Stem Cell Biotechnology Series: Stem Cells in Disease Modelling and Cancer Research
Foreword
The field of stem cells is brimming with promise and intrigue. As the understanding of these remarkable foundational components of life continues to evolve, so does the capacity to harness their extraordinary potential. Stem cells have enchanted the minds of scientists, medical professionals, and curious individuals alike, presenting unparalleled opportunities to revolutionise healthcare and regenerative medicine. This series of articles aims to unravel the mysteries of stem cell differentiation, explore the mechanisms governing their self-renewal, and examine the factors that shape their destiny. Within these articles, readers may discover the immense potential of induced pluripotent stem cells (iPSCs) in reshaping personalised medicine while uncovering their awe-inspiring regenerative capabilities. Moreover, this series sheds light on the critical challenges and limitations inherently intertwined with this field, from ensuring the safety and efficacy of stem cell therapies through navigating the complex terrain of regulatory frameworks and public perception to debating ethical uncertainties.
This series is divided into eight articles:
7. Stem Cell Biotechnology Series: Stem Cells in Disease Modelling and Cancer Research
Stem Cell Biotechnology Series: Stem Cells in Disease Modelling and Cancer Research
Stem cells play a crucial role in unravelling the secrets behind diseases. These special cells, distinguished by their unique capacity to differentiate into various specialised cell types, emerge as indispensable instruments for researchers navigating the cellular biology of diseases. Stem cells can be perceived as flexible guides, and it is precisely their adaptability that might open new paths towards revolutionary treatments (Chen et al., 2022).
During early mammalian development, pluripotent stem cells, or embryonic stem cells (ESCs), exhibit remarkable developmental plasticity. Cultured in vitro, ESCs have gained widespread attention for their unparalleled ability to generate various somatic cell types, making them promising candidates for treating degenerative diseases. Conditions such as ischemic heart failure, Parkinson's disease, Alzheimer's disease, diabetes, spinal cord injuries, and age-related macular degeneration have been targeted for therapeutic exploration using human ESCs. Despite promising results, human ESC-based clinical trials face hefty challenges. Ethical concerns surround the use of embryonic cells, and issues arising from failed in vitro fertilisation leading to abnormal development pose obstacles. Additionally, worries about immune rejection after transplantation due to the allogenic origin of ESCs further complicate their clinical application. These hindrances have prompted the exploration of alternative stem cell sources.
iPSC-Based Disease Modelling
The key to understanding the causes and processes of human diseases, as well as discovering new drugs lies in available relevant experimental models that accurately mimic the physiology of diseases and their clinical features. Animal models, primarily mice, have played a crucial role in fundamental and pharmaceutical research, serving as non-clinical efficacy models (Gunaseeli et al., 2010). However, translating findings from these models to human trials often fails due to species-specific differences in biological responses, leading to high failure rates in drug development. Consequently, there is a growing interest in using human in vitro models that replicate disease mechanisms. While human primary cell-based disease modelling is beneficial, its potential is limited by not being able to acquire enough of given cells, especially when it comes to cells from difficult-to-access organs like the heart, brain, and pancreas (Doss & Sachinidis, 2019).
Pluripotency and self-renewal are characteristics of iPSC that make them ideal for disease modelling and regenerative medicine. The efficient and safe generation of patient-specific iPSCs is achieved through precise biochemical and epigenetic protocols. Undoubtedly, iPSCs stand out as an up-and-coming and virtually limitless source of autologous cells for regenerative medicine. The creation of disease-specific iPSC lines began with two innovative studies by Dimos (2008) and Park (2008). In these investigations, iPSCs were successfully generated from individuals diagnosed with familial amyotrophic lateral sclerosis and other genetic diseases. Following these pioneering efforts, subsequent studies have continued to emphasise the crucial role of iPSCs in disease modelling and in vitro drug screening. Despite all the possibilities that iPSC technology offers, the risk of tumorigenicity remains one of the main concerns (Doi et al., 2020). Nonetheless, a clinical trial on iPSC-derived dopaminergic neurons for Parkinson's disease was launched after successful in vivo studies in immunodeficient mice. It revealed no tumorigenic risk. iPSC-derived tissue-resident macrophages exhibit enhanced immunological characteristics, showcasing improved antibacterial responses compared to traditional counterparts (Nenasheva et al., 2020).
The versatility of patient-specific iPSCs has positioned them as invaluable resources in advancing drug discovery and personalised precision medicine. These iPSCs can be manipulated to generate various clinically relevant cell types—cardiomyocytes, neuronal cells, hepatocytes, insulin-secreting pancreatic beta cells, and renal progenitor cells—in limitless quantities. This possibility facilitates high-throughput assays, allowing for efficient screening of potential drugs. Moreover, iPSCs can be derived from both individual patients and healthy subjects, enhancing their applicability. Their popularity as in vitro human disease models has surged due to their reliability. By conducting large-scale "-omics" analyses on phenotypic cells derived from patients with diseases and comparing them to cells from healthy subjects, iPSCs provide a powerful tool for unravelling disease-perturbed and drug-affected regulatory networks. This analytical approach not only accelerates drug discovery in the pharmaceutical industry but also lays the foundation for developing personalised and precise therapeutic interventions tailored to individual patient profiles (Karagiannis et al., 2019).
