Search Results (130)

Recent studies support that hematopoietic stem cell (HSC)-derived myeloid dendritic cells, monocytes/macrophages (Mo/Mϕ), and osteoclast precursors (OCps) share common progenitor(s) during development. This occurs mainly through receptor activator of NF-κB ligand (RANKL) signaling via its cytoplasmic adaptor protein complex (TRAF6) to subsequent osteoclastogenesis for bone loss and/or remodeling. Presently, mounting new evidence suggests that erythro-myeloid progenitor (EMP)-derived macrophages (Mϕ) and HSC-derived monocytes (Mo) produce embryonic, fetal, and postnatal OCp pools (i.e., primitive OCp), pinpointing a complex network of multiple OCp developmental origins. However, their ontogenic developments, lineage interactions, and contributions to the alternative osteoclastogenesis—in contrast to overall bone remodeling or loss—remain elusive. Interestingly, studies have also elucidated the contributions of immature CD11c⁺ myeloid DC-like OCps to osteoclastogenesis, with or without the classical so-called Mo/Mϕ-derived OCp subsets, and described that CD11c⁺ myeloid DCs (mDCs) develop into functionally active OCs; meanwhile, the cytokine TGF-β mediates a stepwise regulation of de novo immature mDCs/OCps through distinct crosstalk(s) with IL-17, an unrecognized interaction featuring TRAF6^(−/−)CD11c⁺ mDDOCps that coexist and proficiently colocalize in the local environment to drive a bona fide route for alternative osteoclastogenesis in vivo. Collectively, new findings—critically hinged on progenitor osteoclastogenic pathways (primitive OCps, mDCs/OCps, osteomorphs, etc.) and involving classical and/or alternative routes to inflammation-induced bone loss—are discussed via the illustrated schemes. This review highlights plausible ontogenic vs. principal or alternative developmental paths and their consequential downstream effects. Full article

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) are among the most common congenital malformations and the leading cause of chronic kidney disease in children. They arise when key steps in kidney development are disrupted, including ureteric bud induction, branching morphogenesis and nephron progenitor differentiation. These processes depend on coordinated transcriptional programs, signaling pathways, ciliary function and proper extracellular matrix (ECM) organization. Advances in whole exome and whole genome sequencing, as well as copy number variation analysis, have expanded the spectrum of known monogenic causes. Pathogenic variants have now been identified in major transcriptional regulators and multiple ciliopathy-related genes. Evidence also points to defects in central signaling pathways and changes in ECM composition as contributors to CAKUT pathogenesis. Clinical presentations vary widely, shaped by modifying effects of genetic background, epigenetic regulation and environmental influences such as maternal diabetes and fetal hypoxia. Emerging tools, including human kidney organoids, gene-editing approaches and single-cell or spatial transcriptomics, allow detailed exploration of developmental mechanisms and validation of candidate pathways. Overall, CAKUT reflects a multifactorial condition shaped by interacting genetic, epigenetic and environmental determinants. Integrating genomic data with experimental models is essential for improving diagnosis, deepening biological insight and supporting the development of targeted therapeutic strategies. Full article

The prevalence of maternal obesity is rapidly increasing, which represents a major public health concern worldwide. Currently more than 50% of all adult women are overweight or obese, and this trend is reflected in women of child-bearing age. Maternal obesity is characterized by metabolic dysfunction and chronic inflammation, and is associated with health problems in both the mother and the offspring. Intrauterine programming occurs during embryonic and fetal development, a critical period not only for the formation of tissues and organs but also for the etiology of diseases later in life. The principal mechanisms underlying fetal programming in the offspring of obese mothers appear to involve DNA methylation and chromatin remodeling within progenitor cells. Aberrant DNA methylation patterns have been identified in genes involved in insulin signaling, lipid metabolism, and appetite regulation in the placenta and fetal tissues. Histone modifications, such as acetylation and methylation of histone tails, may also play a crucial role in modulating chromatin structure and accessibility of transcriptional machinery to DNA. The persistence of such modifications throughout life, and potentially across generations, can lead to permanent alterations in gene expression, thereby contributing to the intergenerational transmission of metabolic disorders. The aim of this paper is to present an overview of the current knowledge regarding the effects of maternal obesity on fetal development and the occurrence of fetal complications, as well as long-term complications observed in adulthood related to intrauterine exposure to maternal obesity, including hypertension and cardiovascular diseases, impaired insulin secretion and resistance, diabetes mellitus, and metabolic syndrome. The mechanisms underlying fetal programming are also discussed. Full article

