Open access peer-reviewed chapter
Abstract
Reprogramming adult somatic cells into induced pluripotent stem cells (iPSCs) through the ectopic expression of reprogramming factors offers truly personalized cell-based therapy options for numerous human diseases. The iPSC technology also provides a platform for disease modeling and new drug discoveries. Similar to embryonic stem cells, iPSCs can give rise to any cell type in the body and are amenable to genetic correction. These properties of iPSCs allow for the development of permanent corrective therapies for many currently incurable disorders. In this chapter, we summarize recent progress in the iPSC field with a focus on potential clinical applications of these cells.
Keywords
- cell differentiation
- cell-based therapy
- genetic correction
- induced pluripotent stem cells
- iPSCs
- regenerative medicine
- stem cell reprogramming
1. Introduction
Direct reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) through the ectopic expression of reprogramming factors [1, 2, 3, 4, 5] has had a dramatic impact on the field of regenerative medicine and has opened a new era in research and therapy. Human iPSCs represent an unprecedented source of patient-specific pluripotent stem cells suitable for disease modeling and tissue replacement therapy.
Stem cells (SCs) have the ability to self-renew through cell division and can differentiate into various cell types. Based on their origin, SCs are divided into embryonic SCs (ESCs), induced pluripotent SCs (iPSCs), and adult SCs. ESCs are pluripotent cells derived from the inner cell mass of the blastocyst. They can give rise to tissues of the three germ layers and are regarded as a renewable potent cell source for the regeneration of all bodily tissues [6]. Adult SCs are multipotent cells of adult tissues that are also essential for regenerative medicine [7]. iPSCs share many similarities with ECSs, including pluripotency, differentiation potential, and the capability to form teratomas and viable chimeras [8].
Human ESCs are isolated by the use of surplus
Similar to ESCs, iPSCs can proliferate indefinitely and differentiate into all three germ layers. Thus, the iPSC technology solves many problems associated with the use of ESCs and provides an unlimited source of autologous pluripotent SCs, which can be genetically corrected, differentiated into adult lineages, and returned to the same patient as an autograft [10]. Significant advances have been achieved in recent years in improving the safety of the iPSC technology; thus, expanding the opportunities for its clinical application. However, despite the tremendous potential of iPSCs, extensive analyses of their safety and reliability are still required. This chapter discusses the current progress and prospects of using the iPSC technology in tissue replacement therapy and as a tool for studying human pathologies.
2. Reprograming of somatic cells into iPSC
The first attempts to derive pluripotent SCs from adult cells were stimulated by early experiments that demonstrated the feasibility of reprogramming adult frog somatic cell nuclei by the cytoplasm of an enucleated unfertilized frog oocyte [11]. Later findings showed that reprogramming of somatic cells back to the pluripotent state is possible by transferring somatic cell nuclei into oocytes or by fusing somatic cells with pluripotent SCs [12, 13, 14]. Finally, the successful cloning of Dolly the sheep showed the feasibility of complete reprogramming of a mammalian somatic nucleus back to a pluripotent state from which it can develop a new animal [15].
2.1 Main reprograming factors
The success of animal cloning has demonstrated that unfertilized eggs and ESCs contain a set of factors that can confer pluripotency to somatic cells. Oct4, Sox2, c-Myc, and Klf4 were later identified by Takahashi and Yamanaka as sufficient to induce pluripotency in mouse somatic cells, resulting in iPSCs that were functionally equivalent to mouse ESCs [1, 2].
OCT4 is a key transcriptional factor, which maintains pluripotency in both early embryos and ESCs [16]. The level of OCT4 expression is vital for regulating pluripotency and it can both activate or repress the promoter of the
The combination of OCT4, SOX2, KLF4, and c-MYC (abbreviated as OSKM), is widely used to reprogram various types of somatic cells into a pluripotent state. Under specific conditions, reprogramming can also be achieved without c-MYC or with only one or two factors from the OSKM set [23, 24, 25]. An alternative combination of OCT4, SOX2, NANOG, and LIN28 has also been shown to be sufficient to reprogram human cells into iPSCs [5]. Additional factors can be used in combination with OSKM to enhance reprogramming efficiencies, such as LIN28, human telomerase reverse transcriptase (hTERT), and SV40 large T antigen [26, 27, 28]. Regardless of their combination, reprogramming factors remodel the epigenetic configuration of somatic cells in a way that allows for the conversion of these mature somatic cells into immature pluripotent SCs. Mechanisms of reprogramming into iPSCs are reviewed in detail by Meir and Li [29].