Personalised Medicine
The term "personalised medicine" has quickly attracted the attention of many. It aims to individualise patient care, incorporating patient's characteristics, including their genetic profile, to impact clinical decisions. In other words, the treatment is tailored to each patient, ensuring proper treatment at the right time. This evolving field dedicates numerous resources to the search for diagnostic, prognostic, and predictive biomarkers. Personalised medicine is already making significant strides in miscellaneous medical applications. For example, measuring thiopurine methyltransferase before initiating azathioprine treatment in inflammatory bowel disease. This personalised approach is becoming progressively more important in medicine, pharmacology, and toxicology, particularly to address the high frequency of non-responders and adverse side effects of certain drugs. Therefore, human iPSC-based disease models stand out as promising candidates, offering an unlimited supply of clinically relevant cells of human origin that is easily accessible (Jackson & Chester, 2015; Van Den Berg et al., 2019).
iPSCs in Degenerative Diseases
In theory, iPSCs can be programmed into any cell type in the human body. With advancements in reprogramming techniques, this technology has significantly progressed the understanding of disease pathology, facilitated the development of precise therapeutics, and propelled progress in regenerative medicine (Kumar et al., 2018). In neurodegenerative conditions and psychiatric disorders, where the genetic predisposition is complex and involves alterations at a structural and functional level, iPSCs are a powerful tool. In the case of schizophrenia, labelled "the disease of the synapses," iPSCs have been generated from family members carrying a frameshift mutation in the DISC1—disrupted in schizophrenia 1—gene. Gene editing techniques have been applied to create isogenic iPSC lines. Isogenic lines are cell lines that were genetically engineered from the parental iPS cell line (a deletion, an insertion, or a substitution in the genome). These isogenic lines have provided valuable insights, indicating a reduction or loss of the DISC1 protein among mutation carriers. Additionally, dysregulation of genes associated with synapses and psychiatric disorders in the forebrain has been observed (Wen et al., 2014).
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterised by the loss of neurons in the spinal cord and motor cortex. Sadly, it leads to paralysis and, ultimately, death. A stable supply of human motor neurons that carry the specific genetic mutations responsible for the condition is necessary to advance therapeutic research for ALS. In a study by Dimos et al., iPSCs were successfully derived from skin fibroblasts of two sisters diagnosed with ALS, both possessing the L144F mutation in the superoxide dismutase (SOD1) gene associated with a slowly progressing form of the disease. Incredibly, the reprogramming process, accomplished with only four factors, proved successful even in the face of the severe disability of the patients from whom the cells were obtained (Dimos et al., 2008).
Parkinson’s disease (PD) presents a complex challenge, even more so in cases lacking identifiable genetic factors. To understand PD, researchers successfully generated iPSCs from individuals with sporadic cases of PD. Employing doxycycline-inducible lentiviral vectors, the researchers used Cre-/lox-recombinase to remove the vectors after reprogramming. This resulted in iPSCs free of programming factors while preserving their pluripotent characteristics. This novel method reduced the risk of oncogenic transformation and prevented the re-expression of transgenes, showcasing the potential for establishing stable iPSC lines for more effective PD disease modelling (Soldner et al., 2009). Another study aimed to enhance the safety of iPSC-derived dopaminergic neurons for PD cell transplantation therapies. Through NCAM(+)/CD29(low) sorting, researchers selectively enriched ventral midbrain dopaminergic neurons, demonstrating increased expression of key markers. Transplanting these neurons into 6-hydroxydopamine lesioned rats successfully restored motor function, indicating promising therapeutic potential. Significantly, primate iPSC-derived neural cells exhibited remarkable survival without needing immunosuppression one-year-post-autologous transplant, highlighting the feasibility and safety of iPSC-derived transplantation for PD (Sundberg et al., 2013).
iPSCs in Diabetes
The autoimmune destruction of pancreatic β-cells characterises type 1 diabetes and often necessitates transplantation of β-cells or islet tissues to overcome the limitations of exogenous insulin supplementation. Unfortunately, conventional approaches imply a risk of rejection, the need for immunosuppression, and difficulties in maintaining physiological blood glucose levels. Scientists have been exploring ways to create β-cells and islet tissues from human pluripotent stem cells, especially iPSCs, to overcome challenges in diabetes treatment. Although studies generated pancreatic β-like cells capable of insulin secretion, their clinical utility was compromised by the co-excretion of glucagon and somatostatin and the release of inappropriate insulin amounts (D’Amour et al., 2006). In contrast, iPSC-derived pancreatic endoderm cells have demonstrated the potential to differentiate and function comparably to adult β-cells. Moreover, iPSCs have helped with the shortage of donor islets, and pancreatic cells from iPSCs are being tested in clinical trials for transplantation therapy. The differentiation of iPSCs, mimicking natural in vivo processes, has been achieved by employing a combination of growth factors, including Nodal-activin, Wnt, retinoic acid, hedgehog, epidermal and fibroblast growth factor, bone morphogenetic protein, and Notch, which activate and inhibit key signalling pathways (Kondo et al., 2018).
iPSCs in Cardiac Diseases
Cardiovascular conditions have become the leading cause of mortality globally, affecting both developed and developing nations (Roth, 2020). The complexity of heart-related ailments, influenced by genetic factors and environmental triggers, is challenging. The efforts to understand disease aetiology through traditional animal models often result in a fiasco. Animal studies show a staggering 90% failure rate in predicting the safety and efficacy of new drugs during clinical trials, emphasising the limitations in translating findings to human outcomes. To address these obstacles, iPSC-based disease models have earned attention, offering a more precise and human-specific platform for studying various cardiac conditions. These encompass conditions like hereditary long QT syndrome (LQTS), dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), familial pulmonary arterial hypertension (FPAH) impacting endothelial cells, as well as disorders involving smooth muscle cells, including Williams-Beuren syndrome (WBS) and Marfan syndrome (MFS) (Ye et al., 2018).
