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Cureus May 2024Teratomas are rare germ cell tumors derived from multiple germinal cell layers. Thyroid teratomas, specifically, are exceptionally uncommon and present unique diagnostic...
Teratomas are rare germ cell tumors derived from multiple germinal cell layers. Thyroid teratomas, specifically, are exceptionally uncommon and present unique diagnostic and therapeutic challenges. Here, we report a case of cervico-mediastinal thyroid teratoma, highlighting diagnostic difficulties and surgical management. A 37-year-old woman presented with right lateral cervical swelling, leading to radiological imaging suggesting a thymic teratoma. However, cytology indicated a colloid cyst. Surgical removal was performed, revealing a mixed-type teratoma originating from the thyroid gland. Thyroid teratomas pose diagnostic and therapeutic challenges due to their rarity and complex nature. Further research is needed to establish standardized guidelines for their management.
PubMed: 38827013
DOI: 10.7759/cureus.59560 -
Developmental Cell May 2024Embryonic stem cells (ESCs) can differentiate into all cell types of the embryonic germ layers. ESCs can also generate totipotent 2C-like cells and trophectodermal...
Embryonic stem cells (ESCs) can differentiate into all cell types of the embryonic germ layers. ESCs can also generate totipotent 2C-like cells and trophectodermal cells. However, these latter transitions occur at low frequency due to epigenetic barriers, the nature of which is not fully understood. Here, we show that treating mouse ESCs with sodium butyrate (NaB) increases the population of 2C-like cells and enables direct reprogramming of ESCs into trophoblast stem cells (TSCs) without a transition through a 2C-like state. Mechanistically, NaB inhibits histone deacetylase activities in the LSD1-HDAC1/2 corepressor complex. This increases acetylation levels in the regulatory regions of both 2C- and TSC-specific genes, promoting their expression. In addition, NaB-treated cells acquire the capacity to generate blastocyst-like structures that can develop beyond the implantation stage in vitro and form deciduae in vivo. These results identify how epigenetics restrict the totipotent and trophectoderm fate in mouse ESCs.
PubMed: 38823394
DOI: 10.1016/j.devcel.2024.05.009 -
Journal of Dental Research Jul 2024A ligature-induced periodontitis model was established in wild-type and CD146; Rosa mice to explore the function of pericytes in alveolar bone formation. We found that...
A ligature-induced periodontitis model was established in wild-type and CD146; Rosa mice to explore the function of pericytes in alveolar bone formation. We found that during periodontitis progression and periodontal wound healing, CD146/NG2 pericytes were enriched in the periodontal tissue areas, which could migrate to the alveolar bone surface and colocalize with ALP/OCN osteoblasts. Chemokine C-X-C motif receptor 4 (CXCR4) inhibition using AMD3100 blocked CD146-Cre pericyte migration and osteogenesis, as well as further exacerbated periodontitis-associated bone loss. Next, primary pericytes were sorted out by magnetic-activated cell sorting and demonstrated that C-X-C motif chemokine ligand 12 (CXCL12) promotes pericyte migration and osteogenesis via CXCL12-CXCR4-Rac1 signaling. Finally, the local administration of an adeno-associated virus for Rac1 overexpression in NG2 pericytes promotes osteoblast differentiation of pericytes and increases alveolar bone volume in periodontitis. Thus, our results provided the evidence that pericytes may migrate and osteogenesis via the CXCL12-CXCR4-Rac1 axis during the pathological process of periodontitis.
Topics: Pericytes; Animals; Osteogenesis; Periodontitis; Cell Movement; Mice; Chemokine CXCL12; Receptors, CXCR4; Alveolar Bone Loss; Signal Transduction; rac1 GTP-Binding Protein; Disease Models, Animal; CD146 Antigen; Osteoblasts; Cell Differentiation; Cyclams; Benzylamines
PubMed: 38822570
DOI: 10.1177/00220345241244687 -
Stem Cell Research Aug 2024Hereditary fructose intolerance (HFI) is an autosomal recessive metabolic disease associated with a mutation in the aldolase B gene on chromosome 9q31. In this study, we...
Hereditary fructose intolerance (HFI) is an autosomal recessive metabolic disease associated with a mutation in the aldolase B gene on chromosome 9q31. In this study, we generated a human-induced pluripotent stem cell (hiPSC) line, FDCHi015-A, from peripheral blood mononuclear cells (PBMCs) of a patient carrying the compound heterozygous mutations c.360_364delCAAA and c.1013C > T in exons 4 and 9 of the ALDOB gene, respectively. The iPSCs with the confirmed patient-specific mutation demonstrate pluripotency markers expression, a normal karyotype, and the ability to differentiate into derivatives of three germ layers.
Topics: Humans; Induced Pluripotent Stem Cells; Leukocytes, Mononuclear; Mutation; Fructose-Bisphosphate Aldolase; Cell Line; Cell Differentiation; Male; Karyotype
PubMed: 38820866
DOI: 10.1016/j.scr.2024.103451 -
Stem Cell Research Aug 2024Rubinstein Taybi Syndrome (RSTS) is a rare genetic disorder which is caused by mutations in either CREBBP or EP300. RSTS with mutations in CREBBP is known as RSTS-1. We...
