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Cell Nov 2021Current catalogs of regulatory sequences in the human genome are still incomplete and lack cell type resolution. To profile the activity of gene regulatory elements in...
Current catalogs of regulatory sequences in the human genome are still incomplete and lack cell type resolution. To profile the activity of gene regulatory elements in diverse cell types and tissues in the human body, we applied single-cell chromatin accessibility assays to 30 adult human tissue types from multiple donors. We integrated these datasets with previous single-cell chromatin accessibility data from 15 fetal tissue types to reveal the status of open chromatin for ∼1.2 million candidate cis-regulatory elements (cCREs) in 222 distinct cell types comprised of >1.3 million nuclei. We used these chromatin accessibility maps to delineate cell-type-specificity of fetal and adult human cCREs and to systematically interpret the noncoding variants associated with complex human traits and diseases. This rich resource provides a foundation for the analysis of gene regulatory programs in human cell types across tissues, life stages, and organ systems.
Topics: Adult; Chromatin; Cluster Analysis; Fetus; Genetic Variation; Genome, Human; Genome-Wide Association Study; Humans; Organ Specificity; Phylogeny; Regulatory Sequences, Nucleic Acid; Risk Factors; Single-Cell Analysis
PubMed: 34774128
DOI: 10.1016/j.cell.2021.10.024 -
Cell Jan 2024Mounting evidence suggests metabolism instructs stem cell fate decisions. However, how fetal metabolism changes during development and how altered maternal metabolism... (Review)
Review
Mounting evidence suggests metabolism instructs stem cell fate decisions. However, how fetal metabolism changes during development and how altered maternal metabolism shapes fetal metabolism remain unexplored. We present a descriptive atlas of in vivo fetal murine metabolism during mid-to-late gestation in normal and diabetic pregnancy. Using C-glucose and liquid chromatography-mass spectrometry (LC-MS), we profiled the metabolism of fetal brains, hearts, livers, and placentas harvested from pregnant dams between embryonic days (E)10.5 and 18.5. Our analysis revealed metabolic features specific to a hyperglycemic environment and signatures that may denote developmental transitions during euglycemic development. We observed sorbitol accumulation in fetal tissues and altered neurotransmitter levels in fetal brains isolated from hyperglycemic dams. Tracing C-glucose revealed disparate fetal nutrient sourcing depending on maternal glycemic states. Regardless of glycemic state, histidine-derived metabolites accumulated in late-stage fetal tissues. Our rich dataset presents a comprehensive overview of in vivo fetal tissue metabolism and alterations due to maternal hyperglycemia.
Topics: Animals; Female; Mice; Pregnancy; Diabetes Mellitus; Fetus; Glucose; Placenta; Diabetes, Gestational
PubMed: 38070508
DOI: 10.1016/j.cell.2023.11.011 -
Journal of Nippon Medical School =... Dec 2004The metabolic rate of the fetus per tissue weight is relatively high when compared to that of an adult. Moreover, heat is transferred to the fetus via the placenta and... (Review)
Review
The metabolic rate of the fetus per tissue weight is relatively high when compared to that of an adult. Moreover, heat is transferred to the fetus via the placenta and the uterus, resulting in a 0.3 degrees C to 0.5 degrees C higher temperature than that of the mother. Therefore, fetal temperature is maternally dependent until birth. At birth, the neonate rapidly cools in response to the relatively cold extrauterine environment. Thus, the neonatal temperature rapidly drops soon after birth. In order to survive, the neonate must accelerate heat production via nonshivering thermogenesis (NST), which is coupled to lypolysis in brown adipose tissue. Heat is produced by uncoupling ATP synthesis via the oxidation of fatty acids in the mitochondria, utilizing uncoupled protein. Thermogenesis must begin shortly after birth and continue for several hours. Since thermogenesis requires adequate oxygenation, a distressed neonate with hypoxemia cannot produce an adequate amount of heat to increase its temperature. In contrast to the neonate, the fetus cannot produce extra heat production. This is because the fetus is exposed to inhibitors to NST, which are produced in the placenta and then enter the fetal circulation. The important inhibitors include adenosine and prostaglandin E2, both of which have strong anti-lypolytic actions. The inhibitors play an important role in the metabolic adaptation of a physiological hypoxic fetus because NST requires adequate oxygenation. Furthermore, the presence of NST inhibitors allows the