For example, long QT syndrome is an inherited heart condition associated with approximately 17 genes, including crucial ones like KCNQ1, KCNH2, and SCN5A. These three genes account for about 75% of confirmed cases. Current treatments involve β-blockers and a surgical procedure called left cardiac sympathetic denervation. Nonetheless, diagnosing the condition is challenging due to variants of unknown significance present in a third of patients (Aboul-Soud et al., 2021). In a study by Wu et al., patient-derived iPSC cardiomyocytes (iPSC-CMs) were used to minimise variability through specific methods. This research demonstrated that iPSC-CMs could differentiate between harmful and benign variants using CRISPR genome editing (Wu et al., 2020).
In dilated cardiomyopathy (DCM), the heart chambers enlarge and exhibit systolic dysfunction. Researchers used human iPSCs derived from the skin fibroblasts of DCM patients to explore the heart's contraction mechanisms response to specific interventions and study the proteome profile. The study identified defects in the assembly and maintenance of the sarcomeric structure in mutated iPSC-CMs. These mutated cells showed a reduced response to β-adrenergic stimulation with isoproterenol, increased [Ca2+] out, and elevated angiotensin-II levels, indicating a weakened inotropic response in cardiomyocytes from DCM patients (Schick et al., 2018).
Hypertrophic cardiomyopathy (HCM) is a condition that can lead to sudden death. The walls of the left ventricle become thick and stiff, restraining the heart's ability to pump blood effectively. iPSC-CMs are also used to study this disease. The cells were collected from patients with a family history of HCM and a specific mitochondrial gene mutation. The analysis indicated issues with mitochondria, including dysfunction and structural defects, as well as reduced levels of mitochondrial proteins and altered energy ratios. These problems contributed to higher levels of calcium within the cells, and specific electrical issues seen in HCM (Li et al., 2018). Recent research has extended this work by creating iPSCs from the blood cells of another HCM patient with a different gene mutation. These iPSCs successfully transformed into a type of heart cell, showcasing their potential for studying HCM (Jin et al., 2021).
The iPSC models dedicated to familial pulmonary arterial hypertension have uncovered disruptions in BMPR2 signalling, thus diminishing endothelial cell functions such as adhesion, migration, survival, and angiogenesis. Despite the autosomal dominant BMPR2 mutation showing only 20% penetrance, iPSC research highlighted an increased presence of BIRC3, associated with improved survival. This suggests the potential use of protective modifiers in future FPAH treatment strategies (Gu et al., 2017). Turning to Williams-Beuren syndrome, iPSC modelling revealed that haploinsufficiency results in deficiencies of elastin, leading to immature and highly proliferative patient-derived smooth muscle cells with compromised function and contractile properties. To address these issues, the researchers upregulated elastin signalling and administered the anti-proliferative drug rapamycin (Kinnear et al., 2013). In the case of Marfan syndrome, iPSC-based investigations into disease pathogenesis identified various issues, including defects in fibrillin-1 accumulation, extracellular matrix degradation, abnormal activation of transforming growth factor-β, and cellular apoptosis (Granata et al., 2017).
iPSC in Blood Disorders
The treatment of blood disorders, particularly the need for mature erythrocytes for transfusion, encounters challenges related to blood group and Rh antigen compatibility, as well as the risk of infection (Sahu et al., 2014). Erythropoiesis, the process of generating mature erythrocytes from precursor erythroblasts, is complicated. It primarily occurs in the bone marrow, making in vitro culture challenging due to complex interactions involving hormones, cytokines, and growth factors (Seo et al., 2019). Moreover, fully differentiated red blood cells (RBCs) lack proliferative capacity, making establishing an erythropoiesis-like maturation system in precursor cells difficult. The process is further complicated by the requirement for donors, especially those with uncommon blood group types, and the necessity to guarantee safety in vulnerable populations (Chang et al., 2011). Numerous studies have explored developing iPSC models for blood malignancies to address these limitations.
A comprehensive study focused on generating iPSC clones from patients' bone marrow and blood samples, integrating mutational analysis with cell programming. This approach resulted in diverse iPSC clones representing various disease stages and spectrums, including predisposition and low- and high-risk conditions. Researchers utilised the CRISPR/Cas9 system to introduce and correct mutations in the iPSCs. Differentiated AML-iPSCs exhibited a leukemic phenotype, with the derived hematopoietic stem cells containing distinct adherent and non-adherent cell populations. This AML-iPSC model proved efficient for molecular analysis and studying key functional aspects (Papapetrou, 2018).
iPSCs have been generated from genetically corrected somatic cells to study Fanconi anaemia (FA), an inherited bone marrow failure syndrome. This innovative approach aims to produce many genetically stable autologous hematopoietic stem cells for treating bone marrow failure in FA. The reprogramming process involved dermal fibroblasts subjected to two rounds of infection with a retrovirus encoding amino-terminal flag-tagged versions of the Oct4, Sox2, Klf4, and c-Myc transcription factors. Additionally, lentiviral vectors encoding FANCA or FANCD2 (proteins associated with FA) were employed to correct somatic cells prone to apoptosis in FA. Turning FANCA-involved fibroblasts into iPSCs successfully showed the need to bring back the FA pathway for making iPSCs from cells of Fanconi anaemia patients (Raya et al., 2009).