Rubinstein Taybi Syndrome (RSTS) is a rare genetic disorder which is caused by mutations in either CREBBP or EP300. RSTS with mutations in CREBBP is known as RSTS-1. We have generated an induced pluripotent stem cell (iPSC) line, IGIBi018-A from an Indian RSTS-patient using the episomal reprogramming method. The CREBBP gene in the patient harbours a nonsense mutation at position NM_004380.3(c.6876 del C). IGIBi018-A iPSC showed expression of pluripotent stem cell markers, has a normal karyotype and could be differentiated into three germ layers. This iPSC line will help to explore the role of CREBBP in RSTS associated developmental defects.
Topics: Humans; Induced Pluripotent Stem Cells; Rubinstein-Taybi Syndrome; Cell Line; Cell Differentiation; India; Male; CREB-Binding Protein
PubMed: 38820863
DOI: 10.1016/j.scr.2024.103456 -
World Journal of Stem Cells May 2024Embryonic stem cells (ESCs) serve as a crucial model, representing epiblast cells derived from the inner cell mass of blastocyst-stage embryos. ESCs exhibit a unique...
BACKGROUND
Embryonic stem cells (ESCs) serve as a crucial model, representing epiblast cells derived from the inner cell mass of blastocyst-stage embryos. ESCs exhibit a unique combination of self-renewal potency, unlimited proliferation, and pluripotency. The latter is evident by the ability of the isolated cells to differentiate spontaneously into multiple cell lineages, representing the three primary embryonic germ layers. Multiple regulatory networks guide ESCs, directing their self-renewal and lineage-specific differentiation. Apoptosis, or programmed cell death, emerges as a key event involved in sculpting and forming various organs and structures ensuring proper embryonic development. However, the molecular mechanisms underlying the dynamic interplay between differentiation and apoptosis remain poorly understood.
AIM
To investigate the regulatory impact of apoptosis on the early differentiation of ESCs into cardiac cells, using mouse ESC (mESC) models - mESC-B-cell lymphoma 2 (BCL-2), mESC-PIM-2, and mESC-metallothionein-1 (MET-1) - which overexpress the anti-apoptotic genes , , and , respectively.
METHODS
mESC-T2 (wild-type), mESC-BCL-2, mESC-PIM-2, and mESC-MET-1 have been used to assess the effect of potentiated apoptotic signals on cardiac differentiation. The hanging drop method was adopted to generate embryoid bodies (EBs) and induce terminal differentiation of mESCs. The size of the generated EBs was measured in each condition compared to the wild type. At the functional level, the percentage of cardiac differentiation was measured by calculating the number of beating cardiomyocytes in the manipulated mESCs compared to the control. At the molecular level, quantitative reverse transcription-polymerase chain reaction was used to assess the mRNA expression of three cardiac markers: Troponin T, GATA4, and NKX2.5. Additionally, troponin T protein expression was evaluated through immunofluorescence and western blot assays.
RESULTS
Our findings showed that the upregulation of , , and genes led to a reduction in the size of the EBs derived from the manipulated mESCs, in comparison with their wild-type counterpart. Additionally, a decrease in the count of beating cardiomyocytes among differentiated cells was observed. Furthermore, the mRNA expression of three cardiac markers - troponin T, GATA4, and NKX2.5 - was diminished in mESCs overexpressing the three anti-apoptotic genes compared to the control cell line. Moreover, the overexpression of the anti-apoptotic genes resulted in a reduction in troponin T protein expression.
CONCLUSION
Our findings revealed that the upregulation of , , and genes altered cardiac differentiation, providing insight into the intricate interplay between apoptosis and ESC fate determination.
PubMed: 38817332
DOI: 10.4252/wjsc.v16.i5.551 -
Cell Communication and Signaling : CCS May 2024Optimizing the efficiency of definitive endoderm (DE) differentiation is necessary for the generation of diverse organ-like structures. In this study, we used the small...
Optimizing the efficiency of definitive endoderm (DE) differentiation is necessary for the generation of diverse organ-like structures. In this study, we used the small molecule inhibitor saracatinib (SAR) to enhance DE differentiation of human embryonic stem cells and induced pluripotent stem cells. SAR significantly improved DE differentiation efficiency at low concentrations. The interaction between SAR and Focal Adhesion Kinase (FAK) was explored through RNA-seq and molecular docking simulations, which further supported the inhibition of DE differentiation by p-FAK overexpression in SAR-treated cells. In addition, we found that SAR inhibited the nuclear translocation of Yes-associated protein (YAP), a downstream effector of FAK, which promoted DE differentiation. Moreover, the addition of SAR enabled a significant reduction in activin A (AA) from 50 to 10 ng/mL without compromising DE differentiation efficiency. For induction of the pancreatic lineage, 10 ng/ml AA combined with SAR at the DE differentiation stage yielded a comparative number of PDX1/NKX6.1 pancreatic progenitor cells to those obtained by 50 ng/ml AA treatment. Our study highlights SAR as a potential modulator that facilitates the cost-effective generation of DE cells and provides insight into the orchestration of cell fate determination.
