scholarly journals Recapitulate Human Cardio-pulmonary Co-development Using Simultaneous Multilineage Differentiation of Pluripotent Stem Cells

2021 ◽  
Author(s):  
Wai Hoe Ng ◽  
Elizabeth K. Johnston ◽  
Jun Jie Tan ◽  
Jacqueline M. Bliley ◽  
Adam W. Feinberg ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Model Systems ◽  
Cardiac Contraction ◽  
Multilineage Differentiation ◽  
Developing Heart ◽  
Lung Epithelial ◽  
Human Embryogenesis ◽  
Exogenous Growth Factors ◽  
Differentiation Model

AbstractThe extensive crosstalk between the developing heart and lung is pivotal for their proper morphogenesis and maturation. However, there remains a lack of model systems for investigating the critical cardio-pulmonary mutual interaction during human embryogenesis. Here, we reported a novel stepwise strategy for directing simultaneous induction of both mesoderm-derived cardiac and endoderm-derived lung epithelial lineages within a single differentiation of human pluripotent stem cells (hPSCs) via temporal specific tuning of WNT and TGF-β signaling in the absence of exogenous growth factors. Using 3D suspension culture, we established concentric cardio-pulmonary micro-Tissues (μTs), and observed expedited alveolar maturation in the presence of cardiac accompany. Upon withdrawal of WNT agonist, the cardiac and pulmonary components within each dual-lineage μT effectively segregated from each other with concurrent initiation of cardiac contraction. We expect our multilineage differentiation model to offer an experimentally tractable system for investigating human cardio-pulmonary interplay and tissue boundary formation during embryogenesis.

scholarly journals Recapitulating human cardio-pulmonary co-development using simultaneous multilineage differentiation of pluripotent stem cells

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Wai Hoe Ng ◽  
Elizabeth K Johnston ◽  
Jun Jie Tan ◽  
Jacqueline M Bliley ◽  
Adam W Feinberg ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Cardiac Contraction ◽  
Nodal Signaling ◽  
Multilineage Differentiation ◽  
Developing Heart ◽  
Lung Epithelial ◽  
Human Embryogenesis ◽  
Induced Pluripotent ◽  
Exogenous Growth Factors

The extensive crosstalk between the developing heart and lung is critical to their proper morphogenesis and maturation. However, there remains a lack of models that investigate the critical cardio-pulmonary mutual interaction during human embryogenesis. Here, we reported a novel stepwise strategy for directing the simultaneous induction of both mesoderm-derived cardiac and endoderm-derived lung epithelial lineages within a single differentiation of human induced pluripotent stem cells (hiPSCs) via temporal specific tuning of WNT and nodal signaling in the absence of exogenous growth factors. Using 3D suspension culture, we established concentric cardio-pulmonary micro-Tissues (mTs), and expedited alveolar maturation in the presence of cardiac accompaniment. Upon withdrawal of WNT agonist, the cardiac and pulmonary components within each dual-lineage mT effectively segregated from each other with concurrent initiation of cardiac contraction. We expect that our multilineage differentiation model will offer an experimentally tractable system for investigating human cardio-pulmonary interaction and tissue boundary formation during embryogenesis.

scholarly journals Decoding Genetics of Congenital Heart Disease Using Patient-Derived Induced Pluripotent Stem Cells (iPSCs)

2021 ◽  
Vol 9 ◽  
Author(s):  
Hui Lin ◽  
Kim L. McBride ◽  
Vidu Garg ◽  
Ming-Tao Zhao
Keyword(s):  
Stem Cells ◽  
Congenital Heart Disease ◽  
Heart Disease ◽  
Induced Pluripotent Stem Cells ◽  
Genome Sequencing ◽  
Pluripotent Stem Cells ◽  
Congenital Heart ◽  
Model Systems ◽  
Patient Specific ◽  
Induced Pluripotent