Treatment of chronic myeloid leukaemia, where the BCR-ABL gene fusion is a significant driver, involves tyrosine kinase inhibitors (TKIs) that often induce remission. CML-iPSCs resisted TKIs, even in the presence of BCR-ABL expression, implying independence in this differentiated state. Vital factors for maintaining BCR-ABL positivity in CML-iPSCs, such as phosphorylation of AKT, JNK, and ERK1/2, remained unchanged, while the expression of STAT5 and CRKL decreased. Notably, hematopoietic cells derived from CML-iPSCs regained TKI sensitivity (Bedel et al., 2013).
Drug Safety
A significant hurdle in drug development lies in predicting the safety pharmacology of a drug, that is, assessing its toxicity and potency. Current methods often involve using immortalised cell lines of cancerous origin or live animal models, each characterised by specific limitations. Due to chromosomal and genetic aberrations from prolonged in vitro culture, immortalised cell lines do not accurately represent normal cell behaviour. Primary cultures of somatic cells are heterogeneous, making consistent toxicological screening results challenging (Chaudhari et al., 2017). Animal models, while providing in vivo insights, raise ethical concerns, incur high costs, and present technical difficulties. Despite the potential for chromosomal aberrations, iPSCs offer advantages such as derivation from non-cancerous tissues, representation of healthy controls, and the ability to produce physiologically relevant phenotypic cells in large quantities. Disease models based on iPSCs, featuring a variety of ethnic backgrounds and meticulously defined characteristics, present a potential, cost-efficient, and easily automated framework for conducting high-throughput toxicological screening and potency testing (Shinde et al., 2016).
The Use of Other Stem Cell Types
Throughout this article's discourse on disease modelling, a particular emphasis was put on iPSCs. Indeed, they are a significantly influential technology. Their derivation from adult cells through reprogramming offers distinct advantages, especially in personalised disease modelling. However, it is necessary to remember the variety that stem cells exhibit. While iPSCs are a priceless resource, ESCs warrant due consideration despite their limited application because of ethical deliberations and immune compatibility challenges. Moreover, the substantive role of adult stem cells in discerning disease mechanisms should not be understated. Scientists carefully pick from the spectrum of stem cell varieties to judiciously probe and comprehend the complexities of various maladies.
An example of the use of ESCs can be found in Alzheimer's research. In a study exploring the neurotoxic effects of silver nanoparticles, human ESC-derived glutamatergic neurons were used to demonstrate that citrate-coated silver nanoparticles induce glutamate excitotoxicity through specific signalling pathways (Begum et al., 2016). Another investigation focused on the impact of chronic exposure to bisphenol-A on glutamatergic neurons derived from human ESCs, revealing that neurotoxicity is linked to an increase in reactive nitrogen species and reactive oxygen species (Wang et al., 2019). ESC-derived neurons have played a crucial role in auditory neuron research, where human ESCs were differentiated into neural precursor cells and grown on aligned nanofiber mats. The goal of that strategy is a potential transplantation to replace auditory nerves. In Alzheimer's disease research, human ESC-derived cortical neurons treated with amyloid-β (Aβ) displayed reduced synaptic currents, and histone methyltransferase inhibitors partially restored this effect. Additionally, a cellular model was created using human ESC-derived neurons expressing a secretory form of Aβ40 or Aβ42 to investigate neurodegeneration in AD, offering valuable insights into the disease. The diverse applications of human ESC-derived glutamatergic neurons showcase significant advancements in AD-related research (Ubina et al., 2019).
Major progress has been made in COVID-19 research with the help of adult stem cells (ASC)—an important study by Tindle and colleagues (2021) disclosed a significant advancement in organoid technology. Their research focused on creating adult lung organoids (ALOs) integrating proximal airway and distal alveolar epithelia. These organoids, derived from adult lung stem cells, have demonstrated exceptional stability and expandability within 3D cultures, marking a significant leap forward in the field. The versatility of these adult lung organoids positions them as a sophisticated and adaptable model designed explicitly for exploring viral and host immune responses during respiratory viral pandemics. One distinctive feature of this study lay in the successful propagation and expansion of ALOs, a testament to their robustness as a model system. Including both proximal and distal alveolar signatures within these organoids addressed a longstanding challenge in achieving a holistic representation of the diverse cell types in the lung. This comprehensive approach set the stage for a more accurate and nuanced understanding of lung biology and function. The researchers employed adult stem cells sourced from deep lung biopsies, a strategic choice that added a layer of personalisation to the model. By capturing the genetic makeup and preserving organ-specific epigenetic programming, this methodology ensured that the ALO model closely mirrored the complexities of the human lung. Such a personalised approach is invaluable in comprehending lung-related diseases and opens new avenues for developing targeted therapies.
