Human in vitro gametogenesis may transform reproductive medicine. Human pluripotent stem cells (hPSCs) have been induced into primordial germ cell-like cells (hPGCLCs); however, further differentiation to a mature germ cell has not been achieved. Here, we show that hPGCLCs differentiate progressively into oogonia-like cells during a long-term in vitro culture (approximately 4 months) in xenogeneic reconstituted ovaries with mouse embryonic ovarian somatic cells. The hPGCLC-derived oogonia display hallmarks of epigenetic reprogramming-genome-wide DNA demethylation, imprint erasure, and extinguishment of aberrant DNA methylation in hPSCs-and acquire an immediate precursory state for meiotic recombination. Furthermore, the inactive X chromosome shows a progressive demethylation and reactivation, albeit partially. These findings establish the germline competence of hPSCs and provide a critical step toward human in vitro gametogenesis.
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http://dx.doi.org/10.1126/science.aat1674 | DOI Listing |
Parasitol Res
December 2024
Institute of Hygiene and Microbiology, University of Würzburg, Josef-Schneider-Strasse 2, 97080, Würzburg, Germany.
Pluripotent somatic stem cells are the drivers of unlimited growth of Echinococcus multilocularis metacestode tissue within the organs of the intermediate host. To understand the dynamics of parasite proliferation within the host, it is therefore important to delineate basic mechanisms of Echinococcus stem cell maintenance and differentiation. We herein undertake the first step towards characterizing the role of an evolutionarily old metazoan cell-cell communication system, delta/notch signalling, in Echinococcus cell fate decisions.
View Article and Find Full Text PDFElife
December 2024
Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, United Kingdom.
A major challenge in the stem cell biology field is the ability to produce fully functional cells from induced pluripotent stem cells (iPSCs) that are a valuable resource for cell therapy, drug screening, and disease modelling. Here, we developed a novel inducible CRISPR-mediated activation strategy (iCRISPRa) to drive the expression of multiple endogenous transcription factors (TFs) important for in vitro cell fate and differentiation of iPSCs to haematopoietic progenitor cells. This work has identified a key role for IGFBP2 in developing haematopoietic progenitors.
View Article and Find Full Text PDFBiochem J
December 2024
Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, U.S.A.
In mammals, molecular mechanisms of circadian rhythms involve a time-delayed negative feedback loop generating autonomous oscillations of ∼24 h. Most cell types in mammals possess circadian rhythms regulating temporal organization of cellular and physiological processes. Intriguingly, pluripotent stem cells do not possess circadian rhythms and oscillations arise after a defined period of differentiation.
View Article and Find Full Text PDFJ Cell Biol
February 2025
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
Endocytosis, required for the uptake of receptors and their ligands, can also introduce pathological aggregates such as α-synuclein (α-syn) in Parkinson's Disease. We show here the unexpected presence of intrinsically perforated endolysosomes in neurons, suggesting involvement in the genesis of toxic α-syn aggregates induced by internalized preformed fibrils (PFFs). Aggregation of endogenous α-syn in late endosomes and lysosomes of human iPSC-derived neurons (iNs), seeded by internalized α-syn PFFs, caused the death of the iNs but not of the parental iPSCs and non-neuronal cells.
View Article and Find Full Text PDFCarcinogenesis
December 2024
Division of Hematology, Second Xiangya Hospital, Central South University, No.139th Renmin Middle Road, Changsha, 410011, Hunan, China.
Chronic myeloid leukemia (CML) is a malignant hyperplastic tumor that originats from pluripotent hematopoietic stem cells in the bone marrow. The introduction of tyrosine kinase inhibitors (TKIs) has significantly improved the survival rates of CML patients. This study aimed to identify immune-related genes (IRGs) associated with the response to imatinib therapy in CML.
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