2.2 Reprograming approaches
Early approaches to obtain iPSCs relied on the use of integrating retro- and lentiviral vectors to deliver reprogramming factors into somatic cells [1]. However, the expression of these exogenous factors is only essential in the initial step of reprogramming, and their silencing must occur to ensure the stability of iPSCs [2]. The use of retroviral vectors can not only result in the reactivation of exogenous reprogramming factors and in turn destabilization of iPSCs [2] but also increase the risk of insertional mutagenesis and cancer transformation in iPSC-derived tissues. The development of integration-free reprogramming approaches made the production of iPSCs safer for potential clinical applications. Somatic cells have been successfully reprogrammed into iPSCs using episomal plasmids encoding the reprogramming factors and adenoviral vectors [30, 31]. A number of other non-integrating vectors of viral origins have been utilized for reprogramming, such as those based on Sendai virus [32], Epstein–Barr virus [26], and various circular plasmid constructs [33, 34]. While these methods produce integration-free iPSCs, many of these approaches suffer from extremely low efficiency, which hampers their potential clinical application [35].
The generation of iPSCs has been recently accomplished with defined chemicals that can functionally replace reprogramming factors [36]. iPSCs can also be generated by fusing reprogramming factors with cell-penetrating proteins that allow for the efficient transport of reprogramming proteins through cell membrane [37]. Despite their safety, these DNA-free approaches also suffer from low reprogramming efficiency.
A more promising approach for the transgene-free generation of iPSCs can be the use of synthetic modified mRNAs encoding the reprogramming factors. This approach has been shown to reprogram a variety of cell lines with an efficiency superior to that of other integration-free approaches [38]. The disadvantage of this method is that RNAs have to be delivered into the cells daily during the reprogramming process. MicroRNA (miRNAs), such as miR-200c, miR-291-3p, miR-294, miR-295, and miR-302a-d, have also been shown to significantly enhance the efficiency of pluripotency induction [39]. When combined with modified mRNAs encoding reprogramming factors, miR-367 and miR-302a-d have been shown to increase the reprogramming efficiency of human primary fibroblasts to an unprecedented level, and reprogramming up to 90.7% of individually plated cells [40].
2.3 Reprogramming process
Different cell types have been used for the generation of iPSCs, albeit with different reprogramming efficiencies. Fibroblasts are the most commonly used cells due to their availability and easy culture conditions. Keratinocytes, melanocytes, blood cells, hepatocytes, and gastric epithelial cells are also suitable for reprogramming [41].
The reprogramming process has been extensively studied in fibroblasts and has been shown to follow an organized sequence of events, which begins with the downregulation of somatic gene expression [42]. The first step requires a phenotype transition initiated by the activation of the early pluripotency stage-specific embryonic antigen (SSEA1) and alkaline phosphatase, and the inactivation of the differentiation-related antigen Thy-1 (CD90), followed by the activation of
Reprogramming somatic cells often results in the generation of heterogeneous iPSCs with different molecular phenotypes and differentiation potentials [45]. The duration of the reprogramming process also affects the characteristics of the resulting iPSC. Prolonged cultivation of iPSCs yields phenotypes closer to those of ESCs as compared to cells in the early phase of reprogramming. This suggests that reprogramming continues even after iPSCs have been established [46]. Alterations in epigenetic modifications, such as DNA methylation, are also important for iPSC induction [47]. Interestingly, epigenetic profiling of iPSCs has revealed that reprogrammed cells retain epigenetic marks of the cell type of origin [48] although these marks disappear upon continued passaging [42].
