondrial activity in HSCs, an activity accompanied by preferential differentiation to an Mk lineage. Thpo-induced mitochondrial activity correlates with the tetraspanin CD9 expression pattern on HSCs. The findings suggest that Thpo-dependent changes in mitochondrial metabolism prime HSCs to undergo direct differentiation to an Mk lineage.

hematopoietic stem cell, lineage differentiation, megakaryocyte, mitochondria, thrombopoietin
2211-1247
1772-1785.e6
Nakamura-Ishizu, Ayako
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Matsumura, Takayoshi
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Stumpf, Patrick S.
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Umemoto, Terumasa
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Takizawa, Hitoshi
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Takihara, Yuji
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O'Neil, Aled
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Majeed, A'Qilah Banu Bte Abdul
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MacArthur, Ben D.
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Suda, Toshio
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Nakamura-Ishizu, Ayako
83f297fb-2935-498e-93b3-69d027ae5241
Matsumura, Takayoshi
a644331e-f2cb-4c82-aceb-1e257e646818
Stumpf, Patrick S.
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Umemoto, Terumasa
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Takizawa, Hitoshi
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Takihara, Yuji
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O'Neil, Aled
f75a430a-5cba-46a7-9020-7c818c797610
Majeed, A'Qilah Banu Bte Abdul
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MacArthur, Ben D.
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Suda, Toshio
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Nakamura-Ishizu, Ayako, Matsumura, Takayoshi, Stumpf, Patrick S., Umemoto, Terumasa, Takizawa, Hitoshi, Takihara, Yuji, O'Neil, Aled, Majeed, A'Qilah Banu Bte Abdul, MacArthur, Ben D. and Suda, Toshio (2018) Thrombopoietin metabolically primes hematopoietic stem cells to megakaryocyte-lineage differentiation. Cell Reports, 25 (7), 1772-1785.e6. (doi:10.1016/j.celrep.2018.10.059).

Record type: Article

Abstract

During acute myelosuppression or thrombocytopenia, bone marrow (BM) hematopoietic cells respond rapidly to replenish peripheral blood platelets. While the cytokine thrombopoietin (Thpo) both regulates platelet production and maintains HSC potential, whether Thpo controls megakaryocyte (Mk)-lineage differentiation of HSCs is unclear. Here, we show that Thpo rapidly upregulates mitochondrial activity in HSCs, an activity accompanied by differentiation to an Mk lineage. Moreover, in unperturbed hematopoiesis, HSCs with high mitochondrial activity exhibit Mk-lineage differentiation in vitro and myeloid lineage-biased reconstitution in vivo. Furthermore, Thpo skewed HSCs to express the tetraspanin CD9, a pattern correlated with mitochondrial activity. Mitochondria-active HSCs are resistant to apoptosis and oxidative stress upon Thpo stimulation. Thpo-regulated mitochondrial activity associated with mitochondrial translocation of STAT3 phosphorylated at serine 727. Overall, we report an important role for Thpo in regulating rapid Mk-lineage commitment. Thpo-dependent changes in mitochondrial metabolism prime HSCs to undergo direct differentiation to an Mk lineage. Nakamura-Ishizu et al. show that Thpo rapidly upregulates HSC mitochondrial activity in HSCs, an activity accompanied by preferential differentiation to an Mk lineage. Thpo-induced mitochondrial activity correlates with the tetraspanin CD9 expression pattern on HSCs. The findings suggest that Thpo-dependent changes in mitochondrial metabolism prime HSCs to undergo direct differentiation to an Mk lineage.

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Accepted/In Press date: 15 October 2018
e-pub ahead of print date: 13 November 2018
Published date: 13 November 2018
Keywords: hematopoietic stem cell, lineage differentiation, megakaryocyte, mitochondria, thrombopoietin

Identifiers

Local EPrints ID: 426507
URI: http://eprints.soton.ac.uk/id/eprint/426507
ISSN: 2211-1247
PURE UUID: e1edbed0-7409-4aa6-8c4a-f0f3524bd864
ORCID for Patrick S. Stumpf: ORCID iD orcid.org/0000-0003-0862-0290

Catalogue record

Date deposited: 29 Nov 2018 17:30
Last modified: 26 Nov 2021 00:09

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Contributors

Author: Ayako Nakamura-Ishizu
Author: Takayoshi Matsumura
Author: Patrick S. Stumpf ORCID iD
Author: Terumasa Umemoto
Author: Hitoshi Takizawa
Author: Yuji Takihara
Author: Aled O'Neil
Author: A'Qilah Banu Bte Abdul Majeed
Author: Toshio Suda

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