Cancer Stem Cells
The idea of cancer stem cells (CSCs) comes from recognising that tumours are not uniform; rather than being homogeneous masses of identical cells, they display heterogeneity. This insight into a potential hierarchical organisation within tumours gained momentum when it was observed that a single mouse tumour cell was able to start a new tumour. This observation stressed that not all cells within a tumour are equal in their tumorigenic potential. Instead, a distinct subset of cells (cancer stem cells) plays the role of tumour initiation and sustained growth (Furth & Kahn, 1937). Early studies, especially in acute myeloid leukaemia, found CSCs as CD34+CD38− fractions that reliably grow in mice (Lapidot et al., 1994). Nevertheless, interpreting studies with mouse lymphomas and leukaemias posed challenges, suggesting tumours could be sustained by a larger proportion of cells, challenging the idea of rare CSCs. Solid tumors like breast, brain, prostate, pancreatic, colon, lung, and ovarian cancers had subpopulations with significant tumor-propagating abilities.
The concept remains debated, discussing whether CSCs are rare or common and if they have fixed or diverse characteristics. Nowadays, cancer is seen as a complex, adaptive ecosystem, suggesting CSCs are not fixed due to evolution and genetic variety. Despite progress, understanding the relationship among CSC-derived clones in a tumour remains vague. A handful of studies aimed to reveal how hematopoietic stem cells (HSCs) in the bone marrow (BM) are supported. Positioned around sinusoids, HSCs get crucial support from mesenchymal stem cells (MSCs) and endothelial cells. MSCs give rise to osteoblastic cells and produce factors like Scf and Cxcl12, which are vital for HSCs. Lack of MSCs leads to reduced BM cellularity, anaemia, and fewer osteogenic cells. Another player, CAR cells, coexist with HSCs, playing a crucial role in their maintenance. Removal of CAR cells reduces HSCs and affects BM cell capabilities (Mukherjee, 2010).
Beyond MSCs and CAR cells, contributors to the HSC niche include CD146+ skeletal stem cells, endothelial cells, and even sympathetic nerves. Endothelial cells lining blood vessels support HSCs during homeostasis and regeneration. Sympathetic nerves play a role in modulating HSC function, particularly in HSC trafficking. Macrophages are key regulators, influencing niche cells and producing CXCL12, which is crucial for HSC retention. Other cell types, like myelinating Schwann cells, adipocytes, and osteoclasts, also play roles in HSC regulation (Wang, 2019).
Choosing the Stem Cell Type for Disease Modelling
Stem cells, particularly the iPSCs, ESCs, and ASCs triad, represent a priceless source for scientific exploration and medical applications. Each type of stem cell carries distinct characteristics and offers specific advantages. This way, they contribute to ameliorating the understanding of the nuanced and often very complicated aetiologies of human diseases.
As already explored in previous articles from this series, embryonic stem cells are derived from the inner cell mass of blastocysts and retain unparalleled pluripotency. This unique property allows them to differentiate into any cell type in the human body, making them invaluable for early developmental studies and disease modelling. Regrettably, their use is accompanied by ethical dilemmas due to their origin, which will be discussed in the next and final article of this series. Despite this, ESCs have been pivotal in deciphering the molecular mechanisms surrounding various genetic conditions and providing insights into early embryonic development.
On the other hand, adult stem cells, found in various tissues throughout the body, offer a more ethically acceptable alternative. Mesenchymal stem cells, especially, have gained importance for their regenerative potential. MSCs offer insights into conditions affecting the tissues from which they are derived. These cells are instrumental in studying osteoarthritis, cardiovascular disorders, and autoimmune conditions, providing a more targeted and relevant platform for modelling specific pathologies.
Without a shadow of a doubt, the appearance of iPSCs has revolutionised science. iPSCs are generated by reprogramming adult cells into a pluripotent state, typically from sources like skin or blood. This breakthrough technology circumvents the ethical concerns associated with ESCs and allows the creation of patient-specific cells for personalised medicine. iPSCs have become instrumental not only in disease modelling but also in drug discovery. The strategic selection of a particular stem cell type hinges on the research goals and the exact differentiation potential required. While ESCs offer insights into early development and genetic conditions, ASCs, particularly MSCs, excel in regenerative applications. iPSCs, with their ability to mimic the characteristics of ESCs without ethical problems, provide a powerful tool for personalised medicine and disease modelling. Altogether, the synergistic work will surely continue advancing knowledge of human diseases (Aboul-Soud et al., 2021; Doss & Sachinidis, 2019).
Conclusion
Stem cell biotechnology surfaced as one of the most important tools in humanity's struggle in trying to understand diseases. iPSCs, ESCs, and ASCs form a versatile toolkit tailored to specific research objectives. iPSCs take centre stage in disease modelling since they offer a groundbreaking platform to faithfully replicate pathological conditions in vitro. Since 2008, when disease-specific iPSC lines were first used, research has been propelled forward. They opened avenues for targeted drug development and personalised medicine. The concept of cancer stem cells has revolutionised cancer research. This belief is rooted in the recognition of tumour heterogeneity and the unbelievable ability of a single tumour cell to instigate new growth. Despite ongoing debates about CSC characteristics, their role in sustaining tumour growth across various solid tumours is undeniable. Unquestionably, stem cell biotechnology is a cornerstone and even though the future of disease modelling looks encouraging, prudent optimism is always advisable.
