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Deficiency of thioredoxin-interacting protein results in age-related thrombocytopenia due to megakaryocyte oxidative
Eunju Shin1, Charny Park2, Taeho Park3
1Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Korea; College of Pharmacy, Chungnam National University, Yuseong-gu, Daejeon, Korea.
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 developed thrombocytopenia at 4 to 5 months that worsened 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, 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.
Conclusion:
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.
Insights
Thioredoxin-interacting protein (TXNIP) is crucial for megakaryopoiesis, regulating mitochondrial metabolism and preventing age-related platelet count decline. Loss of TXNIP leads to impaired megakaryocyte development and thrombocytopenia in mice.
Area of Science:
- Hematology
- Molecular Biology
- Cellular Metabolism
Background:
- Platelets are essential blood components generated from megakaryocytes (MKs) in the bone marrow.
- Megakaryopoiesis, the process of MK development, is complex and can be disrupted by various factors, including aging.
- The precise molecular regulators of platelet production remain incompletely understood.
Purpose of the Study:
- To investigate the role of thioredoxin-interacting protein (TXNIP) in megakaryopoiesis.
- To elucidate TXNIP's function in regulating cellular metabolism during MK development.
- To utilize a Txnip knockout (Txnip-/-) mouse model to study these processes.
Main Methods:
- Comparative analysis of wild-type (WT) and Txnip-/- mice across a range of ages (2-27 months).
- In vitro analysis of bone marrow-derived MKs and megakaryocyte precursors (MkPs).
- Global transcriptome analysis of MkPs and differentiation of human CD34+ hematopoietic stem cells into MKs.
Main Results:
- Txnip-/- mice exhibited age-dependent thrombocytopenia, with reduced MK size and decreased MK-specific markers.
- Reduced mitochondrial reactive oxygen species and altered AKT activity were observed in Txnip-/- MkPs.
- Elevated glycolysis, increased glucose uptake for ATP production, and differential gene expression related to oxidative stress and apoptosis were noted in Txnip-/- MkPs.
- Similar effects were observed in human cord blood-derived MKs, confirming TXNIP's conserved role.
Conclusions:
- TXNIP plays a critical role in maintaining the megakaryopoiesis pathway, particularly in preventing age-related exhaustion.
- Loss of TXNIP impairs mitochondrial metabolism and promotes a shift towards glycolysis in MKs.
- TXNIP is essential for normal megakaryocyte development and platelet production, highlighting its therapeutic potential.
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