Maternal immune activation (MIA) during pregnancy has been associated with increased risk of fetal loss and neurodevelopmental disorders in offspring. This review summarizes recent findings on the effects of MIA on fetal survival and microglial phenotype. Studies using polyinosinic–polycytidylic acid [poly(I:C)-induced MIA mouse models have revealed the crucial role of interleukin-17A (IL-17A) in mediating these effects. Overexpression of RORγt, a key transcription factor for IL-17A production, enhances poly(I: C)-induced fetal loss, possibly due to increased placental vulnerability. Intraventricular administration of IL-17A in fetal brains activates microglia and alters their localization, particularly in periventricular regions and the medial cortex. These activated microglia may contribute to abnormal synaptic pruning and excessive phagocytosis of neural progenitor cells, potentially leading to long-term neurodevelopmental abnormalities. The insights gained from MIA research have important clinical implications, including the potential for early identification of high-risk pregnancies and the development of novel preventive and therapeutic strategies. Future research should focus on elucidating the roles of other cytokines, determining critical periods of MIA susceptibility, and translating findings to human populations, while carefully considering ethical implications and the need for appropriate risk communication. Full article

First-trimester placental development comprises many critical yet understudied cellular events that determine pregnancy outcomes. Improper placentation leads to a host of health issues that not only impact the fetal period but also influence later-life offspring health. Thus, an experimental paradigm for studying early placental development is necessary and has spurred the development of new in vitro models. Organoid model systems are three-dimensional structures comprising multiple differentiated cell types that originate from a progenitor population. Trophoblasts are the progenitor cells that serve as the proliferative base for the differentiation and maintenance of the placenta. Due to research constraints, experimental studies on the causal mechanisms underlying pathological pregnancies cannot readily be performed in human subjects. The nonhuman primate (NHP) offers a solution to this problem as it circumvents the limitations of human pregnancy sampling. Importantly, NHPs share many developmental features of human pregnancy, including placenta type and a similar fetal growth trajectory, making longitudinal pregnancy studies feasible and relevant. Since perturbations made in vivo can be validated in vitro, an NHP model of early pregnancy would facilitate mechanistic studies of pregnancy disorders. Herein, we describe the methodology for the establishment of a first-trimester NHP placenta trophoblast organoid model system. Full article

Prenatal and postnatal skeletal muscle development in ruminants is coordinated by interactions between genetic, nutritional, epigenetic, and endocrine factors. This review focuses on the influence of maternal nutrition during gestation on fetal myogenesis, satellite cell dynamics, and myogenic regulatory factors expression, including MYF5, MYOD1, and MYOG. Studies in sheep and cattle indicate that nutrient restriction or overnutrition alters muscle fiber number, the cross-sectional area, and the transcriptional regulation of myogenic genes in offspring. Postnatally, muscle hypertrophy is primarily mediated by satellite cells, which are activated via PAX7, MYOD, and MYF5, and regulated through mechanisms such as CARM1-induced chromatin remodeling and miR-31-mediated mRNA expression. Hormonal signaling via the GH–IGF1 axis and thyroid hormones further modulate satellite cell proliferation and protein accretion. Genetic variants, such as myostatin mutations in Texel sheep and Belgian Blue cattle, enhance muscle mass but may compromise reproductive efficiency. Nutritional interventions, including the plane of nutrition, supplementation strategies, and environmental stressors such as heat and stocking density, significantly influence muscle fiber composition and carcass traits. This review provides a comprehensive overview of skeletal muscle programming in ruminants, tracing the developmental trajectory from progenitor cell differentiation to postnatal growth and maturation. These insights underscore the need for integrated approaches combining maternal diet optimization, molecular breeding, and precision livestock management to enhance muscle growth, meat quality, and production sustainability in ruminant systems. Full article

