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A, Mouse embryonic stem cell-like colonies of M13 cells on a feeder layer. B, Embryoid bodies on day 6 of a floating culture of M13 cells. C, Alkaline phosphatase staining of M13 colonies. D, M13 cells maintain a normal diploid karyotype of male rat origen (42XY) at passage 31. Scale bars: 100 µm.
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Induced pluripotent stem cells (iPSCs) are a novel candidate for use in cardiac stem cell therapy. However, their intrinsic tumorigenicity requires further investigation prior to use in a clinical setting. In this study we investigated whether undifferentiated iPSCs are tumorigenic after intramyocardial transplantation into immunocompetent allogene...
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... As a potential source to generate various cell types for cell therapy, the conversion of patient-derived somatic cells into induced pluripotent stem cells (iPSCs) bypasses many ethical issues that are associated with the use of human embryonic stem cells (hESCs). 1 Although these iPSCs hold great potential in regenerative medicine, the tumorigenicity of iPSCs remains a significant hurdle for the safe therapeutic application of iPSC-derived differentiated cells. [2][3][4][5] Due to their unlimited self-renewal and pluripotency, the residual undifferentiated iPSCs can form teratomas in a dose-dependent manner. 2,6,7 The potential tumorigenicity risk of the residual undifferentiated iPSCs depends on the number of undifferentiated cells, the features of the cell lines, 3 and culture adaptation. ...
The transplantation of spinal cord progenitor cells (SCPCs) derived from human-induced pluripotent stem cells (iPSCs) has beneficial effects in treating spinal cord injury (SCI). However, the presence of residual undifferentiated iPSCs among their differentiated progeny poses a high risk as these cells can develop teratomas or other types of tumors post-transplantation. Despite the need to remove these residual undifferentiated iPSCs, no specific surface markers can identify them for subsequent removal. By profiling the size of SCPCs after a 10-day differentiation process, we found that the large-sized group contains significantly more cells expressing pluripotent markers. In this study, we used a sized-based, label-free separation using an inertial microfluidic-based device to remove tumor-risk cells. The device can reduce the number of undifferentiated cells from an SCPC population with high throughput (ie, >3 million cells/minute) without affecting cell viability and functions. The sorted cells were verified with immunofluorescence staining, flow cytometry analysis, and colony culture assay. We demonstrated the capabilities of our technology to reduce the percentage of OCT4-positive cells. Our technology has great potential for the “downstream processing” of cell manufacturing workflow, ensuring better quality and safety of transplanted cells.
... Similarly, iPSCs have been employed in fabricating biomaterials for tissue repair and regeneration, capitalizing on their differentiation potential [56,113]. Nevertheless, their clinical application has been hindered by genomic instability and the potential for malignancy [114,115]. To address the concerns of cell leakage and uncontrolled proliferation of theranostic biomaterials used in implantation, strategies have been explored in the form of physical containment. ...
Biomaterials have evolved from inert materials to responsive entities, playing a crucial role in disease diagnosis, treatment, and modeling. However, their advancement is hindered by limitations in chemical and mechanical approaches. Synthetic biology enabling the genetically reprograming of biological systems offers a new paradigm. It has achieved remarkable progresses in cell reprogramming, engineering designer cells for diverse applications. Synthetic biology also encompasses cell-free systems and rational design of biological molecules. This review focuses on the application of synthetic biology in theranostics, which boost rapid development of advanced biomaterials. We introduce key fundamental concepts of synthetic biology and highlight frontier applications thereof, aiming to explore the intersection of synthetic biology and biomaterials. This integration holds tremendous promise for advancing biomaterial engineering with programable complex functions.
... The capacity to generate cardiomyocyte tissue, triggering the heart's contractile movement, presents an advanced approach in the field of regenerative medicine. Despite the potential utility of undifferentiated induced pluripotent stem (iPS) cells in therapy, substantial evidence indicates the risk of tumor formation in both control and IHD rats, regardless of the administered dose [8]. Various methods have been developed to remove undifferentiated cells that form tumors from differentiated cells, and the results of animal studies have demonstrated that the risk of tumor formation is quite low. ...
