한빛사논문
- 조회553
Eunju Shin 1,2∗, Charny Park 3∗, Taeho Park 1,6, Hyunmin Chung 2,4, Hyeyeong Hwang 3, Seong Ho Bak 1,6, Kyung-Sook Chung 5,6, Suk Ran Yoon 4,6, Tae-Don Kim 4,6, Inpyo Choi 4, Chang Hoon Lee 7,8†, Haiyoung Jung 1,6†, Ji-Yoon Noh 1,6†
1Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon 34141, Korea
2College of Pharmacy, Chungnam National University, Yuseong-gu, Daejeon 34134, Korea
3Bioinformatics Team, Research Institute, National Cancer Center, Ilsandong-gu, Gyeonggi-do, 10408, Korea
4Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon 34141, Korea
5Stem Cell Convergence Research Center and Biomedical Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon 34141, Korea
6Department of Functional Genomics, Korea University of Science & Technology, Yuseong-gu, Daejeon 34113, Korea
7R&D Center, SCBIO Co., Ltd., 282-30, Munji-ro, Yuseong-gu, Daejeon 34050, Korea
8Therapeutics & Biotechnology Division, Drug Discovery Platform Research Center, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 34114, Korea
∗ES and CP contributed equally as co-first authors.
†CHL, HJ, and JYN jointly supervised this work as co-senior authors.
Correspondence: Ji-Yoon Noh
Abstract
Background: Platelets are generated from megakaryocytes (MKs), mainly located in the bone marrow (BM). Megakaryopoiesis can be affected by genetic disorders, metabolic diseases, and aging. The molecular mechanisms underlying platelet count regulation have not been fully elucidated.
Objectives: In the present study, we investigated the role of thioredoxin-interacting protein (TXNIP), a protein that regulates cellular metabolism in megakaryopoiesis, using a Txnip-/- mouse model.
Methods: Wild-type (WT) and Txnip-/- mice (2-27-month-old) were studied. BM-derived MKs were analyzed to investigate the role of TXNIP in megakaryopoiesis with age. The global transcriptome of BM-derived CD41+ megakaryocyte precursors (MkPs) of WT and Txnip-/- mice were compared. The CD34+ hematopoietic stem cells isolated from human cord blood were differentiated into MKs.
Results: Txnip-/- mice develop thrombocytopenia at 4-5 months that worsens with age. During ex vivo megakaryopoiesis, Txnip-/- MkPs remained small, with decreased levels of MK-specific markers. Critically, Txnip-/- MkPs exhibited reduced mitochondrial reactive oxygen species, of which was related to AKT activity. Txnip-/- MkPs also showed elevated glycolysis, alongside increased glucose uptake for ATP production. Total RNA-sequencing revealed enrichment for oxidative stress- and apoptosis-related genes in differentially expressed genes between Txnip-/- and WT MkPs. The effects of TXNIP on MKs were recapitulated during the differentiation of human cord blood-derived CD34+ hematopoietic stem cells.
Conclusions: We provide evidence that the megakaryopoiesis pathway becomes exhausted with age in Txnip-/- mice with a decrease in terminal, mature MKs that response to thrombocytopenic challenge. Overall, this study demonstrates the role of TXNIP in megakaryopoiesis, regulating mitochondrial metabolism.
논문정보
- Research article
- 2023년 12월 (BRIC 등록일 2023-12-12)
- 국내 연구진
- 생명과학 > 세포생물학
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