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Thrombopoietin Metabolically Primes Hematopoietic Stem Cells to Megakaryocyte-Lineage Differentiation. (Cell Rep, Nov 2018)

Nakamura-Ishizu A1, Matsumura T2, Stumpf PS3, Umemoto T4, Takizawa H4, Takihara Y2, O’Neil A2, Majeed ABBA2, MacArthur BD5, Suda T6.

Author information
1Cancer Science Institute, National University of Singapore, 14 Medical Drive, MD6, 117599 Singapore, Singapore; International Research Center for Medical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto City 860-0811, Japan. Electronic address: ayaknakm@gmail.com.
2Cancer Science Institute, National University of Singapore, 14 Medical Drive, MD6, 117599 Singapore, Singapore.
3Centre for Human Development Stem Cells and Regeneration, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK.
4International Research Center for Medical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto City 860-0811, Japan.
5International Research Center for Medical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto City 860-0811, Japan; Mathematical Sciences, University of Southampton, Southampton SO17 1BJ, UK; Centre for Human Development StemCells and Regeneration, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK.
6Cancer Science Institute, National University of Singapore, 14 Medical Drive, MD6, 117599 Singapore, Singapore; International Research Center for Medical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto City 860-0811, Japan. Electronic address: sudato@keio.jp.

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.

KEYWORDS: hematopoietic stem cell; lineage differentiation; megakaryocyte; mitochondria; thrombopoietin

PMID: 30428347