Ischemic heart disease (IHD) poses a significant challenge in cardiovascular health, with current treatments showing limited success. Induced pluripotent derived–cardiomyocyte (iPSC-CM) therapy within regenerative medicine offers potential for IHD patients, although its clinical impacts remain uncertain. This study utilizes meta-analysis to assess iPSC-CM outcomes in terms of efficacy and safety in IHD animal model studies. A meta-analysis encompassing PUBMED, ScienceDirect, Web of Science, and the Cochrane Library databases, from inception until October 2023, investigated iPSC therapy effects on cardiac function and safety outcomes. Among 51 eligible studies involving 1012 animals, despite substantial heterogeneity, the iPSC-CM transplantation improved left ventricular ejection fraction (LVEF) by 8.23% (95% CI, 7.15 to 9.32%; p < 0.001) compared to control groups. Additionally, cell-based treatment reduced the left ventricle fibrosis area and showed a tendency to reduce left ventricular end-systolic volume (LVESV) and end-diastolic volume (LVEDV). No significant differences emerged in mortality and arrhythmia risk between iPSC-CM treatment and control groups. In conclusion, this meta-analysis indicates iPSC-CM therapy’s promise as a safe and beneficial intervention for enhancing heart function in IHD. However, due to observed heterogeneity, the efficacy of this treatment must be further explored through large randomized controlled trials based on rigorous research design.
... The intrinsic oncogenic potential of iPSCs presents a confounding factor in cancer-iPSC-and CSC-related studies [163][164][165][166] and needs to be addressed carefully with proper experimental controls. Interestingly, incomplete reprogramming of kidney cells through the transient expression of OSKM factors in vivo has been shown to develop Wilm's tumor-like neoplasia, but iPSCs generated from the tumor were non-cancerous. ...
Cancer cells, especially cancer stem cells (CSCs), share many molecular features with induced pluripotent stem cells (iPSCs) that enable the derivation of induced pluripotent cancer cells by reprogramming malignant cells. Conversely, normal iPSCs can be converted into cancer stem-like cells with the help of tumor microenvironment components and genetic manipulation. These CSC models can be utilized in oncogenic initiation and progression studies, understanding drug resistance, and developing novel therapeutic strategies. This review summarizes the role of pluripotency factors in the stemness, tumorigenicity, and therapeutic resistance of cancer cells. Different methods to obtain iPSC-derived CSC models are described with an emphasis on exposure-based approaches. Culture in cancer cell-conditioned media or cocultures with cancer cells can convert normal iPSCs into cancer stem-like cells, aiding the examination of processes of oncogenesis. We further explored the potential of reprogramming cancer cells into cancer-iPSCs for mechanistic studies and cancer dependencies. The contributions of genetic, epigenetic, and tumor microenvironment factors can be evaluated using these models. Overall, integrating iPSC technology into cancer stem cell research holds significant promise for advancing our knowledge of cancer biology and accelerating the development of innovative and tailored therapeutic interventions.
... Although the transplantation of stem cells has therapeutic efficacy, there are still drawbacks to applying stem cells directly to the site of tissue injury. For example, uncontrolled proliferation can lead to tissue debris formation, tumorigenesis (e.g., teratoma), and mutagenesis [150][151][152]. Numerous studies have shown that stem cells exert their therapeutic effects through the production of secretome (in-cluding EVs) [153,154]. ...
Spinal cord injury (SCI) is an intractable and poorly prognostic neurological disease, and current treatments are still unable to cure it completely and avoid sequelae. Extracellular vesicles (EVs), as important carriers of intercellular communication and pharmacological effects, are considered to be the most promising candidates for SCI therapy because of their low toxicity and immunogenicity, their ability to encapsulate endogenous bioactive molecules (e.g., proteins, lipids, and nucleic acids), and their ability to cross the blood-brain/cerebrospinal barriers. However, poor targeting, low retention rate, and limited therapeutic efficacy of natural EVs have bottlenecked EV-based SCI therapy. A new paradigm for SCI treatment will be provided by engineering modified EVs. Furthermore, our limited understanding of the role of EVs in SCI pathology hinders the rational design of novel EVbased therapeutic approaches. In this study, we review the pathophysiology after SCI, especially the multicellular EVs-mediated crosstalk; briefly describe the shift from cellular to cell-free therapies for SCI treatment; discuss and analyze the issues related to the route and dose of EVs administration; summarize and present the common strategies for EVs drug loading in the treatment of SCI and point out the shortcomings of these drug loading methods; finally, we analyze and highlight the feasibility and advantages of bio-scaffold-encapsulated EVs for SCI treatment, providing scalable insights into cell-free therapy for SCI.
