Orthogonally induced differentiation of stem cells for the programmatic patterning of vascularized organoids and bioprinted tissues

Skylar‐Scott, Mark A.; Huang, Julian; Lu, Aric; Ng, Alex H. M.; Duenki, Tomoya; Liu, Songlei; Nam, Lucy; Damaraju, Sarita; Church, George M.; Lewis, Jennifer A.

doi:10.1038/s41551-022-00856-8

Cited by 70 publications

(50 citation statements)

References 57 publications

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“…Human iPSCs represent an unlimited source of cells for replacing damaged tissues. They can be successfully differentiated into different subtypes of vascular cells, such as ECs ( 19 , 20 ) and smooth muscle cells (SMCs) ( 21 , 22 ). In this study, we used an efficient method for differentiating hiPSCs to CD31 + CD144 + ECs as a source of EVs ( Figure 1A ).…”

Section: Resultsmentioning

confidence: 99%

Extracellular vesicles produced by human-induced pluripotent stem cell-derived endothelial cells can prevent arterial stenosis in mice via autophagy regulation

Feng

et al. 2022

Front. Cardiovasc. Med.

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Intravascular transplantation of human-induced pluripotent stem cells (hiPSCs) demonstrated a significant therapeutic effect in the treatment of restenosis by the paracrine function of extracellular vesicles (EVs). However, the risk of tumorigenicity and poor cell survival limits its clinical applications. In this study, we for the first time applied a highly efficient and robust three-dimensional (3D) protocol for hiPSC differentiation into endothelial cells (ECs) with subsequent isolation of EVs from the derived hiPSC-EC (ECs differentiated from hiPSCs), and validated their therapeutic effect in intimal hyperplasia (IH) models. We found that intravenously (iv) injected EVs could accumulate on the carotid artery endothelium and significantly alleviate the intimal thickening induced by the carotid artery ligation. To elucidate the mechanism of this endothelial protection, we performed miRNA expression profiling and found out that among the most conserved endothelial miRNAs, miR-126 was the most abundant in hiPSC-EC-produced EVs (hiPSC-EC-EV). MiR-126 depletion from hiPSC-EC-EV can hinder its protective effect on human umbilical vein endothelial cells (HUVECs) in an inflammatory process. A variety of functional in vitro studies revealed that miR-126 was able to prevent endothelial apoptosis after inflammatory stimulation, as well as promote EC migration and tube formation through autophagy upregulation. The latter was supported by in vivo studies demonstrating that treatment with hiPSC-EC-EV can upregulate autophagy in mouse carotid artery ECs, thereby preventing IH and modulating vascular homeostasis via remodeling of the vascular intima. Our findings suggest a regulatory mechanism for the therapeutic effect on arterial restenosis by autophagy regulation, and provide a potential strategy for clinical treatment of the disease.

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Section: Resultsmentioning

confidence: 99%

Extracellular vesicles produced by human-induced pluripotent stem cell-derived endothelial cells can prevent arterial stenosis in mice via autophagy regulation

Feng

et al. 2022

Front. Cardiovasc. Med.

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“…The use of lineage-committed progenitors represents a novel strategy for the fabrication of 3D tissues. Recently, the Lewis group reported a co-differentiating strategy in 3D tissues derived from two types of hiPSCs, transfected with either neural or endothelial-associated transcription factors (TFs), to produce vascularised neural tissues 47 . Although the study produced patterned neural tissues containing distinct cell types, it relied on lentivirus-based genetic modifications, which might have limited application potential in implantation therapies 48,49 .…”

Section: Discussionmentioning

confidence: 99%

Functional Integration of 3D-Printed Cerebral Cortical Tissue into a Brain Lesion