Congenital heart disease (CHD) is the most common cause of infant death associated with birth defects. Recent next-generation genome sequencing has uncovered novel genetic etiologies of CHD, from inherited and de novo variants to non-coding genetic variants. The next phase of understanding the genetic contributors of CHD will be the functional illustration and validation of this genome sequencing data in cellular and animal model systems. Human induced pluripotent stem cells (iPSCs) have opened up new horizons to investigate genetic mechanisms of CHD using clinically relevant and patient-specific cardiac cells such as cardiomyocytes, endothelial/endocardial cells, cardiac fibroblasts and vascular smooth muscle cells. Using cutting-edge CRISPR/Cas9 genome editing tools, a given genetic variant can be corrected in diseased iPSCs and introduced to healthy iPSCs to define the pathogenicity of the variant and molecular basis of CHD. In this review, we discuss the recent progress in genetics of CHD deciphered by large-scale genome sequencing and explore how genome-edited patient iPSCs are poised to decode the genetic etiologies of CHD by coupling with single-cell genomics and organoid technologies.

Towards the Generation of Patient-Specific Pluripotent Stem Cells for Combined Gene and Cell Therapy of Hematologic Disorders

Hematology ◽  
2007 ◽  
Vol 2007 (1) ◽  
pp. 17-22 ◽  
Author(s):  
George Q. Daley
Keyword(s):  
Stem Cells ◽  
Gene Therapy ◽  
Cell Therapy ◽  
Somatic Cell ◽  
Pluripotent Stem Cells ◽  
Tissue Transplantation ◽  
Model Systems ◽  
Patient Specific ◽  
Gene Repair ◽  
Hematopoietic Stem

Abstract Hematopoietic stem cell transplantation (HSCT) has proven successful for the treatment of a host of genetic and malignant diseases of the blood, but immune barriers to allogeneic tissue transplantation have hindered wider application. Likewise, gene therapy now appears effective in the treatment of various forms of immune deficiency, and yet insertional mutagenesis from viral gene transfer has raised safety concerns. One strategy for addressing the limitations of both gene therapy and allogeneic transplantation entails the creation of pluripotent stem cells from a patient’s own somatic cells, thereby enabling precise in situ gene repair via homologous recombination in cultured cells, followed by autologous tissue transplantation. In murine model systems, the methods of somatic cell nuclear transfer, parthenogenesis, and direct somatic cell reprogramming with defined genetic factors have been used to generate pluripotent stem cells, and initial efforts at therapeutic gene repair and tissue transplantation suggest that the technology is feasible. Generating patient-specific autologous pluripotent stem cells provides an opportunity to combine gene therapy with autologous cell therapy to treat a host of human conditions. However, a number of technical hurdles must be overcome before therapies based on pluripotent human stem cells will appear in the clinic.

scholarly journals Model systems for studying trophoblast differentiation from human pluripotent stem cells

2012 ◽  
Vol 349 (3) ◽  
pp. 809-824 ◽  
Author(s):  
Toshihiko Ezashi ◽  
Bhanu Prakash V. L. Telugu ◽  
R. Michael Roberts
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Human Pluripotent Stem Cells ◽  
Model Systems ◽  
Trophoblast Differentiation

scholarly journals In vitro induction and in vivo engraftment of lung bud tip progenitor cells derived from human pluripotent stem cells

2017 ◽  
Author(s):  
Alyssa J. Miller ◽  
David R. Hill ◽  
Melinda S. Nagy ◽  
Yoshiro Aoki ◽  
Briana R. Dye ◽  
...  
Keyword(s):  
Stem Cells ◽  
Progenitor Cells ◽  
Pluripotent Stem Cells ◽  
Fetal Lung ◽  
Branching Morphogenesis ◽  
Human Pluripotent Stem Cells ◽  
3 Dimensional ◽  
Lung Epithelial ◽  
Human Fetal Lung