Testicular orphan receptors TR2 and TR4 serve as central regulators of erythropoiesis, orchestrating the entire continuum of erythroid progenitor cell proliferation, differentiation, and maturation. As core components of the direct repeat erythroid determinant (DRED) complex, they activate erythroid-specific transcriptional programs to dynamically control the spatiotemporal expression of globin genes. These nuclear receptors not only engage in functional interactions with key erythroid transcription factors GATA1 and KLF1 to coregulate erythroid differentiation and maturation but also recruit epigenetic modifier complexes such as DNMT1 and LSD1 to modulate chromatin states dynamically. Research has established that dysfunctions in TR2/TR4 are implicated in β-thalassemia and sickle cell disease (SCD): β-thalassemia is associated with the defective silencing of γ-globin genes, while in SCD, TR2/TR4 antagonizes BCL11A to reactivate fetal hemoglobin (HbF) expression. This review systematically dissects the molecular regulatory networks of TR2/TR4 in erythroid cells, interprets their dual regulatory properties across different stages of erythroid differentiation, and explores the therapeutic potential of targeting TR2/TR4 for treating erythroid-related disorders such as β-thalassemia and SCD, thereby providing novel directions for hematological disorder therapy. Full article

Background: The extracellular matrix (ECM), primarily composed of collagen and elastin synthesized by dermal fibroblasts, is critical for mesenchymal tissue integrity. Fibroblast phenotypes vary significantly with the anatomical location and developmental stage. Fetal skin, particularly prior to 14 weeks of gestation, exhibits a simplified structure compared to adult skin, characterized by a thin, loose dermal matrix and a single-layered epithelium. Objectives: This study aimed to characterize and functionally compare homogenous progenitor fetal fibroblast (PFF) populations derived from 14-week-old fetal skin with fibroblasts isolated from adult burn patients. Methods: We evaluated the proliferative capacity, collagen synthesis, and differentiation potential (adipogenesis and osteogenesis) of PFF and adult burn patient fibroblasts. Furthermore, we assessed their ability to support skin regeneration using a de-epidermized dermis (DED) model seeded with both PFF and patient-derived keratinocytes. The stability of PFF characteristics was monitored across multiple passages (P5–P12). Results: PFF demonstrated a 2–4-fold increase in proliferation rate and a 30–50% enhancement in collagen production in vitro compared to adult fibroblasts. Notably, PFF exhibited a consistent lack of adipogenic and osteogenic differentiation, an attribute distinct from adult fibroblasts. In the DED model, PFF, even at a low fibroblast-to-keratinocyte ratio (1:5), effectively facilitated the formation of well-organized skin structures, including rete ridges, surpassing the performance of adult fibroblasts and adipose-derived cells. These properties remained stable over multiple passages. Conclusions: The unique attributes of PFF, likely attributable to the simplified microenvironment (i.e., collagen organization) of developing fetal tissue, positions them as a promising source for cell-based therapies. Their inherent high collagen synthesis capacity is particularly advantageous for wound healing applications. Consequently, PFF represent a consistent and readily available resource for developing “off-the-freezer” cutaneous cell therapies, potentially enabling accelerated and improved treatment of severe burn injuries. Full article

Cerebral organoids (cORGs) obtained from induced pluripotent stem cells (iPSCs) have become significant instruments for investigating human neurophysiology, with the possibility of simulating diseases and enhancing drug discovery. The current approaches require a strict process of manual inclusion in animal-derived matrix Matrigel^® and are challenged by unpredictability, operators’ skill and expertise, elevated costs, and restricted scalability, impeding their extensive applicability and translational potential. In this study, we present a novel method to generate brain organoids that address these limitations. Our approach does not require a manual, operator-dependent embedding. Instead, it employs a chemically defined hydrogel in which the Matrigel^® is diluted in a solution enriched with sodium alginate (SA) and sodium carboxymethylcellulose (CMC) and used as a bioink to print neural embryoid bodies (nEBs). Immunohistochemical, immunofluorescence, and gene expression analyses confirmed that SA-CMC-Matrigel^® hydrogel can sustain the generation of iPSC-derived cortical cORGs as the conventional Matrigel^®-based approach does. By day 40 of differentiation, hydrogel-based 3D-bioprinted cORGs showed heterogeneous and consistent masses, with a cytoarchitecture resembling an early-stage developmental fetal brain composed of neural progenitor cells PAX6⁺/Ki67⁺ organized into tubular structures, and densely packed cell somas with extensive neurites SYP⁺, suggestive of cortical tissue-like neuronal layer formation. Full article