3. Clinical applications of iPSCs
The rapid progress of the iPSC technology increases efforts to translate autologous iPSC-based therapies into the clinic. While only a few clinical trials have directly tested the delivery of iPSC-derived cells into patients, the technology continues to develop and researchers from virtually every field develop iPSC-based cell therapies for relevant diseases. These therapies are still at different stages of development and rely on the feasibility to derive functional somatic cell types from iPSCs. Examples of the efforts toward the development of iPSC-based therapies for a variety of tissues and organs are summarized for selected fields below.
3.1 Dermatology
The skin may represent an ideal tissue for testing novel iPSC-based therapies. It is readily accessible, highly proliferative, and can be easily monitored. Multiple skin cell lineages have been generated from iPSCs, such as keratinocytes [49], melanocytes [50], fibroblasts [51], and ectodermal precursor cells [52]. Mouse iPSC-derived keratinocytes display characteristics similar to those of primary keratinocytes and can regenerate differentiated epidermis and skin appendages when grafted together with mouse fibroblasts into athymic mice [49]. Human iPSC-derived keratinocytes have also been shown to establish functional organotypic skin in culture and 3D skin models [53]. These and other studies have demonstrated the potential of iPSCs to generate autologous donor cells for cell-based therapies for skin diseases.
As an essential step toward future clinical use,
Many of the most devastating forms of inherited skin diseases that are caused by known mutations, such as Epidermolysis Bullosa (EB), can be treated with genetically corrected iPSC-derived cells [54]. EB is a group of inherited skin blistering diseases that results in severe blistering and scarring [57]. Precise gene editing techniques, such as those based on CRISPR (clustered regularly interspaced short palindromic repeats)/CRISPR-associate (Cas) systems, can be used for the generation of these patient-specific genetically corrected iPSCs. These corrected iPSCs can then be differentiated into skin cells and transplanted back to the same patient in need of treatment. Similar strategies can be implemented for a variety of other diseases affecting many other organs (Figure 1). In fact, the generation of iPSCs, coupled with gene targeting, can solve many obstacles that are associated with gene correction in somatic cells. Unlike somatic cells, iPSCs can be expanded indefinitely, allowing for easier selection and expansion of corrected clones. In addition, iPSCs derived from very old patients can differentiate into “rejuvenated” cells [58].
Figure 1.
Cell therapy strategies using iPSC-derived cells. Patient-specific primary cells of different origin can be isolated, cultured
While currently there are no approved clinical trials to test iPSC-based therapies for the treatment of skin diseases, EB is likely to be the first skin disease to benefit from the iPSC-based therapy due to the severity of this disorder. For example, Anthony Oro’s team at Stanford University has received an award from the California Institute for Regenerative Medicine (CIRM) to translate an iPSC-based gene correction therapy for the severe recessive dystrophic form of EB into the clinic by producing transplantable epidermal sheets from genetically corrected EB iPSCs [59]. Dr. Oro’s team is currently generating data for an investigational new drug application (IND) with the Food and Drug Administration (FDA) to initiate a clinical trial.
3.2 Vascular therapy
Endothelial cells, pericytes, and vascular smooth muscle cells have been derived from animal and human iPSCs [60, 61]. iPSCs can also be directed into cord-blood endothelial colony-forming cells that can be used to derive highly proliferative blood vessel-forming cells applicable for the restoration of endothelial function in patients with vascular diseases [62].
Coronary artery disease continues to be the leading cause of death and morbidity around the world, with the existing therapy being not always efficient. Studies have shown that transplanted iPSCs can promote angiogenesis and effective tissue revascularization [63].
In diabetes, prolonged hyperglycemia causes aberrant angiogenesis in both micro- and macro-vessels, resulting in deficient functionality of endothelial progenitor cells and leading to decreased neovascularization. iPSC-derived endothelial cells have been widely explored as a model to study the mechanisms and novel treatments for endothelial dysfunction in type 1 and 2 diabetes and maturity-onset diabetes of the young (MODY) [64, 65].
iPSC-derived endothelial cells have also been used to study the mechanisms of macular degeneration and ischemic retinopathies [66, 67]. iPSC-derived spinal motor neurons and cerebral microvascular endothelial cells seeded into the spinal cord lead to vascular-neural interaction with specific maturation effects of endothelial cells on the neural tissue [68].