fetus to accumulate an adequate amount of brown adipose tissue before birth. The umbilical circulation transfers 85% of the heat produced by the fetus to the maternal circulation. The remaining 15% is dissipated through the fetal skin to the amnion, and is then transferred through the uterine wall to the maternal abdomen. As long as fetal heat production and loss are appropriately balanced, the temperature differential between the fetus and the mother remains constant (heat clump). However, when the umbilical circulation is occluded for any reason, the fetal temperature will rise in relation to the extent of the occlusion. The fetal temperature may elevate to the hyperthermic range in cases of acute cord occlusion; if this occurs, fetal growth, including brain development, may be impacted. Experimentally induced cord occlusion, which is recognized as a significant cause of brain damage, results in a rapid elevation of body temperature; however, the brain temperature tends to remain constant. This is considered to be a cerebral thermoregulatory adaptation to hypoxemia, which has the physiologic advantage of protecting the fetus from hyperthermia, a condition that predisposes the fetus to hypoxic injury (cerebral hypometabolism). A number of thermoregularatory mechanisms are in place to maintain normal fetal and neonatal growth. Data has primarily been collected from animal studies; aside from the strict thermal control provided in the newborn nursery, little information exists concerning these mechanisms in the human fetus and neonate. Probably further information on thermoregulation is necessary specially to improve perinatal management for hypoxic fetuses.
Topics: Body Temperature Regulation; Fetus; Humans; Infant, Newborn
PubMed: 15673956
DOI: 10.1272/jnms.71.360 -
Nature Oct 2019Definitive haematopoiesis in the fetal liver supports self-renewal and differentiation of haematopoietic stem cells and multipotent progenitors (HSC/MPPs) but remains...
Definitive haematopoiesis in the fetal liver supports self-renewal and differentiation of haematopoietic stem cells and multipotent progenitors (HSC/MPPs) but remains poorly defined in humans. Here, using single-cell transcriptome profiling of approximately 140,000 liver and 74,000 skin, kidney and yolk sac cells, we identify the repertoire of human blood and immune cells during development. We infer differentiation trajectories from HSC/MPPs and evaluate the influence of the tissue microenvironment on blood and immune cell development. We reveal physiological erythropoiesis in fetal skin and the presence of mast cells, natural killer and innate lymphoid cell precursors in the yolk sac. We demonstrate a shift in the haemopoietic composition of fetal liver during gestation away from being predominantly erythroid, accompanied by a parallel change in differentiation potential of HSC/MPPs, which we functionally validate. Our integrated map of fetal liver haematopoiesis provides a blueprint for the study of paediatric blood and immune disorders, and a reference for harnessing the therapeutic potential of HSC/MPPs.
Topics: Blood Cells; Cellular Microenvironment; Female; Fetus; Flow Cytometry; Gene Expression Profiling; Hematopoiesis; Humans; Liver; Lymphoid Tissue; Single-Cell Analysis; Stem Cells
PubMed: 31597962
DOI: 10.1038/s41586-019-1652-y -
Advanced Science (Weinheim,... Mar 2022Euthyroidism is of profound importance for lifetime health. However, the early diagnosis or therapeutics of thyroid developmental defects has not been established,...
Euthyroidism is of profound importance for lifetime health. However, the early diagnosis or therapeutics of thyroid developmental defects has not been established, mainly due to limited understanding of human thyroid development and a lack of recapitulating research model. Herein, the authors elaborate the cell atlas and potential regulatory signaling of the evolution of heterogeneous thyrocyte population from 12 to 16 gestational weeks. Moreover, they establish a long-term culture of human fetal thyroid organoids (hFTOs) system, which retains the fetal thyroid lineages and molecular signatures, as well as the ability to generate functional human thyroid follicles post mice renal transplantation. Notably, cAMP signaling activation in hFTOs by forskolin boosts the maturation of follicle and thus thyroid hormone T4 secretion, which recapitulates the key developmental events of fetal thyroid. Employing this ex vivo system, it is found that enhanced chromatin accessibility at thyroid maturation genes (such as TPO and TG) loci permits the transcription for hormone production. This study provides the cell atlas of and an organoid model for human thyroid development, which will facilitate thyroid research and prospective medicine.