Background/Objectives: The oncofetal membrane protein Claudin 6 (CLDN6) is an attractive target for T cell-based therapies. There is a lack of detailed analyses on the age-dependent expression of CLDN6 in normal tissues is lacking, which limits the expansion of CLDN6 CAR-T cell clinical trials to pediatric populations. Methods: We analyzed CLDN6 expression in extracranial solid tumors and normal tissues of children using RNA-sequencing data from over 500 pediatric solid tumor samples, qRT-PCR and immunohistochemistry (IHC) in more than 100 fresh-frozen tumor samples and, approximately, 250 formalin-fixed paraffin-embedded (FFPE) samples. We examined normal tissue expression via qRT-PCR in 32 different infant tissues and via IHC in roughly 290 tissues from donors across four age groups, as well as in fetal autopsy samples. Results: In fetal tissues, we detected CLDN6 expression primarily in the epithelial cells of several organs, including the skin, lungs, kidneys, intestinal tract, and pancreas, but not in undifferentiated blastemal cells. Postnatally, we found CLDN6-positive epithelial progenitors only during the first few weeks of life. In older-age groups, isolated clusters of CLDN6-positive progenitors were present, but in scarce quantities. In tumor tissues, we found strong and homogeneous CLDN6 expression in desmoplastic small round cell tumors and germ cell tumors. Wilms tumors demonstrated heterogeneous CLDN6 expression, notably absent in the blastemal component. Conclusions: These findings highlight an organ-specific presence of CLDN6-positive epithelial precursors that largely disappear in terminally differentiated epithelia within weeks after birth. Therefore, our data support CLDN6 as a viable therapeutic target in pediatric patients and justify their inclusion in basket studies for anti-CLDN6-based therapies. Full article

Erythropoietin (EPO) is a key regulator of erythrocyte production, promoting erythroid progenitor cell survival, division, and differentiation in the fetal liver and adult bone marrow. Mice lacking EPO or its receptor (EPOR) die in utero due to severe anemia. Beyond hematopoiesis, EPO influences non-hematopoietic tissues, including glucose and fat metabolism in adipose tissue, skeletal muscle, and the liver. EPO is used to treat anemia associated with chronic kidney disease clinically and plays a role in maintaining metabolic homeostasis and regulating fat mass. EPO enhances lipolysis while inhibiting lipogenic gene expression in white adipose tissue, brown adipose tissue, skeletal muscle, and the liver, acting through the EPO-EPOR-RUNX1 axis. The non-erythroid EPOR agonist ARA290 also improves diet-induced obesity and glucose tolerance providing evidence for EPO regulation of fat metabolism independent of EPO stimulated erythropoiesis. Therefore, in addition to the primary role of EPO to stimulate erythropoiesis, EPO contributes significantly to EPOR-dependent whole-body metabolic response. Full article

Accurate normalization in miRNA studies requires the use of appropriate endogenous controls, which can vary significantly depending on cell types, treatments, and physiological or pathological conditions. This study aimed to identify suitable endogenous miRNA controls for neural progenitor cells (NPCs) and hippocampal tissues, both of which play crucial roles in neurogenesis. Using small RNA sequencing, we identified the most stable miRNAs in primary mouse NPCs and hippocampal tissues and accessed their stability using NormFinder analysis. Six miRNAs—miR-181d-5p, miR-93-5p, miR-103-3p, let-7d-5p, miR-26a-5p, and miR-125a-5p—demonstrated high stability and were evaluated for their suitability as endogenous controls across multiple experimental conditions. All selected miRNAs exhibited consistent expression in the NE-4C mouse cell line but not in ReNcells, a human cell line. For ReNcells, only miR-186-5p, one of the known reference miRNAs tested for comparison, showed stable expression. Notably, miR-103-3p and let-7d-5p were stably expressed in hippocampal tissues from both mouse and human samples but were absent in human brain pericytes, human brain microvascular endothelial cells, and SVG p12 cells, a human fetal glial cell line. This study is the first to identify optimal reference miRNAs for adult neurogenesis in both mouse and human samples, providing reliable options for miRNA normalization and improving the accuracy and reproducibility of miRNA expression analyses in neurogenesis research. Full article

