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
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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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13 November 2018
Nakamura-Ishizu, Ayako
83f297fb-2935-498e-93b3-69d027ae5241
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, 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), .
(doi:10.1016/j.celrep.2018.10.059).
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.
Text
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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
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Date deposited: 29 Nov 2018 17:30
Last modified: 06 Jun 2024 01:39
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Contributors
Author:
Ayako Nakamura-Ishizu
Author:
Takayoshi Matsumura
Author:
Patrick S. Stumpf
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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