Topics: Humans; Cell Differentiation; Endoderm; Benzodioxoles; Signal Transduction; Quinazolines; Transcription Factors; Induced Pluripotent Stem Cells; Adaptor Proteins, Signal Transducing; YAP-Signaling Proteins; Focal Adhesion Kinase 1; Human Embryonic Stem Cells; Activins; Molecular Docking Simulation
PubMed: 38816763
DOI: 10.1186/s12964-024-01679-7 -
American Journal of Human Genetics May 2024Epigenetic dysregulation has emerged as an important etiological mechanism of neurodevelopmental disorders (NDDs). Pathogenic variation in epigenetic regulators can...
Epigenetic dysregulation has emerged as an important etiological mechanism of neurodevelopmental disorders (NDDs). Pathogenic variation in epigenetic regulators can impair deposition of histone post-translational modifications leading to aberrant spatiotemporal gene expression during neurodevelopment. The male-specific lethal (MSL) complex is a prominent multi-subunit epigenetic regulator of gene expression and is responsible for histone 4 lysine 16 acetylation (H4K16ac). Using exome sequencing, here we identify a cohort of 25 individuals with heterozygous de novo variants in MSL complex member MSL2. MSL2 variants were associated with NDD phenotypes including global developmental delay, intellectual disability, hypotonia, and motor issues such as coordination problems, feeding difficulties, and gait disturbance. Dysmorphisms and behavioral and/or psychiatric conditions, including autism spectrum disorder, and to a lesser extent, seizures, connective tissue disease signs, sleep disturbance, vision problems, and other organ anomalies, were observed in affected individuals. As a molecular biomarker, a sensitive and specific DNA methylation episignature has been established. Induced pluripotent stem cells (iPSCs) derived from three members of our cohort exhibited reduced MSL2 levels. Remarkably, while NDD-associated variants in two other members of the MSL complex (MOF and MSL3) result in reduced H4K16ac, global H4K16ac levels are unchanged in iPSCs with MSL2 variants. Regardless, MSL2 variants altered the expression of MSL2 targets in iPSCs and upon their differentiation to early germ layers. Our study defines an MSL2-related disorder as an NDD with distinguishable clinical features, a specific blood DNA episignature, and a distinct, MSL2-specific molecular etiology compared to other MSL complex-related disorders.
PubMed: 38815585
DOI: 10.1016/j.ajhg.2024.05.001 -
Stem Cell Research Aug 2024We report the establishment of a human induced pluripotent stem cell (iPSC) line from a 54-year-old male patient with an A1555G mutation in the mitochondrial 12S...
We report the establishment of a human induced pluripotent stem cell (iPSC) line from a 54-year-old male patient with an A1555G mutation in the mitochondrial 12S ribosomal RNA gene (MTRNR1), associated with sensorineural hearing loss. The established iPSC line expressed stemness markers or undifferentiated state markers. We also demonstrated the capacity of the cells to differentiate into the three germ layers, suggesting its pluripotency and utility in the pathological study of sensorineural hearing loss and drug screening for ear disorders.
Topics: Humans; Induced Pluripotent Stem Cells; DNA, Mitochondrial; Male; Middle Aged; Mutation; Cell Differentiation; Cell Line; RNA, Ribosomal; Hearing Loss, Sensorineural; Hearing Loss
PubMed: 38815527
DOI: 10.1016/j.scr.2024.103452 -
Development (Cambridge, England) Jun 2024Apical expansion of calvarial osteoblast progenitors from the cranial mesenchyme (CM) above the eye is integral to calvarial growth and enclosure of the brain. The...
Apical expansion of calvarial osteoblast progenitors from the cranial mesenchyme (CM) above the eye is integral to calvarial growth and enclosure of the brain. The cellular behaviors and signals underlying the morphogenetic process of calvarial expansion are unknown. Time-lapse light-sheet imaging of mouse embryos revealed calvarial progenitors intercalate in 3D in the CM above the eye, and exhibit protrusive and crawling activity more apically. CM cells express non-canonical Wnt/planar cell polarity (PCP) core components and calvarial osteoblasts are bidirectionally polarized. We found non-canonical ligand Wnt5a-/- mutants have less dynamic cell rearrangements and protrusive activity. Loss of CM-restricted Wntless (CM-Wls), a gene required for secretion of all Wnt ligands, led to diminished apical expansion of Osx+ calvarial osteoblasts in the frontal bone primordia in a non-cell autonomous manner without perturbing proliferation or survival. Calvarial osteoblast polarization, progressive cell elongation and enrichment for actin along the baso-apical axis were dependent on CM-Wnts. Thus, CM-Wnts regulate cellular behaviors during calvarial morphogenesis for efficient apical expansion of calvarial osteoblasts. These findings also offer potential insights into the etiologies of calvarial dysplasias.
Topics: Animals; Osteoblasts; Skull; Mice; Mesoderm; Morphogenesis; Wnt Proteins; Cell Polarity; Wnt-5a Protein; Cell Movement; Cell Proliferation
PubMed: 38814743
DOI: 10.1242/dev.202596