Human iPSC-derived cardiomyocytes and tissue engineering strategies for disease modeling and drug screening

Induced pluripotent stem cells (iPSCs) originate from the reprogramming of adult somatic cells using four Yamanaka transcription factors. Since their discovery, the stem cell (SC) field achieved significant milestones and opened several gateways in the area of disease modeling, drug discovery, and regenerative medicine. In parallel, the emergence of clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (CRISPR-Cas9) revolutionized the field of genome engineering, allowing the generation of genetically modified cell lines and achieving a precise genome recombination or random insertions/deletions, usefully translated for wider applications. Cardiovascular diseases represent a constantly increasing societal concern, with limited understanding of the underlying cellular and molecular mechanisms. The ability of iPSCs to differentiate into multiple cell types combined with CRISPR-Cas9 technology could enable the systematic investigation of pathophysiological mechanisms or drug screening for potential therapeutics. Furthermore, these technologies can provide a cellular platform for cardiovascular tissue engineering (TE) approaches by modulating the expression or inhibition of targeted proteins, thereby creating the possibility to engineer new cell lines and/or fine-tune biomimetic scaffolds. This review will focus on the application of iPSCs, CRISPR-Cas9, and a combination thereof to the field of cardiovascular TE. In particular, the clinical translatability of such technologies will be discussed ranging from disease modeling to drug screening and TE applications.

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The ECM: To Scaffold, or Not to Scaffold, That Is the Question

International Journal of Molecular Sciences ◽

10.3390/ijms222312690 ◽

2021 ◽

Vol 22 (23) ◽

pp. 12690

Author(s):

Jonard Corpuz Valdoz ◽

Benjamin C. Johnson ◽

Dallin J. Jacobs ◽

Nicholas A. Franks ◽

Ethan L. Dodson ◽

...

Keyword(s):

Tissue Engineering ◽

Extracellular Matrix ◽

Cell Adhesion ◽

Cell Survival ◽

High Throughput ◽

Drug Screening ◽

Disease Modeling ◽

Pleiotropic Effects ◽

Cell Aggregates ◽

Trade Off

The extracellular matrix (ECM) has pleiotropic effects, ranging from cell adhesion to cell survival. In tissue engineering, the use of ECM and ECM-like scaffolds has separated the field into two distinct areas—scaffold-based and scaffold-free. Scaffold-free techniques are used in creating reproducible cell aggregates which have massive potential for high-throughput, reproducible drug screening and disease modeling. Though, the lack of ECM prevents certain cells from surviving and proliferating. Thus, tissue engineers use scaffolds to mimic the native ECM and produce organotypic models which show more reliability in disease modeling. However, scaffold-based techniques come at a trade-off of reproducibility and throughput. To bridge the tissue engineering dichotomy, we posit that finding novel ways to incorporate the ECM in scaffold-free cultures can synergize these two disparate techniques.

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Deterministically patterned biomimetic human iPSC-derived hepatic model via rapid 3D bioprinting

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1524510113 ◽

2016 ◽

Vol 113 (8) ◽

pp. 2206-2211 ◽

Cited By ~ 336

Author(s):

Xuanyi Ma ◽

Xin Qu ◽

Wei Zhu ◽

Yi-Shuan Li ◽

Suli Yuan ◽

...

Keyword(s):

Tissue Engineering ◽

Stem Cells ◽

Drug Screening ◽

Disease Modeling ◽

Umbilical Vein ◽

Cell Types ◽

Supporting Cell ◽

Specific Gene ◽

3D Bioprinting

The functional maturation and preservation of hepatic cells derived from human induced pluripotent stem cells (hiPSCs) are essential to personalized in vitro drug screening and disease study. Major liver functions are tightly linked to the 3D assembly of hepatocytes, with the supporting cell types from both endodermal and mesodermal origins in a hexagonal lobule unit. Although there are many reports on functional 2D cell differentiation, few studies have demonstrated the in vitro maturation of hiPSC-derived hepatic progenitor cells (hiPSC-HPCs) in a 3D environment that depicts the physiologically relevant cell combination and microarchitecture. The application of rapid, digital 3D bioprinting to tissue engineering has allowed 3D patterning of multiple cell types in a predefined biomimetic manner. Here we present a 3D hydrogel-based triculture model that embeds hiPSC-HPCs with human umbilical vein endothelial cells and adipose-derived stem cells in a microscale hexagonal architecture. In comparison with 2D monolayer culture and a 3D HPC-only model, our 3D triculture model shows both phenotypic and functional enhancements in the hiPSC-HPCs over weeks of in vitro culture. Specifically, we find improved morphological organization, higher liver-specific gene expression levels, increased metabolic product secretion, and enhanced cytochrome P450 induction. The application of bioprinting technology in tissue engineering enables the development of a 3D biomimetic liver model that recapitulates the native liver module architecture and could be used for various applications such as early drug screening and disease modeling.

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Three-dimensional artificial liver platforms for drug screening and tissue engineering applications

10.32657/10356/142517 ◽

2020 ◽

Author(s):

◽

Gaia Ferracci

Keyword(s):

Tissue Engineering ◽

Drug Screening ◽

Three Dimensional ◽

Artificial Liver ◽

Engineering Applications

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Faculty Opinions recommendation of Human primary liver cancer-derived organoid cultures for disease modeling and drug screening.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.732110855.793542075 ◽

2018 ◽

Author(s):

Kalpana Ghoshal

Keyword(s):

Liver Cancer ◽

Drug Screening ◽

Disease Modeling ◽

Primary Liver Cancer ◽

Organoid Cultures

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Engineering the Vasculature of Stem-Cell-Derived Liver Organoids

Biomolecules ◽

10.3390/biom11070966 ◽

2021 ◽

Vol 11 (7) ◽

pp. 966

Author(s):

Xv Zhang ◽

Liling Tang ◽

Qian Yi

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Drug Screening ◽

Disease Modeling ◽

Liver Development ◽

Embryonic Liver ◽

Hepatic Cells ◽

Hepatic Vessels ◽

Liver Organoids ◽

Application Prospects

The vasculature of stem-cell-derived liver organoids can be engineered using methods that recapitulate embryonic liver development. Hepatic organoids with a vascular network offer great application prospects for drug screening, disease modeling, and therapeutics. However, the application of stem cell-derived organoids is hindered by insufficient vascularization and maturation. Here, we review different theories about the origin of hepatic cells and the morphogenesis of hepatic vessels to provide potential approaches for organoid generation. We also review the main protocols for generating vascularized liver organoids from stem cells and consider their potential and limitations in the generation of vascularized liver organoids.

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