Bibliographical References
Aach, J., Lunshof, J., Iyer, E., & Church, G. M. (2017). Addressing the ethical issues raised by synthetic human entities with embryo-like features. ELife, 6. https://doi.org/10.7554/eLife.20674
Aboul-Soud, M. A. M., Alzahrani, A. J., & Mahmoud, A. (2021). Induced pluripotent stem cells (Ipscs)—roles in regenerative therapies, disease modelling and drug screening. Cells, 10(9). https://doi.org/10.3390/cells10092319
Bedel, A., Pasquet, J. M., Lippert, É., Taillepierre, M., Lagarde, V., Dabernat, S., Dubus, P., Charaf, L., Beliveau, F., de Verneuil, H., Richard, E., Mahon, F. X., & Moreau-Gaudry, F. (2013). Variable behavior of iPSCs derived from CML patients for response to TKI and hematopoietic differentiation. PLoS ONE, 8(8), e71596. https://doi.org/10.1371/journal.pone.0071596
Begum, A. N., Aguilar, J. S., Elias, L., & Hong, Y. (2016). Silver nanoparticles exhibit coating and dose-dependent neurotoxicity in glutamatergic neurons derived from human embryonic stem cells. NeuroToxicology, 57, 45–53. https://doi.org/10.1016/j.neuro.2016.08.015
Chang, K. H., Bonig, H., & Papayannopoulou, T. (2011). Generation and characterization of erythroid cells from human embryonic stem cells and induced pluripotent stem cells: An overview. Stem Cells International. https://doi.org/10.4061/2011/791604
Chaudhari, U., Ellis, J. K., Wagh, V., Nemade, H., Hescheler, J., Keun, H. C., & Sachinidis, A. (2017). Metabolite signatures of doxorubicin induced toxicity in human induced pluripotent stem cell-derived cardiomyocytes. Amino Acids, 49(12), 1955–1963. https://doi.org/10.1007/s00726-017-2419-0
Chen, G., Yin, S., Zeng, H., Li, H., & Wan, X. (2022). Regulation of embryonic stem sell Self-renewal. Life, 12(8), 1–17. https://doi.org/10.3390/life12081151
Chuang, J. H., Yang, W. C., & Lin, Y. (2021). Glutamatergic neurons differentiated from embryonic stem cells: An investigation of differentiation and associated diseases. In International Journal of Molecular Sciences, 22(9). https://doi.org/10.3390/ijms22094592
Cyranoski, D. (2018). The cells that sparked a revolution. Nature, 555(7697), 429–430. https://doi.org/10.1038/d41586-018-03268-4
D’Amour, K. A., Bang, A. G., Eliazer, S., Kelly, O. G., Agulnick, A. D., Smart, N. G., Moorman, M. A., Kroon, E., Carpenter, M. K., & Baetge, E. E. (2006). Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nature Biotechnology, 24(11), 1392–1401. https://doi.org/10.1038/nbt1259
Dimos, J. T., Rodolfa, K. T., Niakan, K. K., Weisenthal, L. M., Mitsumoto, H., Chung, W., Croft, G. F., Saphier, G., Leibel, R., Goland, R., Wichterle, H., Henderson, C. E., & Eggan, K. (2008). Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science, 321(5893), 1218–1221. https://doi.org/10.1126/science.1158799
Doi, D., Magotani, H., Kikuchi, T., Ikeda, M., Hiramatsu, S., Yoshida, K., Amano, N., Nomura, M., Umekage, M., Morizane, A., & Takahashi, J. (2020). Pre-clinical study of induced pluripotent stem cell-derived dopaminergic progenitor cells for Parkinson’s disease. Nature Communications, 11(1). https://doi.org/10.1038/s41467-020-17165-w
Doss, M. X., & Sachinidis, A. (2019). Current challenges of iPSC-based disease modeling and therapeutic implications. Cells, 8(5). https://doi.org/10.3390/cells8050403
Evans, M. J., & Kaufman, M. H. (1981). Establishment in culture of pluripotential cells from mouse embryos. Nature, 292(5819), 154–156. https://doi.org/10.1038/292154a0
Furth, J., & Kahn, M. C. (1937). The transmission of leukemia of mice with a single cell. American Journal of Cancer, 31(2), 276–282. https://doi.org/10.1158/ajc.1937.276
Granata, A., Serrano, F., Bernard, W. G., McNamara, M., Low, L., Sastry, P., & Sinha, S. (2017). An iPSC-derived vascular model of Marfan syndrome identifies key mediators of smooth muscle cell death. Nature Genetics, 49(1), 97–109. https://doi.org/10.1038/ng.3723
Gu, M., Shao, N. Y., Sa, S., Li, D., Termglinchan, V., Ameen, M., Karakikes, I., Sosa, G., Grubert, F., Lee, J., Cao, A., Taylor, S., Ma, Y., Zhao, Z., Chappell, J., Hamid, R., Austin, E. D., Gold, J. D., Wu, J. C., … Rabinovitch, M. (2017). Patient-specific iPSC-derived endothelial cells uncover pathways that protect against pulmonary hypertension in BMPR2 mutation carriers. Cell Stem Cell, 20(4), 490-504.e5. https://doi.org/10.1016/j.stem.2016.08.019