... The risk of tumorigenesis following ciPSC transplantation is due to the highly proliferative nature of ciPSCs and difficulties in complete silencing of transgenes. The Yamanaka factor and proto-oncogene c-MYC plays a key role in selfrenewal and metabolic regulation during iPSC generation and normal embryonic development, but once transplanted, this TF may become tumorigenic if it continues to be expressed [112,113]. In fact, the aberrant expression of c-MYC has been observed in *70% of cancers [114]. However, MYC proteins are important regulators of cell growth, making other members of this protein family strong candidates for the replacement of c-MYC. ...
Induced pluripotent stem cells (iPSCs) are produced by resetting the epigenetic and transcriptional landscapes of somatic cells to express the endogenous pluripotency network and revert them back to an undifferentiated state. The reduced ethical concerns associated with iPSCs, their capacity for extensive self-renewal and differentiation capabilities, make them an unparalleled resource for drug discovery, disease modelling and novel therapies. Canines (c) share many human diseases and environmental exposures, making them a superior translational model for drug screening and investigating human pathologies compared to other mammals. However, well-defined protocols for legitimate ciPSC production are lacking. Problems during canine somatic cell reprogramming (SCR) yield putative ciPSCs with incomplete pluripotency, at very low efficiencies. Despite the value of ciPSCs, the molecular mechanisms underlying their unsuccessful production and how these may be addressed have not been fully elucidated. Factors including cost, species differences, safety and feasibility may also limit the widespread clinical adoption of ciPSCs for treating canine disease. The purpose of this narrative review is to identify barriers to canine SCR on molecular and cellular levels, using comparative research to inform potential solutions to their use in both research and clinical contexts. Current research is opening new doors for the application of ciPSCs in regenerative medicine for the mutual benefit of veterinary and human medicine.
... Safety concerns are the primary priority for clinical applications that apply the use of iPSC-derived cardiac cells. Recent studies have shown that incompletely differentiated hiPSCs could form malignant tumors after transplantation in in vivo application [58]. ...
Continuous loss of cardiomyocytes (CMs) is one of the fundamental characteristics of many heart diseases, which eventually can lead to heart failure. Due to the limited proliferation ability of human adult CMs, treatment efficacy has been limited in terms of fully repairing damaged hearts. It has been shown that cell lineage conversion can be achieved by using cell reprogramming approaches, including human induced pluripotent stem cells (hiPSCs), providing a promising therapeutic for regenerative heart medicine. Recent studies using advanced cellular reprogramming-based techniques have also contributed some new strategies for regenerative heart repair. In this review, hiPSC-derived cell therapeutic methods are introduced, and the clinical setting challenges (maturation, engraftment, immune response, scalability, and tumorigenicity), with potential solutions, are discussed. Inspired by the iPSC reprogramming, the approaches of direct cell lineage conversion are merging, such as induced cardiomyocyte-like cells (iCMs) and induced cardiac progenitor cells (iCPCs) derived from fibroblasts, without induction of pluripotency. The studies of cellular and molecular pathways also reveal that epigenetic resetting is the essential mechanism of reprogramming and lineage conversion. Therefore, CRISPR techniques that can be repurposed for genomic or epigenetic editing become attractive approaches for cellular reprogramming. In addition, viral and non-viral delivery strategies that are utilized to achieve CM reprogramming will be introduced, and the therapeutic effects of iCMs or iCPCs on myocardial infarction will be compared. After the improvement of reprogramming efficiency by developing new techniques, reprogrammed iCPCs or iCMs will provide an alternative to hiPSC-based approaches for regenerative heart therapies, heart disease modeling, and new drug screening.