Vascular grafts have been successfully developed from iPSC-derived cells, recapitulating the cellular composition and orientation, as well as the anti-inflammatory properties, of functional blood vessels [69, 70].
Endothelial derived from iPSCs are yet to be evaluated in clinical trials. However, these cells are now successfully used for drug testing [71].
3.3 Cardiology
The recent advances in iPSC reprogramming into cardiomyocytes and other types of cardiac cells have provided potential avenues for cardiac repair, and functional cardiomyocytes have been successfully generated from iPSCs [72]. iPSC-derived cardiomyocyte-like cells demonstrate spontaneous contractility and exhibit molecular and structural similarities to cardiomyocytes.
Many studies have focused on testing iPSC-derived cells for post-myocardial infarction repair [73], which is one of the leading causes of morbidity and death throughout the world. In patients with extensive myocardial infarction, more than a billion cardiomyocytes can be lost, overwhelming the heart’s repair capacity. Such massive cell death in the myocardium initiates the replacement of cardiomyocytes with fibrous tissue, resulting in heart failure. Beating iPSC-derived cardiomyocytes have been generated from patients with hypertrophic cardiomyopathy associated with diastolic dysfunction to study the cellular mechanisms and potential therapeutic targets of diastolic dysfunction [74].
Patient-specific iPSC-derived cardiomyocytes have also been generated from patients with different types of diabetes and used for modeling and studying the molecular mechanisms underlying diabetic cardiomyopathies [75]. Human iPSC-derived cardiomyocytes, endothelial cells, and cardiac fibroblasts have been generated and integrated in beating 3D cardiac microtissues as a platform for cardiovascular disease modeling [76].
Human iPSC lines have also been generated from patient-derived cells to study ventricular and atrial arrhythmias, which often lead to sudden cardiac death [77].
A few clinical trials to test the efficacy of iPSC-derived cardiomyocytes have been initiated. For example, an Osaka University spin-off company, Cuorips, Inc. has recently initiated a clinical trial to determine the efficacy and safety of a human allogeneic iPSC-derived cardiomyocyte sheet for ischemic cardiomyopathy patients (NCT04696328). Heartseed, Inc. is currently testing iPSC-derived cardiomyocyte spheroids in patients with severe heart failure in Phase I/II study (NCT04945018). Since both studies are still ongoing, no results have been reported.
3.4 Skeletal muscle regeneration
Converting iPSCs into skeletal muscle cells can offer a tool for
Skeletal muscle satellite cells, which drive skeletal muscle regeneration, have been shown to play an important role in the early regeneration of damaged skeletal muscles in muscular dystrophies and have been generated from human iPSCs for the identification of new therapeutic targets for the treatment of these disorders [80]. 3D functional skeletal muscle tissues have also been successfully generated from human iPSC-derived skeletal myotubes with sarcomeric structures as an
Developing treatments for muscular dystrophy is a priority topic for researchers. Vita Therapeutics, Inc. has recently received an orphan drug designation from the FDA to initiate a clinical study that will test the efficacy of iPSC-derived myogenic stem cells to treat Duchenne muscular dystrophy [59]. More iPSC-based therapies for muscular dystrophies are currently in development [81].
3.5 Neurology
Several types of well-differentiated and functional populations of neural cells and neuronal multipotent progenitors have been generated from human and murine iPSCs. These progenitors have also been tested in cell replacement studies in rodent models with promising results [82]. Spinal neural progenitors have been differentiated from human iPSCs and together with human iPSC-derived brain microvascular endothelial cells were included in the dual-channel spinal cord chip system as an
iPSCs are becoming an important source for the development of personalized therapeutic and preclinical strategies for research focusing on neurodegeneration. Parkinson’s disease is one of the most common neurodegenerative disorders, resulting from the loss of dopamine neurons in substantia nigra. Cell replacement therapy, such as the transplantation of iPSC-derived neural progenitors, provides an alternative treatment strategy for Parkinson’s disease (PD) [85]. An ongoing clinical trial in Japan is testing iPSC-derived dopaminergic neurons for PD [86]. In 2018, midbrain dopaminergic progenitor cells derived from autologous iPSCs were successfully transplanted into the brain of a patient with PD, and clinical symptoms improved in this patient at 18 to 24 months after implantation [85]. Aspen Neuroscience is currently developing two iPSC-based therapies for PD: an autologous iPSC-derived dopaminergic neuron therapy for idiopathic PD and an autologous gene-corrected iPSC-derived dopaminergic neuron therapy for genetic PD [87]. These and other therapies currently in development provide hope in the treatment of many neurological conditions.