Gunaseeli, I., Doss, M., Antzelevitch, C., Hescheler, J., & Sachinidis, A. (2010). Induced pluripotent stem cells as a model for accelerated patient- and disease-specific drug discovery. Current Medicinal Chemistry, 17(8), 759–766. https://doi.org/10.2174/092986710790514480
Jackson, S. E., & Chester, J. D. (2015). Personalised cancer medicine. International Journal of Cancer, 137(2), 262–266. https://doi.org/10.1002/ijc.28940
Jin, J., Lu, L., Chen, J., Wang, K., Han, J., Xue, S., & Weng, G. (2021). Generation of an induced pluripotential stem cell (iPSC) line from a patient with hypertrophic cardiomyopathy carrying myosin binding protein C (MYBPC3) c.3369–3370 insC mutation. Stem Cell Research, 50. https://doi.org/10.1016/j.scr.2020.102144
Karagiannis, P., Takahashi, K., Saito, M., Yoshida, Y., Okita, K., Watanabe, A., Inoue, H., Yamashita, J. K., Todani, M., Nakagawa, M., Osawa, M., Yashiro, Y., Yamanaka, S., & Osafune, K. (2019). Induced pluripotent stem cells and their use in human models of disease and development. Physiological Reviews, 99(1), 79–114. https://doi.org/10.1152/physrev.00039.2017
Kinnear, C., Chang, W. Y., Khattak, S., Hinek, A., Thompson, T., de Carvalho Rodrigues, D., Kennedy, K., Mahmut, N., Pasceri, P., Stanford, W. L., Ellis, J., & Mital, S. (2013). Modeling and rescue of the vascular phenotype of Williams-Beuren syndrome in patient induced pluripotent ctem Cells. Stem Cells Translational Medicine, 2(1), 2–15. https://doi.org/10.5966/sctm.2012-0054
Kondo, Y., Toyoda, T., Inagaki, N., & Osafune, K. (2018). iPSC technology-based regenerative therapy for diabetes. Journal of Diabetes Investigation, 9(2), 234–243. https://doi.org/10.1111/jdi.12702
Kumar, S., Blangero, J., & Curran, J. E. (2018). Induced pluripotent stem cells in disease modeling and gene identification. Methods in Molecular Biology, (1706), 17–38. https://doi.org/10.1007/978-1-4939-7471-9_2
Lapidot, T., Sirard, C., Vormoor, J., Murdoch, B., Hoang, T., Caceres-Cortes, J., Minden, M., Paterson, B., Caligiuri, M. A., & Dick, J. E. (1994). A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature, 367(6464), 645–648. https://doi.org/10.1038/367645a0
Li, S., Pan, H., Tan, C., Sun, Y., Song, Y., Zhang, X., Yang, W., Wang, X., Li, D., Dai, Y., Ma, Q., Xu, C., Zhu, X., Kang, L., Fu, Y., Xu, X., Shu, J., Zhou, N., Han, F., … Yan, Q. (2018). Mitochondrial dysfunctions contribute to hypertrophic cardiomyopathy in patient iPSC-derived cardiomyocytes with MT-RNR2 mutation. Stem Cell Reports, 10(3), 808–821. https://doi.org/10.1016/j.stemcr.2018.01.013
Mukherjee, S. (2010). The emperor of all maladies: A biography of cancer. Large print ed. Waterville, Me., Thorndike Press. ISBN:9781410447159
Nenasheva, T., Gerasimova, T., Serdyuk, Y., Grigor’eva, E., Kosmiadi, G., Nikolaev, A., Dashinimaev, E., & Lyadova, I. (2020). Macrophages derived from human induced pluripotent stem cells are low-activated “naïve-like” cells capable of restricting mycobacteria growth. Frontiers in Immunology, 11. https://doi.org/10.3389/fimmu.2020.01016
Papapetrou, E. P. (2018). Induced pluripotent stem cells to model blood diseases. Blood, 132(Supplement 1), SCI-15-SCI-15. https://doi.org/10.1182/blood-2018-99-109425
Park, I. H., Arora, N., Huo, H., Maherali, N., Ahfeldt, T., Shimamura, A., Lensch, M. W., Cowan, C., Hochedlinger, K., & Daley, G. Q. (2008). Disease-specific induced pluripotent stem cells. Cell, 134(5), 877–886. https://doi.org/10.1016/j.cell.2008.07.041
Raya, Á., Rodríguez-Piz, I., Guenechea, G., Vassena, R., Navarro, S., Barrero, M. J., Consiglio, A., Castell, M., Río, P., Sleep, E., González, F., Tiscornia, G., Garreta, E., Aasen, T., Veiga, A., Verma, I. M., Surrallés, J., Bueren, J., & Belmonte, J. C. I. (2009). Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 460(7251), 53–59. https://doi.org/10.1038/nature08129
Roth, G. A., Mensah, G. A., Johnson, C. O., Addolorato, G., Ammirati, E., Baddour, L. M., Barengo, N. C., Beaton, A., Benjamin, E. J., Benziger, C. P., Bonny, A., Brauer, M., Brodmann, M., Cahill, T. J., Carapetis, J. R., Catapano, A. L., Chugh, S., Cooper, L. T., Coresh, J., … Fuster, V. (2020). Global burden of cardiovascular diseases and risk factors, 1990–2019: Update from the GBD 2019 study. Journal of the American College of Cardiology, 76(25), 2982. https://doi.org/10.1016/J.JACC.2020.11.010