SummaryThe bud tip epithelium of the branching mouse and human lung contains multipotent progenitors that are able to self-renew and give rise to all mature lung epithelial cell types. The current study aimed to understand the developmental signaling cues that regulate bud tip progenitor cells in the human fetal lung, which are present during branching morphogenesis, and to use this information to induce a bud tip progenitor-like population from human pluripotent stem cells (hPSCs) in vitro. We identified that FGF7, CHIR-99021 and RA maintained isolated human fetal lung epithelial bud tip progenitor cells in an undifferentiated state in vitro, and led to the induction of a 3-dimensional lung-like epithelium from hPSCs. 3-dimensional hPSC-derived lung tissue was initially patterned, with airway-like interior domains and bud tip-like progenitor domains at the periphery. Epithelial bud tip-like domains could be isolated, expanded and maintained as a nearly homogeneous population by serial passaging. Comparisons between human fetal lung epithelial bud tip cells and hPSC-derived bud tip-like cells were carried out using immunostaining, in situ hybridization and transcriptome-wide analysis, and revealed that in vitro derived tissue was highly similar to native lung. hPSC-derived epithelial bud tip-like structures survived in vitro for over 16 weeks, could be easily frozen and thawed and maintained multi-lineage potential. Furthermore, hPSC-derived epithelial bud tip progenitors successfully engrafted in the proximal airways of injured immunocompromised NSG mouse lungs, where they persisted for up to 6 weeks and gave rise to several lung epithelial lineages.

scholarly journals Reconstructing aspects of human embryogenesis with pluripotent stem cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Berna Sozen ◽  
Victoria Jorgensen ◽  
Bailey A. T. Weatherbee ◽  
Sisi Chen ◽  
Meng Zhu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Pluripotent Stem Cells ◽  
Clinical Importance ◽  
Early Embryo ◽  
Transcriptional Level ◽  
Cell Models ◽  
Human Embryogenesis ◽  
Cavitation Characteristic ◽  
Stem Cell Models

AbstractUnderstanding human development is of fundamental biological and clinical importance. Despite its significance, mechanisms behind human embryogenesis remain largely unknown. Here, we attempt to model human early embryo development with expanded pluripotent stem cells (EPSCs) in 3-dimensions. We define a protocol that allows us to generate self-organizing cystic structures from human EPSCs that display some hallmarks of human early embryogenesis. These structures mimic polarization and cavitation characteristic of pre-implantation development leading to blastocyst morphology formation and the transition to post-implantation-like organization upon extended culture. Single-cell RNA sequencing of these structures reveals subsets of cells bearing some resemblance to epiblast, hypoblast and trophectoderm lineages. Nevertheless, significant divergences from natural blastocysts persist in some key markers, and signalling pathways point towards ways in which morphology and transcriptional-level cell identities may diverge in stem cell models of the embryo. Thus, this stem cell platform provides insights into the design of stem cell models of embryogenesis.

scholarly journals A Closer Look to the Evolution of Neurons in Humans and Apes Using Stem-Cell-Derived Model Systems

2021 ◽  
Vol 9 ◽  
Author(s):  
Maria Schörnig ◽  
Elena Taverna
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Cell Biology ◽  
Model Systems ◽  
Post Mortem ◽  
Living Tissue ◽  
Closely Related Species ◽  
Important Species ◽  
Induced Pluripotent ◽  
Species Specific

The cellular, molecular and functional comparison of neurons from closely related species is crucial in evolutionary neurobiology. The access to living tissue and post-mortem brains of humans and non-human primates is limited and the state of the tissue might not allow recapitulating important species-specific differences. A valid alternative is offered by neurons derived from induced pluripotent stem cells (iPSCs) obtained from humans and non-human apes and primates. We will review herein the contribution of iPSCs-derived neuronal models to the field of evolutionary neurobiology, focusing on species-specific aspects of neuron’s cell biology and timing of maturation. In addition, we will discuss the use of iPSCs for the study of ancient human traits.

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