3.6 Hearing loss
Hearing loss is a common impairment in humans that mainly results from the irreversible loss of sensory hair cells and auditory neurons. Patient-specific iPSCs are a promising tool for the regeneration of sensory hair cells and spiral ganglion neurons of the affected cochlea. iPSCs can be successfully reprogrammed into otic epithelial progenitors and otic neuroprogenitors that can subsequently be differentiated into inner ear hair cells [88, 89]. Functional cochlear supporting cells that can be important therapeutic targets for the treatment of hereditary deafness have also been successfully generated from mouse iPSCs [90]. Human iPSC-derived neural progenitors have been shown to innervate early postnatal cochlear hair cells
Sensorineural hearing loss is a prevalent form of deafness, commonly arising from damage to the cochlear sensory hair cells and degeneration of the spiral ganglion neurons. iPSCs can serve as an autologous source of replacement neurons in an injured cochlea for the treatment of sensorineural hearing loss and as a model system to develop therapies to treat hereditary hearing loss [89]. While many iPSC-based treatment options are being developed in research settings, there are no approved clinical trials for hearing loss using iPSCs.
3.7 Ophthalmology
Transplantation of ocular cells derived from both autologous and allogeneic iPSCs in animal models and clinical trials showed great promise for cell-based therapies and disease modeling in ophthalmology. Using patient’s own cells and the ability to correct disease-related gene mutations in patient-derived iPSCs provided a powerful approach for the treatment of ophthalmologic diseases. Various ocular cells have been generated from iPSCs, including corneal epithelial progenitor cells capable of terminal differentiation toward mature corneal epithelial-like cells [92], conjunctival epithelial cells, and conjunctival goblet-like cells [93], retinal pigment epithelial cells [92], photoreceptors, and retinal ganglion cells among others [94]. Human iPSCs can, in an autonomous manner, recapitulate the main steps of retinal development and form 3D retinal cups containing all major retinal cell types arranged in layers via retinal progenitors [95].
iPSCs hold a promise for the treatment of various degenerative eye disorders by filling clinical gaps in the use of adult limbal SCs or ESCs [96]. iPSC-derived photoreceptor cells and retinal pigment epithelium cells provide a cell replacement therapy for visual impairment associated with inherited retinal degeneration and age-related degeneration of photoreceptors [97].
Similar to the skin, the eye may represent an ideal tissue for testing iPSC therapies: it is relatively easy to monitor and access. Unsurprisingly, retinal pigment epithelium (RPE) cells derived from iPSCs were the first autologous iPSC-derived cell type to be transplanted into a human patient [85]. These RPE cells were used to treat age-related macular degeneration (AMD), the leading cause of vision loss in the elderly. A 4-year follow-up demonstrated that the iPSC-derived RPE sheets transplanted into the right eye of a 77-year-old patient had survived post-engraftment. While no improvement in vision was noted, the patient’s vision remained stable, emphasizing the safety of the iPSC-based therapy to treat eye diseases [98]. Additional iPSC-based therapies are being assessed for the treatment of AMD in clinical trials in Japan [99] and in the United States by the team at the National Institute of Health (NCT04339764). The use of iPSC-derived photoreceptors to cure blindness is also being tested in preclinical research [59].
3.8 Bone and cartilage regeneration
While autologous bone grafting remains the main approach to reconstruct bone defects, the risk of bone resorption, infection, and insufficient amount of tissue available for transplantation is high. Therefore, iPSC technologies may provide a suitable alternative to grafting autologous bone/cartilage-forming cells. Functional osteoblasts, osteocytes, and chondrocytes have been generated from iPSCs [100, 101].