Sahu, S., Hemlata, & Verma, A. (2014). Adverse events related to blood transfusion. In Indian Journal of Anaesthesia 58(5), 543–551. https://doi.org/10.4103/0019-5049.144650
Schick, R., Mekies, L. N., Shemer, Y., Eisen, B., Hallas, T., Jehuda, R. Ben, Ben-Ari, M., Szantai, A., Willi, L., Shulman, R., Gramlich, M., Pane, L. S., My, I., Freimark, D., Murgia, M., Santamaria, G., Gherghiceanu, M., Arad, M., Moretti, A., & Binah, O. (2018). Functional abnormalities in induced pluripotent stem cell-derived cardiomyocytes generated from titin-mutated patients with dilated cardiomyopathy. PLoS ONE, 13(10), e0205719. https://doi.org/10.1371/journal.pone.0205719
Seo, Y., Shin, K. H., Kim, H. H., & Kim, H. S. (2019). Current advances in red blood cell generation using stem cells from diverse sources. Stem Cells International. https://doi.org/10.1155/2019/9281329
Shinde, V., Perumalinivasan, S., Henry, M., Rotshteyn, T., Hescheler, J., Rahnenführer, J., Grinberg, M., Meisig, J., Blüthgen, N., Waldmann, T., Leist, M., Hengstler, J. G., & Sachinidis, A. (2016). Comparison of a teratogenic transcriptome-based predictive test based on human embryonic versus inducible pluripotent stem cells. Stem Cell Research and Therapy, 7(1), 1–15. https://doi.org/10.1186/s13287-016-0449-2
Soldner, F., Hockemeyer, D., Beard, C., Gao, Q., Bell, G. W., Cook, E. G., Hargus, G., Blak, A., Cooper, O., Mitalipova, M., Isacson, O., & Jaenisch, R. (2009). Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell, 136(5), 964–977. https://doi.org/10.1016/j.cell.2009.02.013
Sundberg, M., Bogetofte, H., Lawson, T., Jansson, J., Smith, G., Astradsson, A., Moore, M., Osborn, T., Cooper, O., Spealman, R., Hallett, P., & Isacson, O. (2013). Improved cell therapy protocols for Parkinson’s disease based on differentiation efficiency and safety of hESC-, hiPSC-, and non-human primate iPSC-derived dopaminergic neurons. Stem Cells, 31(8), 1548–1562. https://doi.org/10.1002/stem.1415
Tindle, C., Fuller, M., Fonseca, A., Taheri, S., Ibeawuchi, S. R., Beutler, N., Katkar, G. D., Claire, A., Castillo, V., Hernandez, M., Russo, H., Duran, J., Alexander, L. E. C., Tipps, A., Lin, G., Thistlethwaite, P. A., Chattopadhyay, R., Rogers, T. F., Sahoo, D., … Das, S. (2021). Adult stem cell-derived complete lung organoid models emulate lung disease in COVID-19. ELife, 10. https://doi.org/10.7554/ELIFE.66417
Ubina, T., Magallanes, M., Srivastava, S., Warden, C. D., Yee, J. K., & Salvaterra, P. M. (2019). A human embryonic stem cell model of Aβ-dependent chronic progressive neurodegeneration. Frontiers in Neuroscience, 13. https://doi.org/10.3389/fnins.2019.01007
Van Den Berg, A., Mummery, C. L., Passier, R., & Van der Meer, A. D. (2019). Personalised organs-on-chips: Functional testing for precision medicine. Lab on a Chip, 19(2), 198–205. https://doi.org/10.1039/c8lc00827b
Wang, H., Chang, L., Aguilar, J. S., Dong, S., & Hong, Y. (2019). Bisphenol-A exposure induced neurotoxicity in glutamatergic neurons derived from human embryonic stem cells. Environment International, 127, 324–332. https://doi.org/10.1016/j.envint.2019.01.059
Wang, X. (2019). Stem cells in tissues, organoids, and cancers. In Cellular and Molecular Life Sciences 76(20), 4043–4070. https://doi.org/10.1007/s00018-019-03199-x
Wen, Z., Nguyen, H. N., Guo, Z., Lalli, M. A., Wang, X., Su, Y., Kim, N. S., Yoon, K. J., Shin, J., Zhang, C., Makri, G., Nauen, D., Yu, H., Guzman, E., Chiang, C. H., Yoritomo, N., Kaibuchi, K., Zou, J., Christian, K. M., … Ming, G. L. (2014). Synaptic dysregulation in a human iPS cell model of mental disorders. Nature, 515(7527), 414–418. https://doi.org/10.1038/nature13716
Wu, J. C., Garg, P., Yoshida, Y., Yamanaka, S., Gepstein, L., Hulot, J. S., Knollmann, B. C., & Schwartz, P. J. (2020). Towards Precision Medicine with Human iPSCs for Cardiac Channelopathies. Circulation Research, 653–658. https://doi.org/10.1161/CIRCRESAHA.119.315209
Ye, L., Ni, X., Zhao, Z. A., Lei, W., & Hu, S. (2018). The application of induced pluripotent stem cells in cardiac disease modeling and drug testing. Journal of Cardiovascular Translational Research, 11(5), 366–374. https://doi.org/10.1007/s12265-018-9811-3
Comments