In livestock production, oxidative stress (OS) is ubiquitous, reducing animal productivity and product quality. Hence, investigating the mechanisms of oxidative stress in livestock and inhibiting oxidative stress-induced damage is crucial. Curcumin, a plant-derived bioactive compound, exhibits antioxidant and anti-apoptotic properties. Adipose-derived stem cells (ADSCs) from animal adipose tissue are easily accessible and possess multilineage differentiation potential. Therefore, this work utilized bovine ADSCs to establish an oxidative stress model and investigated the effects of curcumin on oxidative stress and apoptosis. Firstly, bovine ADSCs were isolated and cultured from fetal calf subcutaneous adipose tissue. Their surface markers were identified by immunofluorescence, confirming the expression of CD29, CD44, CD73, CD90, CD105 and Vimentin, but not CD34, indicative of mesenchymal stem/progenitor cell characteristics. Secondly, to explore the effects of curcumin on oxidative damage and apoptosis in bovine ADSCs, an oxidative stress model was induced using H₂O₂. CCK-8 assays showed significantly reduced cell viability and SOD activity, along with increased malondialdehyde (MDA) and reactive oxygen species (ROS) levels, indicating successful modeling. RT-qPCR further confirmed that 500 μM of H₂O₂ treatment for 24 h promoted apoptosis. Herein, CCK-8 assays indicated a significant reduction in cell viability at >8 μM of curcumin. Thirdly, using 4 μM and 8 μM of curcumin for pre-protection, 8 μM maintained SOD activity, reduced MDA and ROS, inhibited apoptosis-related gene changes (Bcl-2, Bax, Caspase-3), and suppressed apoptosis according to a TUNEL assay. Fourthly, curcumin’s autophagy-inducing potential was hypothesized, which was confirmed by increased LC3-II and decreased P62 expression upon co-treatment with 3-MA. 3-MA inhibited curcumin’s antioxidant and anti-apoptotic effects, suggesting that curcumin’s antioxidant and anti-apoptotic roles may involve autophagy induction. In conclusion, bovine ADSCs are abundant, easily accessible, and multipotent, making them suitable for in vitro expansion. Curcumin alleviated H₂O₂-induced oxidative stress in bovine ADSCs, with curcumin also inhibiting apoptosis, likely through autophagy induction. This study validates the protective role of curcumin in bovine ADSCs, with potential applications in livestock production. Full article

In mice, the fetal brain is dependent upon the placenta for factors that guide its early development. This linkage between the two organs has given rise to the term, the placenta–brain axis. A similar interrelationship between the two organs may exist in humans. We hypothesize that extracellular vesicles (EVs) released from placental trophoblast (TB) cells transport small RNA and other informational biomolecules from the placenta to the brain where their contents have pleiotropic effects. Here, EVs were isolated from the medium in which human trophoblasts (TBs) had been differentiated in vitro from induced pluripotent stem cells (iPSC) and from cultured iPSC themselves, and their small RNA content analyzed by bulk RNA-seq. EVs derived from human TB cells possess unique profiles of miRs, including hsa-miR-0149-3p, hsa-302a-5p, and many long non-coding RNAs (lncRNAs) relative to EVs isolated from parental iPSC. These miRs and their mRNA targets are enriched in neural tissue. Human neural progenitor cells (NPCs), generated from the same iPSC, were exposed to EVs from either TB or iPSC controls. Both sets of EVs were readily internalized. EVs from TB cells upregulate several transcripts in NPCs associated with forebrain formation and neurogenesis; those from control iPSC upregulated a transcriptional phenotype that resembled glial cells more closely than neurons. These results shed light on the possible workings of the placenta–brain axis. Understanding how the contents of small RNA within TB-derived EVs affect NPCs might yield new insights, possible biomarkers, and potential treatment strategies for neurobehavioral disorders that originate in utero, such as autism spectrum disorders (ASDs). Full article

During mouse development, hematopoietic cells first form in the extraembryonic tissue yolk sac. Hematopoietic stem cells (HSCs), which retain their ability to differentiate into hematopoietic cells for a long time, form intra-aortic hematopoietic cell clusters (IAHCs) in the dorsal aorta at midgestation. These IAHCs emerge from the hemogenic endothelium, which is the common progenitor of hematopoietic cells and endothelial cells. HSCs expand in the fetal liver, and finally migrate to the bone marrow (BM) during the peripartum period. IAHCs are absent in the dorsal aorta in mice deficient in transcription factors such as Runx-1, GATA2, and c-Myb that are essential for definitive hematopoiesis. In this review, we focus on the transcription factor Sry-related high mobility group (HMG)-box (Sox) F family of proteins that is known to regulate hematopoiesis in the hemogenic endothelium and IAHCs. The SoxF family is composed of Sox7, Sox17, and Sox18, and they all have the HMG box, which has a DNA-binding ability, and a transcriptional activation domain. Here, we describe the functional and phenotypic properties of SoxF family members, with a particular emphasis on Sox17, which is the most involved in hematopoiesis in the fetal stages considering that enhanced expression of Sox17 in hemogenic endothelial cells and IAHCs leads to the production and maintenance of HSCs. We also discuss SoxF-inducing signaling pathways. Full article