Written by |NovemberAdvances in the isolation and reprogramming of human induced pluripotent stem cells and the differentiation into cardiomyocytes have facilitated the application of this experimental platform in cardiovascular diseases. Therefore, how to ensure the traceability of human induced pluripotent stem cell-derived cardiomyocytes in the large-scale production of human induced pluripotent stem cells, quality controllability, and cost control are important aspects to increase the usability of the platform. Recently, the University of Nottingham, UKchris denningStudy group withk**ita raniga(First author) incell stem cell, entitled:strengthening cardiac therapy pipelines using human pluripotent stem cell-derived cardiomyocytes, proposedUnification of working methods for human pluripotent stem cell-derived cardiomyocytes
The differentiation and maturation of human-induced pluripotent stem cells** cardiomyocyte (HIPSC-CM) is helpful for exploring the study of cardiogenesis, cardiovascular disease, etc. This opinion paper summarizes key developments in the application of HIPSC-CMS at the research and clinical levels, thereby enhancing the workflow from model development to clinical application. 1. Generation of high-quality HIPSC-CMS cellsThe first human embryonic stem cells were produced in 1998, while the first human induced pluripotent stem cells were produced in 2008。The generation of HIPSC-CM and the control of its differentiation state have contributed to unprecedented developments in the cardiovascular field. Human chemically induced pluripotent stem cells (HCIPSCs) were established to more flexibly regulate cell fate using small molecules. Human induced pluripotent stem cell-derived ventricular progenitor cells are able to expand in vitro and self-assemble into a function similar to that of ventricular myocardium。These models have the potential for self-renewal, preservation of progenitor cell phenotypes, and restricted differentiation of cell lineages, making them useful for drug screening, disease modeling, and cardiac regeneration**. Depending on the specific genetic background or disease mutation, coupled with the use of gene editing tools such as CRISPR-Cas9, the platform is uniquely positioned to elucidate the genetics of cardiac genetic diseases. HIPSC-CMS now provides accessibility, scalability, quality control, and relevant laws and regulations. Cell lines** currently used for commercially exploited and available stem cell banks are in the range of $700-$2,000. In order to obtain high-quality HIPSC-CMS, traceability of this cell line is required, especially for donor-specific traceability. In addition, the high cost of available HIPSC-CMS and the reproducibility of experimental results have hindered many institutions and companies from scaling up production. Finally, data sharing on HIPSC-based clinical trials** is very limited, so the clinical safety and efficacy of HIPSCs are not ideal. When it comes to the cardiovascular system**, opportunities and challenges coexist. 2. Commercial HIPSC-CMS cellsWith regard to commercial HIPSC-CMS cells, FCDI is a leader in the production of HIPSCs, including cardiomyocytes. HIPSC-CMS (icell cardiomyocytes) has played a key role in in vitro arrhythmia detection, and this cell line is also widely used。Further, through these case studies, steps and rules such as HIPSC reprogramming, HIPSC banking, and quality control can be integrated. The main aspects to note are: 1) not integrating reprogramming factors into the genome; 2) culture under the specified conditions; 3) maintain the fidelity and stability of the genome; 4) SNP STR spectra of matched donors; 5) expression of pluripotency-related markers; 6) Sterile and mycoplasma-free. 3. Challenges of HIPSC-CMS in research and cell-**Over the past decade, HPSCS has been involved in a large number of clinical studies. By the end of 2019, hipscs or HESCs had been used in 54 studies for 22 diseases, with a significant shift to HIPSCs for drug screening. Small-scale culture of HIPSCs is sufficient for academic research purposes, but when large-scale production is attempted, the variability of the cells makes it impossible to use them directly in cells**. For cardiac patients, about 1 billion cells are needed, so a clear, low-cost, and high-performance system is needed to produce HIPSC-CMS on a large scale for clinical use. One of the challenges with large-scale production is characterizing the starting material, as studies have shown that different HIPSC-CMS cells can vary greatly in a variety of ways, such as up to 5-fold differences in performance in terms of metabolic oxygen consumption。Another challenge is the large-scale production of HIPSCs cell types, which requires the development of appropriate methods for cryopreservation and transport. Finally, provide a high degree of traceability to provide a critical track record for regulatory review and approval. HIPSC repositories generally provide donor-specific information, but certificates on reprogramming techniques and infectious disease surveillance are difficult to obtain. To date, he has published a number of studies in the Human Pluripotent Stem Cell Registry (HPSCREG; There were only 10 cases of HESC and no HIPSCs were registered. Failure to fully trace the results will hinder the assessment and transformation of cells. 4. Screening platform of HIPSC-CMS in drug-induced cardiotoxicityOver the past 20 years, tremendous progress has been made in the use of HIPSC-CMS as a screening platform for drug-induced cardiotoxicity. It is used for clinical drug discovery, typically for or 1536-well plate screening. This platform can be used to study the response of compounds in cells in the short or long term, and can be used to elucidate the mechanisms of cardiotoxicity and to detect structural and functional manifestations of cardiotoxicity. Through the development of software such as Cardiomotion, the role of 136 drugs in the systolic response of the heart can be quantitatively and specifically described5. Development of complex models in vitroIn order to increase physiological relevance, 2D monoculture models need to be further developed and optimized to increase the likelihood of transformation of these models. Currently, a variety of cell combinations, such as HIPSC-CMS, are being used to fabricate 3D tissues or "heart-on-a-chip" models。Such methods are replacing primary cell methods and can improve the maturity of HIPSC-CMS by co-culturing HIPSC-CMS with immune cells, etc., to form syncytia. What needs to be further addressed is to increase the throughput of this technology for large-scale screening and application. 
Fig.1 Progress of HIPSC-CMSOverall, this review summarizes the current research and clinical applications of HIPSC-CMS, and also clarifies the challenges encountered in large-scale production of cells, etc., which will contribute to the further standardization and large-scale production of HIPSC-CMS, as well as the optimization of regenerative stem cells. Original link:
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