Human and animal iPSCs, as well as iPSC-derived mesenchymal stem/stromal cells (MSCs), have been differentiated into osteoblast- and osteocyte-like cells, which could be transplanted to achieve bone formation or regeneration of calvarial bone defects in
iPSCs also represent a potential source of viable chondroprogenitors for articular cartilage repair and engineering [104]. The regenerative potential of iPSCs is attractive for the therapy of intervertebral disc degeneration—a common cause of musculoskeletal diseases, such as low back pain, which is often attributed to a reduced number of nucleus pulposus cells that form the intervertebral disc. Current treatment strategies fail to replenish nucleus pulposus cells. The latter, however, have been successfully differentiated from iPSCs [105].
The development of iPSC-based therapies for bone and cartilage diseases is still ongoing. However, Australian Cynata Therapeutics has already tested allogeneic MSCs derived from iPSCs in a clinical trial for graft vs. host disease (GvHD) (NCT02923375). The infusion of these iPSC-derived MSCs was well tolerated by patients and promoted encouraging improvement in symptoms of GvHD [106]. Cynata therapeutics is also initiating a Phase III trial that will use iPSC-derived MSCs for the treatment of osteoarthritis [107].
3.9 Dentistry
Human iPSCs can potentially be a source to derive human odontoblasts for tissue engineering and regenerative therapy for the treatment of dental pulp damage [108]. The tooth is formed by sequential reciprocal interactions between epithelial cells originating from mesenchymal cells and surface ectoderm cells from cranial neural crest. iPSCs can be differentiated into neural crest-like cells, which in turn can be differentiated into odontogenic mesenchymal cells, odontoblast progenitors, and odontoblasts suitable for transplantation [109].
Periodontal disease is an important health problem that ultimately leads to tooth loss. An alternative to the existing artificially manufactured tooth replacements is the generation of complete or partial biological replacements, consisting of living periodontal tissues. Animal and human iPSCs and iPSC-derived MSCs transplanted to animals with a model of molar defects demonstrate periodontal tissue regeneration. Transplanted neural crest-like cells derived from iPSCs have also been shown to form a well-organized vascularized dentin-pulp complex and calcified tooth-like structures, demonstrating the feasibility for iPSCs use in dental tissue regeneration [108]. However, extensive research is still needed to advance the iPSC technology into dental applications.
3.10 Nephrology and urology
Renal failure is one of the most common causes of mortality and morbidity in the world. An iPSC-based cell therapy may offer an alternative therapeutic approach to kidney transplantation.
iPSCs have been successfully differentiated into nephrogenic intermediate mesoderm and renal progenitor cells [110, 111]. These cells pose the ability to differentiate into multiple cell types that constitute the adult kidney, such as metanephric mesenchyme cells, metanephric stromal cells, nephric duct, ureteric bud cells, proximal tubular cells, mature glomerular podocytes, and other types of cells capable of forming renal tubule-like structures [110]. iPSC-derived kidney organoids have been created containing multiple cell types and mimicking nephrogenesis that have a potential for regenerative medicine and personalized therapy [112]. iPSC-derived cells are also used to recellularize decellularized kidney scaffolds as an approach to bioengineering human replacement kidneys [113]. iPSCs generated from patients with specific kidney disorders have also been used in disease modeling [114]. The iPSC technology is now widely used to model kidney diseases and perform drug screening. However, no clinical trials have been approved to date.
3.11 Pulmonology
Lung transplantation remains the only treatment for many severe lung diseases. The use of iPSCs may be an effective strategy for developing patient-specific cells for lung cell therapy and lung tissue engineering as an alternative to whole-organ transplantation. iPSC-based models of lung diseases can also help to better understand lung pathologies and identify new therapeutic approaches.
Human alveolar and airway epithelial and basal cells have been successfully generated from iPSCs [115, 116]. Airway basal cells, in particular, can give rise to other airway lineages, such as secretory and ciliated cells, and can restore airway functionality [117].
Human iPSC-derived type II alveolar epithelial cells are capable of repopulating acellular lung matrices prepared from rat and human adult lungs, adhering and proliferating to form alveolar structures as a 3D lung tissue model of the distal lung regions [118]. Recently, scaffold-free structures for airway regeneration were also created using 3D bioprinting and a combination of human native chondrocytes, MSCs, and iPSC-derived endothelial cells [119].
