Hypoimmunogenic hPSC-derived cardiac organoids for immune evasion and heart repair [scRNA-seq]
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PROVIDER: PRJNA1273020 | ENA |
REPOSITORIES: ENA
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Project description:Human pluripotent stem cell (hPSC)-derived cardiac therapies hold great promise for heart 41 regeneration but face major translational barriers due to allogeneic immune rejection. Here, we 42 engineered hypoimmunogenic hPSCs using a two-step CRISPR-Cas9 strategy: (1) B2M 43 knockout, eliminating HLA class I surface expression, and (2) knock-in of HLA-E or HLA-G trimer 44 constructs in the AAVS1 safe harbor locus to confer robust immune evasion. Hypoimmunogenic 45 hPSCs maintained pluripotency, efficiently differentiated into cardiac cell types that resisted both 46 T and NK cell-mediated cytotoxicity in vitro, and self-assembled into engineered cardiac 47 organoids. Comprehensive analyses of the hypoimmunogenic cells and organoids revealed 48 preservation of transcriptomic, structural, and functional properties with minimal off-target effects 49 from gene editing. In vivo, hypoimmunogenic cardiac organoids restored contractile function in 50 infarcted rat hearts and demonstrated superior graft retention and immune evasion in humanized 51 mice compared to wild-type counterparts. These findings establish the therapeutic potential of 52 hypoimmunogenic hPSC-CMs in the cardiac organoid platform, laying the foundation for off-the shelf cardiac cell therapies to treat cardiovascular disease, the leading cause of death worldwide.
2025-06-08 | GSE299171 | GEO
Project description:Human pluripotent stem cell (hPSC)-derived cardiac therapies hold great promise for heart 41 regeneration but face major translational barriers due to allogeneic immune rejection. Here, we 42 engineered hypoimmunogenic hPSCs using a two-step CRISPR-Cas9 strategy: (1) B2M 43 knockout, eliminating HLA class I surface expression, and (2) knock-in of HLA-E or HLA-G trimer 44 constructs in the AAVS1 safe harbor locus to confer robust immune evasion. Hypoimmunogenic 45 hPSCs maintained pluripotency, efficiently differentiated into cardiac cell types that resisted both 46 T and NK cell-mediated cytotoxicity in vitro, and self-assembled into engineered cardiac 47 organoids. Comprehensive analyses of the hypoimmunogenic cells and organoids revealed 48 preservation of transcriptomic, structural, and functional properties with minimal off-target effects 49 from gene editing. In vivo, hypoimmunogenic cardiac organoids restored contractile function in 50 infarcted rat hearts and demonstrated superior graft retention and immune evasion in humanized 51 mice compared to wild-type counterparts. These findings establish the therapeutic potential of 52 hypoimmunogenic hPSC-CMs in the cardiac organoid platform, laying the foundation for off-the shelf cardiac cell therapies to treat cardiovascular disease, the leading cause of death worldwide.
2025-06-08 | GSE299172 | GEO
Project description:Hypoimmunogenic hPSC-derived cardiac organoids for immune evasion and heart repair [bulkRNA-seq]
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Project description:We utilized a dual reporting hPSC line that identified cells expressing NKX2.5 and endothelal cells to characterize discrete milestones during cardiac and vascular differentiaiton. Comparing populations that express either or both reporters to human umbilical vein endothelial cells, we document a unique molecular phenotype in hPSC-derived endocardium that points toward an important role for Wnt signaling during vascular specification of cardiac progenitors.
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Project description:Neurons derived from human pluripotent stem cells (hPSCs) are a remarkable tool for modeling human neural development and diseases. However, it remains largely unknown whether the hPSC-derived neurons can be functionally coupled with their target tissues in vitro, which is essential for understanding inter-cellular physiology and further translational studies. Here, we demonstrate that hPSC-derived sympathetic neurons can be obtained from hPSCs and that the resulting neurons form physical and functional connections with cardiac muscle cells. By use of multiple hPSC reporter lines, we recapitulated human autonomic neuron development in vitro, and successfully isolated PHOX2B::eGFP+ neurons exhibiting sympathetic marker expression, electrophysiological properties, and norepinephrine secretion. With pharmacological and optogenetic manipulations, the PHOX2B::eGFP+ neurons controlled the beating rates of cardiomyocytes, and their physical interaction led to neuronal maturation. Our study lays a foundation for the specification of human sympathetic neurons and for the hPSC-based neuronal control of end organs in a dish. Using the four genetic reporter systems (OCT4::eGFP, SOX10::eGFP, ASCL1::eGFP, and PHOX2B::eGFP reporter hESC lines), we were able to purify discrete cell populations at four differentiation stages, recapitulating the sympathoadrenal differentiation process in vitro with purified and defined populations in four specific differentiation stages. We performed transcriptome analysis of OCT4::eGFP+ cells (3 biological replicates, representing undifferentiated hESCs), SOX10::eGFP+ cells (3 biological replicates, multi-potent neural crest), ASCL1::eGFP+ cells (3 biological replicates, putative sympathoadrenal progenitors), and PHOX2B::eGFP+ cells (2 biological replicates, putative sympathetic neuronal precursors).
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Project description:The development of human pluripotent stem cell (hPSC)- derived small intestinal organoids (HIOs) has led to an improved understanding of human intestinal development and physiology. HIOs generated using directed differentiation lack some cellular populations found in the native organ, including vasculature. We performed single cell RNA sequencing (scRNA-seq) on approximately 13,000 cells at various timepoints (0, 3, 7, and 14 days) across HIO in vitro development and observed a transient population of endothelial-like cells (ECs) present within HIOs early during differentiation. Our data demonstrate that EC-like cells fail to be robustly maintained in long term culture. Here, we have developed a new directed differentiation approach to enhance co-differentiation and maintenance of ECs within HIOs, leading to the development of vascularized HIOs (vHIOs). scRNAseq was used to compare vHIOs to control HIOs after 59d months in culture.
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Project description:Neurons derived from human pluripotent stem cells (hPSCs) are a remarkable tool for modeling human neural development and diseases. However, it remains largely unknown whether the hPSC-derived neurons can be functionally coupled with their target tissues in vitro, which is essential for understanding inter-cellular physiology and further translational studies. Here, we demonstrate that hPSC-derived sympathetic neurons can be obtained from hPSCs and that the resulting neurons form physical and functional connections with cardiac muscle cells. By use of multiple hPSC reporter lines, we recapitulated human autonomic neuron development in vitro, and successfully isolated PHOX2B::eGFP+ neurons exhibiting sympathetic marker expression, electrophysiological properties, and norepinephrine secretion. With pharmacological and optogenetic manipulations, the PHOX2B::eGFP+ neurons controlled the beating rates of cardiomyocytes, and their physical interaction led to neuronal maturation. Our study lays a foundation for the specification of human sympathetic neurons and for the hPSC-based neuronal control of end organs in a dish.
2016-07-01 | GSE80689 | GEO