... However, the injected iPSCs formed tumors in the immunodeficient mice, ultimately leading to reduced cardiac function due to the stress created by the tumor. Many other studies also verified the tumorigenic potential of the transplanted iPSCs in post-MI murine hearts.222,223 On the other hand, Templin et al. assessed the therapeutic potential of iPSCs in a large animal MI model for the first time and reported vascular differentiation and durability of iPSCs engraftment.224 ...
In the modern world, myocardial infarction is one of the most common cardiovascular diseases, which are responsible for around 18 million deaths every year or almost 32% of all deaths. Due to the detrimental effects of COVID-19 on the cardiovascular system, this rate is expected to increase in the coming years. Although there has been some progress in myocardial infarction treatment, translating pre-clinical findings to the clinic remains a major challenge. One reason for this is the lack of reliable and human representative healthy and fibrotic cardiac tissue models that can be used to understand the fundamentals of ischemic/reperfusion injury caused by myocardial infarction and to test new drugs and therapeutic strategies. In this review, we first present an overview of the anatomy of the heart and the pathophysiology of myocardial infarction, and then discuss the recent developments on pre-clinical infarct models, focusing mainly on the engineered three-dimensional cardiac ischemic/reperfusion injury and fibrosis models developed using different engineering methods such as organoids, microfluidic devices, and bioprinted constructs. We also present the benefits and limitations of emerging and promising regenerative therapy treatments for myocardial infarction such as cell therapies, extracellular vesicles, and cardiac patches. This review aims to overview recent advances in three-dimensional engineered infarct models and current regenerative therapeutic options, which can be used as a guide for developing new models and treatment strategies.
... The study shown that cytokines secreted by iPSCs may play a mechanistic role in the restoration of heart function, even if teratomas occur. In a rat model of MI, undifferentiated iPSCs had similar effects as undifferentiated murine ESC, which resulted in teratoma development in the early experiments (Nussbaum et al., 2007, Zhang et al., 2011. Therefore, the summury of the origin of stem cells for the therapies od cardiac diseases have been illustrated in Table 1. ...
This study intends to evaluate the development, importance, pre-clinical and clinical study evaluation of stem cell therapy for the treatment of cardiovascular disease. Cardiovascular disease is one of the main causes of fatality in the whole world. Though there are great progressions in the pharmacological and other interventional treatment options, heart diseases remain a common disorder that causes long-term warnings. Recent accession promotes the symptoms and slows down the adverse effects regarding cardiac remodelling. But they cannot locate the problems of immutable loss of cardiac tissues. In this case, stem cell treatment holds a promising challenge. Stem cells are the cells that are capable of differentiating into many cells according to their needs. So, it is assumed that these cells can distinguish into many cells and if these cells can be individualized into cardiac cells then they can be used to replace the damaged tissues of the heart. There is some abridgment in this therapy, none the less stem cell therapy remains a hopeful destination in the treatment of heart disease.
... Despite the numerous advantages of iPSCs mentioned above, a major limitation that prevents their use is their tumorigenic potential [19][20][21]. Many studies and reviews have raised concerns regarding the development of teratomas at various body sites after iPSC administration [21][22][23][24]. Various approaches were undertaken to suppress the tumorigenic potential of iPSCs and eliminate any safety concerns. ...
Since their discovery in 2006, induced pluripotent stem cells (iPSCs) have shown promising potential, specifically because of their accessibility and plasticity. Hence, the clinical applicability of iPSCs was investigated in various fields of research. However, only a few iPSC studies pertaining to osteoarthritis (OA) have been performed so far, despite the high prevalence rate of degenerative joint disease. In this review, we discuss some of the most recent applications of iPSCs in disease modeling and the construction of 3D models in various fields, specifically focusing on osteoarthritis and OA-related conditions. Notably, we comprehensively reviewed the successful results of iPSC-derived disease models in recapitulating OA phenotypes for both OA and early-onset OA to encompass their broad etiology. Moreover, the latest publications with protocols that have used iPSCs to construct 3D models in recapitulating various conditions, particularly the OA environment, were further discussed. With the overall optimistic results seen in both fields, iPSCs are expected to be more widely used for OA disease modeling and 3D model construction, which could further expand OA drug screening, risk assessment, and therapeutic capabilities.