Thus, significant progress has been achieved in deriving alveolar epithelial cells from iPSCs. However the complexity of lung tissue prevents rapid development and clinical translation of iPSC-based therapies for lung diseases.
3.12 Hepatology
Currently, liver transplants represent the only way to treat patients suffering from terminal liver failure. However, liver transplantation is associated with numerous problems, such as graft failure. As an alternative to the donor liver, human iPSCs may provide a promising source of hepatocytes for autologous cell therapy. iPSCs have been differentiated into hepatocytes [120]. Since the function of hepatocytes depends on their position in the liver globule, methods have been developed to generate iPSC-derived hepatocytes with zone-specific hepatic properties [121].
In addition to hepatocytes, the liver parenchyma also consists of many types of nonparenchymal cells, which are essential for maintaining hepatic metabolic activity and other functions. Human iPSC-derived hepatic progenitors have been differentiated into multiple liver cell types and produce functional liver models [122].
Hepatocyte transplantation is one of the most attractive approaches for the treatment of liver failure [124], and patient-specific iPSC-derived hepatic cells are expected to be used for patient-specific transplantations. The transplantation of hepatocyte-like cells differentiated from genetically corrected iPSCs has also been shown to ameliorate inherited liver diseases in a mouse model [125]. While iPSC-derived hepatocytes have not yet been translated into clinical trials, these cells are currently being used for screening drug hepatoxicity [126].
3.13 Gastroenterology
The gastrointestinal tract is one of the largest and most active systems, which not only breaks down and absorbs macromolecules from the lumen but also functions as an endocrine organ that regulates digestion and metabolism. The gastrointestinal system requires integrated neuronal, lymphatic, immune, and vascular tissues to function properly. The iPSC technology provides unique opportunities for modeling human diseases and novel therapeutic approaches in regenerative gastroenterology. Human iPSC-derived intestinal and gastric cells, as well as generated
iPSCs can be differentiated into various types of intestinal cells and can even form multicell type intestinal tissue [127]. Among other cell types, human iPSCs have been differentiated into gastric epithelial cells and acid-secreting parietal cells [128], mature exocrine pancreatic cells [129], as well as directed along the gastric endocrine cell fate path [127]. Human iPSCs can also be efficiently differentiated into neural crest SCs and various subtypes of mature enteric neurons [130]. Enterocytes derived from human iPSCs have been used as a model system for predicting the pharmacokinetics of the human intestine and drug absorption and metabolism [131, 132].
The developed cell culture protocols allow for the derivation of self-organizing multicellular intestinal organoids from iPSCs, which resemble
3.14 Metabolic disorders
Several major types of diabetes are caused by the destruction and decrease in the number of functional insulin-producing β-cells. Therefore, the generation of functional insulin-secreting pancreatic β-cells represents an important goal for the treatment of various types of diabetes. Functional insulin-secreting pancreatic β-cells have been successfully generated from healthy human iPSCs [135], providing an important cell source for personalized drug screening and cell transplantation therapy in diabetes. Human iPSC-derived β-cells exhibit many of the properties of functional pancreatic β-cells, such as expression of specific transcription factors and the presence of mature endocrine secretory granules [136].
Brown adipocytes are promising cell targets for the treatment of obesity and type 2 diabetes due to their ability to actively drain and oxidize circulating glucose and triglycerides, which can prevent hyperglycemia and hypertriglyceridemia. Because of the scarcity of brown adipocytes in adults, iPSCs may be an important potential source of these cells and their progenitors for transplantation. Human iPSCs have been successfully differentiated into adipocytes [137].
MODY is a monogenic autosomal dominant disease caused by a mutation in one of the specific genes. Various mutations in each of these genes affect pancreatic β-cells, resulting in their dysfunction and diabetes development. However, despite extensive research, the mechanism by which the mutant MODY gene results in monogenic diabetes is not yet clear [138]. iPSCs have been generated from patients with different types of MODY to establish a human-based model for studying the molecular manifestations and mechanisms of these diseases [139].
iPSCs harboring disease-specific gene mutations have also been generated from somatic cells of patients with a few types of lipodystrophy and other inherited metabolic disorders for studying the pathogenesis of these diseases [140, 141].
