Experimental Hematology, Journal Year: 2024, Volume and Issue: 143, P. 104697 - 104697
Published: Dec. 12, 2024
Language: Английский
Cell stem cell, Journal Year: 2024, Volume and Issue: unknown
Published: Nov. 1, 2024
Venous malformations (VMs) represent prevalent vascular anomalies typically attributed to non-inherited somatic mutations within venous endothelial cells (VECs). The lack of robust disease models for VMs impedes drug discovery. Here, we devise a protocol the generation human induced VECs (iVECs) through manipulation cell-cycle dynamics via retinoic signaling pathway. We introduce an L914F mutation into TIE2 gene locus pluripotent stem (iPSCs) and show that mutated iVECs form dilated blood vessels after transplantation mice, thereby recapitulating phenotypic characteristics observed in VMs. Moreover, utilizing deep neural network high-throughput digital RNA with perturbation genes sequencing (DRUG-seq) approach, perform screening demonstrate bosutinib effectively rescues phenotype vitro vivo. In summary, by leveraging genome editing cell technology, generate VM enable development additional therapeutics.
Language: Английский
Citations
6
STAR Protocols, Journal Year: 2025, Volume and Issue: 6(1), P. 103592 - 103592
Published: Jan. 24, 2025
Language: Английский
Citations
0
Cell Discovery, Journal Year: 2025, Volume and Issue: 11(1)
Published: Jan. 28, 2025
Abstract Hematopoietic stem and progenitor cells (HSPCs) are critical for the treatment of blood diseases in clinic. However, limited source HSPCs severely hinders their clinical application. In embryo, hematopoietic (HSCs) arise from hemogenic endothelial (HE) lining major arteries vivo. this work, by engineering vascular niche (VN-ECs), we generated functional vitro ECs at various sites, including aorta-gonad-mesonephros (AGM) region placenta. Firstly, converted mouse embryonic HE AGM (aHE) into induced (iHSPCs), which have abilities multilineage differentiation self-renewal. Mechanistically, found that VN-ECs can promote generation iHSPCs via secretion CX3CL1 IL1A. Next, through VN-EC co-culture, showed placental (pHE) cells, a type extra-embryonic were successfully (pHE-iHSPCs), capacity, but exhibit self-renewal ability. Furthermore, comparative transcriptome analysis aHE-iHSPCs pHE-iHSPCs highly expressed HSC-specific self-renewal-related genes. Moreover, experimental validation retinoic acid (RA) promoted transformation pHE Collectively, our results suggested possess potential to transform self-renewing RA treatment, will facilitate application cell generation.
Language: Английский
Citations
0
PLoS Biology, Journal Year: 2025, Volume and Issue: 23(2), P. e3003021 - e3003021
Published: Feb. 6, 2025
An important question is whether the placenta a source of, or merely niche for, blood-forming hematopoietic stem cells. A recent PLOS Biology study suggests that does not directly give rise to
Language: Английский
Citations
0
Trends in Cell Biology, Journal Year: 2025, Volume and Issue: unknown
Published: April 1, 2025
Language: Английский
Citations
0
Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)
Published: Jan. 29, 2025
Blood transfusion plays a vital role in modern medicine, but frequent shortages occur. Ex vivo manufacturing of red blood cells (RBCs) from universal donor offers potential solution, yet the high cost recombinant cytokines remains barrier. Erythropoietin (EPO) signaling is crucial for RBC development, and EPO among most expensive media components. To address this challenge, we develop highly optimized small molecule-inducible synthetic receptors (synEPORs) using design-build-test cycles genome editing. By integrating synEPOR at endogenous EPOR locus O-negative induced pluripotent stem cells, achieve equivalent erythroid differentiation, transcriptomic changes, hemoglobin production molecules compared to EPO-supplemented cultures. This approach dramatically reduces culture costs. Our strategy not only addresses challenges also demonstrates how protein engineering can introduce precisely regulated cellular behaviors, potentially improving scalable wide range clinically relevant cell types.
Language: Английский
Citations
0
Published: Feb. 3, 2025
Current in vitro models of developmental blood formation lack spatio-temporal accuracy and weakly replicate successive waves hematopoiesis. Herein, we describe a mouse embryonic stem cell (SC)-derived 3D hemogenic gastruloid (hGx) that captures multi-wave formation, progenitor specification from endothelium (HE), generates hematopoietic SC precursors capable short-term engraftment immunodeficient mice upon maturation an adrenal niche. We took advantage the hGx model to interrogate origins infant acute myeloid leukemia (infAML). focused on MNX1-driven leukemia, representing commonest genetic abnormality unique group. Enforced MNX1 expression promotes expansion transformation yolk sac-like erythroid-myeloid progenitors (EMP) at HE-to-hematopoietic transition faithfully recapitulate patient transcriptional signatures. By combining phenotypic, functional profiling, including single-cell level, establish as useful new for study normal leukemic hematopoiesis .
Language: Английский
Citations
0
Published: Feb. 3, 2025
Current in vitro models of developmental blood formation lack spatio-temporal accuracy and weakly replicate successive waves hematopoiesis. Herein, we describe a mouse embryonic stem cell (SC)-derived 3D hemogenic gastruloid (hGx) that captures multi-wave formation, progenitor specification from endothelium (HE), generates hematopoietic SC precursors capable short-term engraftment immunodeficient mice upon maturation an adrenal niche. We took advantage the hGx model to interrogate origins infant acute myeloid leukemia (infAML). focused on MNX1-driven leukemia, representing commonest genetic abnormality unique group. Enforced MNX1 expression promotes expansion transformation yolk sac-like erythroid-myeloid progenitors (EMP) at HE-to-hematopoietic transition faithfully recapitulate patient transcriptional signatures. By combining phenotypic, functional profiling, including single-cell level, establish as useful new for study normal leukemic hematopoiesis .
Language: Английский
Citations
0
Stem Cell Reviews and Reports, Journal Year: 2024, Volume and Issue: unknown
Published: Sept. 2, 2024
Language: Английский
Citations
2
bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown
Published: July 16, 2024
Summary Embryonic hematopoiesis consists of distinct waves originating in rapid succession from different anatomical locations. Hematopoietic progenitors appearing earlier than definitive hematopoietic stem cells (HSCs) play key roles fetal and postnatal life. However, their precise origin, identity the extent contribution need further clarification. To this aim, we took advantage a genetic fate-mapping strategy mice that allows labeling tracking subsets hemogenic endothelium (HE). Time-course emerging HE between E8.5 E9.5, before intra-embryonic HSC generation, revealed major lympho-myeloid which declined adult. Lineage tracing coupled with whole-mount imaging single-cell RNA sequencing located its source within clusters vitelline umbilical arteries. Functional assays confirmed transient nature these progenitors. We therefore unveiled hitherto unidentified early wave fetal-restricted stem/progenitor poised for differentiation provide to pre-natal hematopoiesis.
Language: Английский
Citations
1