Abstract
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.
Highlights
Historic Considerations: Stem Cell Research and the Foundation of Induced Pluripotent Stem CellsStem cells (SCs) were first described in 1961 by Drs James A
clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPRassociated protein 9 (Cas9) technology brings another tool to investigate the impact of genetic variation against the environmental influence, by creating isogenic human induced pluripotent SCs (hiPSCs) lines harboring a specific mutation out of healthy donor hiPSCs and comparing the resulting phenotype with the one of hiPSCs reprogrammed from diseased patients (Hsu et al, 2014; Dzilic et al, 2018)
The discovery of patient-specific hiPSCs has revolutionized the field of cardiovascular research
Summary
Historic Considerations: Stem Cell Research and the Foundation of Induced Pluripotent Stem Cells. Besides the possibility to generate hiPSCs from patients’ somatic cells and giving access to patientspecific cells, there is an added ability of hiPSCs to proliferate indefinitely, maintain the genetic information of their host, and differentiate into any cell type This makes hiPSCs an ideal cell source to investigate CVD originating from acquired genetic or congenital defects establish a better understanding of the pathological mechanisms and molecular functions regulating cardiac disorders, thereby opening the path for the development of new diagnostic and therapeutic approaches (Matsa et al, 2016; Parrotta et al, 2020). Disease modeling based on hiPSCs generated great progress in the field of cardiovascular research, eventually providing the tools to acquire a more precise understanding of the underlying CVD mechanisms and to develop new therapeutic approaches. Genome editing completely changed the landscape of cardiovascular research and has been demonstrated to be a powerful tool to study and manipulate genome-related molecular function
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