While iPSC-based therapies for metabolic diseases are still being developed, the progress achieved by Melton’s group in using human ESCs to derive functional allogeneic insulin-producing β-cells [142] has created a strong foundation for the use of iPSCs in treating type 1 diabetes. Vertex Pharmaceuticals, Inc. is currently testing the glucose-responsive allogeneic β-cells generated from human ESCs in combination with immunosuppressive therapy in Phase I clinical trial (NCT04786262). The preliminary results of this clinical trial show engraftment and functionality of implanted hESC-derived β-cells [143].
3.15 Gland regeneration
Hypofunction of salivary glands causes various life-disrupting effects. With no satisfactory therapy available, the therapeutic and regenerative potential of iPSCs has been explored for the treatment of salivary gland dysfunction [144].
Inflammatory and degenerative changes in the lacrimal gland often lead to the development of severe dry eye syndrome, a complex disease resulting in visual acuity disruption. Currently, only palliative treatments for this disease exist. iPSCs have been used for developing a therapy for lacrimal gland tissue injuries [145].
The thymus plays a significant role in the establishment of immunological self-tolerance and is required for the generation of T cell-mediated immunity. Thyroid progenitors, thymic epithelial cells, and thymic organoids derived from iPSCs can completely regenerate the thymus
The mammary gland is a primary target for carcinogenesis, and regenerative therapy for damaged mammary gland tissues is the best way to restore breast functions. iPSCs have been successfully reprogrammed into mammary SCs [147]. In addition, human mammary-like organoids have been produced from iPSCs. Such organoids have been shown to regenerate mammary glands upon transplantation [148]. To date, no clinical trials have been approved for the use of iPSCs in gland regeneration.
4. Conclusion
Despite tremendous progress achieved in the iPSC field, broad applications of iPSC-based therapies will take time to establish. Nevertheless, considerable advances have been made in deriving iPSCs from patients, differentiating them into tissues of interest, and using them as a platform for studying the mechanisms of diseases. The development of iPSC-based therapies is just emerging and only a limited number of clinical studies using the transplantation of iPSC-derived cells have been initiated to date. However, clinical studies related to the iPSC technology are not limited to the studies described above. Other studies worth mentioning include the successful use of autologous iPSC-derived platelets for the treatment of aplastic anemia [149] and the derivation of an off-the-shelf allogeneic chimeric antigen receptor (CAR) T-cell therapy targeting B-cell malignancies developed by Fate Therapeutics (NCT04629729). An iPSC-derived, off-the-shelf, CAR natural killer (NK) cell therapy is currently being tested in a Phase I clinic trial for refractory B-cell lymphoma (NCT 04245722) and is showing promising therapeutic efficacy [150]. Other studies have been reviewed by Kim et al. [99].
Even though iPSCs hold great potential in the field of regenerative medicine and personalized medicine, a number of challenges hinder the widespread clinical applications of these cells. These challenges include the safety of methodologies for the generation, gene correction, and differentiation of iPSCs and the high cost associated with the technology.
The first major challenge is reprogramming and gene correction methods that are known to introduce undesired genetic modifications into the patient genome. Other limitations include the heterogeneity of iPSC lines that impairs the consistency of differentiation during manufacturing of iPSC-based cell products. Establishing selection criteria for iPSC-derived cells, such as cell-specific markers, proliferation rate, lifespan, and genomic analyses, help minimize the variability of iPSC-derived cells. Just like ESCs, iPSCs are also predisposed to forming teratomas when undifferentiated. The available cell purification technologies often do not guarantee the complete eradication of undifferentiated iPSCs during manufacturing. Although many problems concerning the clinical applications of iPSCs still remain, iPSC-based therapies have a tremendous therapeutic potential for many diseases that are difficult to treat otherwise.
Acknowledgments
We are grateful for funding support from the National Institutes of Health (R21 AR074642 and U01AR075932). We also thank Epidermolysis Bullosa (EB) Research Partnership, the EB Medical Research Foundation, the Cure EB Charity, Dystrophic Epidermolysis Bullosa Research Association (DEBRA) International, and the Gates Frontiers Fund.
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