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Heterogeneity and chimerism of endothelial cells revealed by single cell transcriptome in orthotopic liver tumors

ABSTRACT: Heterogeneity and chimerism of endothelial cells revealed by single cell transcriptome in orthotopic liver tumors

PROVIDER: PRJNA631541 | ENA |

REPOSITORIES: ENA

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Heterogeneity and chimerism of endothelial cells revealed by single-cell transcriptome in orthotopic liver tumors.

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Heterogeneity and chimerism of endothelial cells revealed by single cell transcriptome in orthotopic liver tumors

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Expression data from the orthotopic tumors of MES-SA

Project description:The spontaneous pulmonary metastasis model of human uterine sarcoma was established using GFP-expressed MES-SA cells. Several sublines with different metastatic potentials were generated by in vivo passaging. We used microarrays to identify the metastatic-related genes using the orthotopic tumors with different metastatic potentials. Orthotopic transplanted uterine sarcoma were observed after 3 weeks post-transplantation and the xenografted tumor reached about 2000 mm3 in additional 3 weeks. After 6 weeks post-transplantation, the animals were sacrificed under isoflurane anesthesia, and the tumors were resected. The GFP-positive regions were collected using Leica MZ10F fluorescent stereomicroscope. This study compared the gene expression profiling between the orthotopic tumors with high (H)- and low (L)-metastatic potentials.

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Project description:Organ shortage remains a major challenge in transplantation medicine. Interspecies blastocyst complementation offers a promising strategy to generate human organs in livestock. However, efficient xenogeneic donor cell engraftment remains challenging. Here, we identify an innate immune barrier wherein host macrophages selectively eliminate viable xenogeneic donor cells, a process we term xenophagocytosis. Mechanistically, xenogeneic cells display elevated phosphatidylserine, an "eat-me" signal recognized by host macrophages through phagocytic receptor Axl. We demonstrate three orthogonal strategies for xenophagocytosis blockade: genetic ablation of macrophages or Axl receptor in the host embryo, or overexpression of “don’t eat me” signal CD47 or the phosphatidylserine-regulating flippase ATP11C in donor cells. Xenophagocytosis blockade enhances rat and human donor chimerism in mouse embryos and improves interspecies pancreas complementation efficiency. These findings reveal a previously unrecognized innate immune barrier that safeguards species integrity during early embryogenesis and provide mechanistic insights to enhance xenogeneic chimerism for generating human organs in livestock.

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