1. Study on Thyroid Hormone (T3) Functions in the Formation of Hematopoietic Organs

Hormones play a vital role in the differentiation and maturation of cells during tissue and rgan formation. Disturbances in these systems can result in various developmental disorders. This research aims to elucidate how T3 regulates the formation of hematopoietic organs such as liver, spleen, bone marrow, and iron-metabolism-related intestines during both fetal and adult stages. This study contributes to endocrinology, zoology, and medicine.

A. Research on the Formation of Hematopoietic Niches via Thyroid Hormones

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  In humans, serum T3 levels transiently increase at birth, driving the restructuring and maturation of various tissues and organs from fetal to adult forms. A deficiency in T3 activity during this critical period can result in issues such as constipation, mental disorders, growth retardation, and anemia. Traditional mammalian models pose analytical challenges due to the complex influence of maternal factors on experimental outcomes. To address these challenges, our laboratory utilizes Xenopus tropicalis as a model for human post-embryonic development. Unlike mammals, Xenopus tropicalis develops independently of maternal influences. Its tadpoles exhibit a transient rise in serum T3 levels similar to that in mammals, triggering metamorphosis. During this process, various tissues and organs undergo remodeling into their adult forms. By leveraging this metamorphic model, we efficiently investigate T3's role in the formation of fetal hematopoietic niches, such as the liver and spleen, as well as adult hematopoietic niches like bone marrow.

Tanizaki Y et al. Liver development during Xenopus tropicalis metamorphosis is controlled by T3-activation of WNT signaling. iScience. 2023

B. Research of the Molecular Mechanisms of Intestinal Formation via T3 Receptors (TR)

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  The intestine not only absorbs iron but has recently been shown to be closely linked to hematopoiesis, with hematopoietic stem and progenitor cells localized there. Historically, the intestine has served as a model organ for studying thyroid hormone (T3)-induced organ formation during metamorphosis, accumulating extensive knowledge in the field. However, our understanding of how T3 receptors (TR) regulate the remodeling of the intestine remains limited. T3 binds to intracellular TRs, which in turn control gene expression in target cells. There are multiple isoforms of TR (TRα, TRβ), each expressed at different times and in different cell types. This study investigates how TRα and TRβ contribute to iron absorption and hematopoietic function acquisition during the remodeling of the intestine in Xenopus tropicalis.

Tanizaki Y et al. Thyroid hormone receptor α controls larval intestinal epithelial cell death by regulating the CDK1 pathway. Commun Biol. 2022
Tanizaki Y et al. Analysis of Thyroid Hormone Receptor α-Knockout Tadpoles Reveals That the Activation of Cell Cycle Program Is Involved in Thyroid Hormone-Induced Larval Epithelial Cell Death and Adult Intestinal Stem Cell Development During Xenopus tropicalis Metamorphosis. Thyroid. 2021

2. Study on the Hormonal Functions in Hematopoietic Stem and Progenitor Cells during Post-Embryonic Development

Research on the effects of hormones on hematopoietic progenitor cells has primarily focused on adult stages, leaving limited knowledge regarding their roles during the fetal period. Hormonal regulation of hematopoiesis involves both direct pathways that act on hematopoietic progenitor cells and indirect pathways mediated by the hematopoietic microenvironment. This study focuses on the direct pathways, utilizing Xenopus tropicalis tadpoles, whose liver functions as a primary hematopoietic niche similar to that of mammalian fetuses. Our objective is to elucidate how T3e and hematopoietic cytokines, such as Erythropoietin (EPO), Thrombopoietin (THPO), and Granulocyte Colony Stimulating Factor (G-CSF) regulate hematopoiesis during the fetal stage.

A. Research on Epigenetic Regulation by T3 in Hematopoietic Progenitor Cells

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  In mammals, hematopoietic progenitor cells in the bone marrow proliferate, differentiate, and mature in response to various cytokine signals. While epigenetic regulation has been shown to play a critical role in determining the fate of these cells, the underlying molecular mechanisms remain insufficiently understood. T3, the focus of our laboratory, is known to act epigenetic regulation. Several reports suggest that T3 works synergistically with hematopoietic cytokines to stimulate hematopoietic cell proliferation and differentiation; however, the precise molecular mechanisms remain unclear. This study aims to investigate how T3 regulates DNA methylation, histone methylation, and histone acetylation in hematopoietic progenitor cells.

Tanizaki Y et al. A Role of Endogenous Histone Acetyltransferase Steroid Hormone Receptor Coactivator 3 in Thyroid Hormone Signaling During Xenopus Intestinal Metamorphosis. Thyroid. 2021

B.Research on the Role of Hematopoietic Cytokines in Hematopoiesis during Post-Embryonic Development

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  Hematopoietic cytokines induce the proliferation, differentiation, and maturation of hematopoietic stem and progenitor cells. In mammals, the primary hematopoietic sites during the fetal period are the liver and spleen, which transition to the bone marrow as development progresses. When hematopoietic function in the bone marrow declines, hematopoiesis can reactivate in the liver and spleen, indicating that the transition of hematopoietic sites is reversible. However, our understanding of hematopoietic regulation by cytokines in the liver and the spleen remains limited. This study investigates how EPO, essential for red blood cell production; THPO, which regulates platelet production and hematopoietic stem cell proliferation; and G-CSF, which promotes differentiation and proliferation in granulocyte lineages, control hematopoietic cell production during the fetal period. We employ Xenopus tadpoles, where the liver serves as the primary hematopoietic site, as a model to study these mechanisms.

Tanizaki Y et al. Thrombopoietin induces production of nucleated thrombocytes from liver cells in Xenopus laevis. Sci Rep. 2015

3. Study of Hormonal Functions on the Environmental Response of Hematopoiesis

Broadly, stressors can be categorized into physical, chemical, biological, and social/psychological factors. Our laboratory plans to study the effects of temperature changes and endocrine disruptors on hormone function. By understanding this environmental response mechanism, we will clarify how hematopoietic homeostasis is maintained.

A. Research on Hormonal Temperature Responses

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  Animals are broadly classified into two categories: endotherms, in which body temperature is maintained mainly by metabolism, and ectotherms, in which some heat sources are sought outside the body. In cold exposure experiments on rodents, it has been shown that increasing the amount of food intake maintains heat and blood cell counts at normal levels. On the other hand, when African clawed frogs (Xenopus laevis), which are ectothermic animals, are exposed to low temperatures, their blood cell counts decrease. This suggests that each animal species has a different mechanism for maintaining homeostasis of blood cell counts. In this study, we will focus on hematopoiesis and investigate the species-specific temperature-responsive regulatory system of hematopoiesis.

Nagasawa K, Tanizaki Y et al. Thrombopoietin induces production of nucleated thrombocytes from liver cells in Xenopus laevis. Biol Open. 2013

B.Research on Endocrine Disruptors of Thyroid Hormones

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  As of 2024, there are approximately 85,000 human-made chemicals in the world, of which more than 1,000 are candidate endocrine disruptor molecules that inhibit or enhance hormone function. Research has been conducted on endocrine disruptors related to fetal development as risk factors for congenital abnormalities, but there are still unresolved issues, such as target signaling mechanisms. Our laboratory will focus on T3 disruptors, which plays a central function in fetal development and metabolism and will explore these issues mainly through in vivo studies.