Topics: Animals; Female; Fetus; Humans; Mice; Organoids; Ovarian Follicle; Prospective Studies; Thyroid Gland
PubMed: 35064652
DOI: 10.1002/advs.202105568 -
Cell Transplantation 2022Recent advances in human organoid technology have greatly facilitated the study of organ development and pathology. In most cases, these organoids are derived from... (Review)
Review
Recent advances in human organoid technology have greatly facilitated the study of organ development and pathology. In most cases, these organoids are derived from either pluripotent stem cells or adult stem cells for the modeling of developmental events and tissue homeostasis. However, due to the lack of human fetal tissue references and research model, it is still challenging to capture early developmental changes and underlying mechanisms in human embryonic development. The establishment of fetal tissue-derived organoids in rigorous time points is necessary. Here we provide an overview of the strategies and applications of fetal tissue-derived organoids, mainly focusing on fetal organ development research, developmental defect disease modeling, and organ-organ interaction study. Discussion of the importance of fetal tissue research also highlights the prospects and challenges in this field.
Topics: Adult; Adult Stem Cells; Fetus; Humans; Organoids; Pluripotent Stem Cells
PubMed: 36121224
DOI: 10.1177/09636897221124481 -
Hormone Molecular Biology and Clinical... May 2016Maternal lipids are strong determinants of fetal fat mass. Here we review the overall lipid metabolism in normal and gestational diabetes mellitus (GDM) pregnancies.... (Review)
Review
Maternal lipids are strong determinants of fetal fat mass. Here we review the overall lipid metabolism in normal and gestational diabetes mellitus (GDM) pregnancies. During early pregnancy, the increase in maternal fat depots is facilitated by insulin, followed by increased adipose tissue breakdown and subsequent hypertriglyceridemia, mainly as a result of insulin resistance (IR) and estrogen effects. The response to diabetes is variable as a result of greater IR but decreased estrogen levels. The vast majority of fatty acids (FAs) in the maternal circulation are esterified and associated with lipoproteins. These are taken up by the placenta and hydrolyzed by lipases. The released FAs enter various metabolic routes and are released into fetal circulation. Although these determinants are modified in maternal GDM, the fetus does not seem to receive more FAs than in non-GDM pregnancies. Long-chain polyunsaturated FAs are essential for fetal development and are obtained from the mother. Mitochondrial FA oxidation occurs in fetal tissue and in placenta and contributes to energy production. Fetal fat accretion during the last weeks of gestation occurs very rapidly and is sustained not only by FAs crossing the placenta, but also by fetal lipogenesis. Fetal hyperinsulinemia in GDM mothers promotes excess accretion of adipose tissue, which gives rise to altered adipocytokine profiles. Fetal lipoproteins are low at birth, but the GDM effects are unclear. The increase in body fat in neonates of GDM women is a risk factor for obesity in early childhood and later life.
Topics: Adipose Tissue; Diabetes, Gestational; Dyslipidemias; Fatty Acids, Nonesterified; Female; Fetal Development; Fetus; Humans; Lipid Metabolism; Maternal-Fetal Exchange; Placenta; Pregnancy; Triglycerides
PubMed: 26351960
DOI: 10.1515/hmbci-2015-0025 -
Medical Image Analysis Aug 2023In-utero fetal MRI is emerging as an important tool in the diagnosis and analysis of the developing human brain. Automatic segmentation of the developing fetal brain is...