Jin

Mikhailova

Lei

et al. 2022

Preprint

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Engineering human tissue with diverse cell types and desired cellular architectures and functions is a considerable challenge. The cerebral cortex, which has a layered cellular architecture composed of layer-specific neurons organised into vertical columns, delivers higher cognition through intricately wired neural circuits. However, current tissue engineering approaches cannot produce such structures. Here, we use a droplet printing technique to fabricate tissues comprising simplified cerebral cortical columns. Human induced pluripotent stem cells (hiPSCs) were differentiated into upper- and deep-layer neural progenitors, which were then printed to form cerebral cortical tissues with a two-layer organization. The tissues showed layer-specific biomarker expression and developed an integrated network of processes. Implantation of the printed cortical tissues into mouse brain explants resulted in substantial implant-host integration across the tissue boundaries as demonstrated by the projection of processes, the migration of neurons and the appearance of correlated Ca2+ signals. The approach we have developed might be used for the evaluation of drugs and nutrients that promote tissue integration. Importantly, our approach might be applied in personalised implantation treatments that restore the cellular structure and function of a damaged brain by using 3D tissues derived from a patient's own iPSCs.

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“…The 3D printed CRC model demonstrated higher cell viability for clinically administered CRC drugs, including 5-fluorouracil, cisplatin, and doxorubicin, compared to 2D controls [120]. A recent study [126] exploited the forced overexpression of specific transcription factors (TFs) to simultaneously differentiate human iPSCs into different cell types, regardless of cell culture media compositions. The authors demonstrated that the doxycycline-induced overexpression of ETS translocation variant 2 (ETV2) efficiently differentiates human iPSCs into inducible ECs, while the overexpression of neurogenin-1 (NGN1) rapidly generates inducible neurons from human iPSCs.…”

Section: Three-dimensional (3d) Bioprinted Blood Vesselsmentioning

confidence: 99%

“…The printed inducible EC filaments exhibited the formation of microvascular networks, while inducible neuron filaments differentiated into neurons that formed neurite networks. Furthermore, the co-printing of WT-, ETV2-overexpressing, and NGN1-overexpressing human iPSCs, followed by doxycycline exposure, gave rise to simultaneous differentiation of neural stem cells, the vascular endothelium, and neurons with a layered tissue architecture that could be maintained for up to 6 days in culture [126].…”

Section: Three-dimensional (3d) Bioprinted Blood Vesselsmentioning

confidence: 99%

Tissue Engineering Approaches to Uncover Therapeutic Targets for Endothelial Dysfunction in Pathological Microenvironments

Ntekoumes

Gerecht

2022

IJMS

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Endothelial cell dysfunction plays a central role in many pathologies, rendering it crucial to understand the underlying mechanism for potential therapeutics. Tissue engineering offers opportunities for in vitro studies of endothelial dysfunction in pathological mimicry environments. Here, we begin by analyzing hydrogel biomaterials as a platform for understanding the roles of the extracellular matrix and hypoxia in vascular formation. We next examine how three-dimensional bioprinting has been applied to recapitulate healthy and diseased tissue constructs in a highly controllable and patient-specific manner. Similarly, studies have utilized organs-on-a-chip technology to understand endothelial dysfunction’s contribution to pathologies in tissue-specific cellular components under well-controlled physicochemical cues. Finally, we consider studies using the in vitro construction of multicellular blood vessels, termed tissue-engineered blood vessels, and the spontaneous assembly of microvascular networks in organoids to delineate pathological endothelial dysfunction.

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Orthogonally induced differentiation of stem cells for the programmatic patterning of vascularized organoids and bioprinted tissues

Cited by 70 publications

References 57 publications

Extracellular vesicles produced by human-induced pluripotent stem cell-derived endothelial cells can prevent arterial stenosis in mice via autophagy regulation

Extracellular vesicles produced by human-induced pluripotent stem cell-derived endothelial cells can prevent arterial stenosis in mice via autophagy regulation

Functional Integration of 3D-Printed Cerebral Cortical Tissue into a Brain Lesion

Tissue Engineering Approaches to Uncover Therapeutic Targets for Endothelial Dysfunction in Pathological Microenvironments

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