In-utero fetal MRI is emerging as an important tool in the diagnosis and analysis of the developing human brain. Automatic segmentation of the developing fetal brain is a vital step in the quantitative analysis of prenatal neurodevelopment both in the research and clinical context. However, manual segmentation of cerebral structures is time-consuming and prone to error and inter-observer variability. Therefore, we organized the Fetal Tissue Annotation (FeTA) Challenge in 2021 in order to encourage the development of automatic segmentation algorithms on an international level. The challenge utilized FeTA Dataset, an open dataset of fetal brain MRI reconstructions segmented into seven different tissues (external cerebrospinal fluid, gray matter, white matter, ventricles, cerebellum, brainstem, deep gray matter). 20 international teams participated in this challenge, submitting a total of 21 algorithms for evaluation. In this paper, we provide a detailed analysis of the results from both a technical and clinical perspective. All participants relied on deep learning methods, mainly U-Nets, with some variability present in the network architecture, optimization, and image pre- and post-processing. The majority of teams used existing medical imaging deep learning frameworks. The main differences between the submissions were the fine tuning done during training, and the specific pre- and post-processing steps performed. The challenge results showed that almost all submissions performed similarly. Four of the top five teams used ensemble learning methods. However, one team's algorithm performed significantly superior to the other submissions, and consisted of an asymmetrical U-Net network architecture. This paper provides a first of its kind benchmark for future automatic multi-tissue segmentation algorithms for the developing human brain in utero.
Topics: Pregnancy; Female; Humans; Image Processing, Computer-Assisted; Brain; Head; Fetus; White Matter; Algorithms; Magnetic Resonance Imaging
PubMed: 37267773
DOI: 10.1016/j.media.2023.102833 -
Current Vascular Pharmacology Sep 2013Although blood flow in the placental vasculature is governed by the same physiological forces of shear, pressure and resistance as in other organs, it is also uniquely... (Review)
Review
Although blood flow in the placental vasculature is governed by the same physiological forces of shear, pressure and resistance as in other organs, it is also uniquely specialized on the maternal and fetal sides. At the materno-fetal interface, the independent uteroplacental and umbilicoplacental circulations must coordinate sufficiently to supply the fetus with the nutrients and substrates it needs to grow and develop. Uterine arterial flow must increase dramatically to accommodate the growing fetus. Recent evidence delineates the hormonal and endothelial mechanisms by which maternal vessels dilate and remodel during pregnancy. The umbilical circulation is established de novo during embryonic development but blood does not flow through the placenta until late in the first trimester. The umbilical circulation operates in the interest of maintaining fetal oxygenation over the course of pregnancy, and is affected differently by mechanical and chemical regulators of vascular tone compared to other organs. The processes that match placental vascular growth and fetal tissue growth are not understood, but studies of compromised pregnancies provide clues. The subtle changes that cause the failure of the normally regulated vascular processes during pregnancy have not been thoroughly identified. Likewise, practical and effective therapeutic strategies to reverse detrimental placental perfusion patterns have yet to be investigated.
Topics: Animals; Female; Fetal Development; Fetus; Humans; Placenta; Placental Circulation; Pregnancy
PubMed: 24063386
DOI: 10.2174/1570161111311050012 -
Stem Cell Reports Dec 2023Human fetal tissue and cells derived from fetal tissue are crucial for biomedical research. Fetal tissues and cells are used to study both normal development and... (Review)
Review
Human fetal tissue and cells derived from fetal tissue are crucial for biomedical research. Fetal tissues and cells are used to study both normal development and developmental disorders. They are broadly applied in vaccine development and production. Further, research using cells from fetal tissue is instrumental for studying many infectious diseases, including a broad range of viruses. These widespread applications underscore the value of fetal tissue research and reflect an important point: cells derived from fetal tissues have capabilities that cells from other sources do not. In many cases, increased functionality of cells derived from fetal tissues arises from increased proliferative capacity, ability to survive in culture, and developmental potential that is attenuated in adult tissues. This review highlights important, representative applications of fetal tissue for science and medicine.
Topics: Adult; Humans; Fetus; Fetal Research
PubMed: 37977142
DOI: 10.1016/j.stemcr.2023.10.008