Diabetes mellitus, a disease with abnormally high level of blood glucose, can cause a wide range of chronic complications that affect almost every parts of the body. The major goal of diabetes treatments is to control elevated blood glucose without causing abnormally low levels of blood glucose. Despite islet transplantation provided endogenous insulin secretion in individuals with diabetes, the scarcity of cadaveric donors for pancreatic β-cell still remains a major obstacle. In this regard, the needs for an unlimited supply for cell replacement strategy have led to explore the way of generating insulin-producing cells to use in the disease treatment. Human embryonic stem cells (hESCs) offer a source to produce the desired kind of cell. Currently, several researchers achieved insulin-producing cells from hESCs using a multistep differentiation protocols, growth factors, and/or chemical compounds. In this review, we summarized the hESCs derivation, culture methods, and characteristics of hESCs. We also emphasized on the current methods for direct differentiation of hESCs into embryoid bodies (EBs) and toward insulin-producing cells, characterization of these insulin-producing cells, and the limitation of hESCs. Since the discovery of induced pluripotent stem cells (iPSCs), which have similar properties to hESCs but less ethical issues than hESCs, can be created directly from somatic cells that hold great promise as the therapeutic source for developing cell-based therapy. Herein, the methods to produce iPSC-derived insulin-producing cells are also discussed. Moreover, the encapsulation technology which is a powerful tool for accelerate hESCs and iPSCs applications in medicine which provide a new avenue for diabetes treatment in the future is also included in this review. Understanding the basic knowledge of hESCs and iPSCs, their differentiation capability toward insulin-producing cells will stimulate more therapeutic value of hESCs and iPSCs for diabetic treatments, drug screening, and regenerative medicine.
- diabetes mellitus
- human embryonic stem cells
- insulin-producing cells
- induced pluripotent stem cells
Diabetes mellitus is one of the most common chronic diseases that threaten the health and health economics worldwide [1–3]. The disease and cases management interventions improve short- and long-term health, and/or economic outcomes of patients are improving health and quality of their lives. General treatments include weight reduction, a diabetes diet, and exercise which are used to control diabetes [4, 5]. When these treatments fail to control the elevated blood glucose, oral medications and insulin injection therapy will be applied in the treatment strategy, respectively. Insulin therapy has the potential to improve symptoms, enhancing quality of life and provide a sense of well-being [6–8]. However, the intensive insulin treatment can cause hypoglycemia [9–11]. Therefore, transplantation of high effective insulin-producing cells containing physiological regulation of blood glucose level is critical choice of treatment. At present, there are three major cell-based therapy approaches to restore insulin-producing cells in diabetes patients: 1) direct transplantation of donor islet and pancreatic cells to patient 2) activation pancreatic progenitors residing in islet mass into insulin-producing cells (neogenesis) and transplantation, and 3) stem cell approach by differentiation pluripotent stem cells into insulin-secreted cells and then transplantation. The direct transplantation of islet cells and neogenesis methods have demonstrated normoglycemia in the absence of exogenous insulin therapy [12–14]. Nevertheless, the limitations of islet cell replacement are the following factors: non-functioning of isolated islets, the small number of transplanted islets, the immunogenicity of isolated islets lead to immune rejection, transplantation to inappropriate sites, recurrence of auto-immunity in the transplanted islets, and immunosuppression [15–18]. The third method, stem cell approach: Pluripotent stem cells including hESCs and iPSCs are the main targets for insulin-producing cell induction. These two sources of stem cells could provide limitless sources of cells for pancreatic β-cell replacement strategy. Therefore, these research areas have led researchers to explore the way of generating effective insulin-producing cells for diabetes treatment. In addition, the hESCs and iPSCs contain the higher differentiation capacity than adult stem cells [19–21].
Herein, we review the current knowledge of hESCs and iPSCs, followed by the directed differentiation of these cells toward the functional insulin-producing cells. In addition, the encapsulation technology, a powerful tool for accelerate hESCs and iPSCs applications in medicine, is also included in this review. We also summarize and discuss evidence that both hESCs and iPSCs are promising cell sources for future diabetes treatment.
2. Human embryonic stem cells
2.1. Derivation, culture, and characterization of hESCs
In the early era of hESCs research, the hESCs are isolated from the inner cell mass (ICM) of blastocyst-stage embryos by immunosurgery or mechanically methods. However, this process involves with animal-derived substances such as mouse antibodies and guinea pig complement [22, 23]. Alternatively, the use of Tyrode’s acid for the removal of zona pellucida and mechanical isolation of ICM can serve as a potentially useful method for the establishment of hESCs line in the present time. Indeed, this technique also implies that the blastocyst could not contact with animal-derived pronase, antibodies, and complement factors . The hESCs lines can be maintained in an undifferentiated or pluripotency state
There are several methods have been reported for culture of undifferentiated hESCs
Characterization of hESCs lines can be achieved by both cellular and molecular analysis. Cellular characterizations can be determined by (1) morphologies of hESCs colonies: form flat and compact colonies with distinct cell borders, (2) morphologies of hESCs have a high ratio of nucleus to cytoplasm and have prominent nucleoli, (3) the hESCs exhibit high levels of telomerase activity and show normal karyotype, (4) most of the cells can be subcultured after freezing, thawing, and replating, (5) the cells can be differentiated into a variety of cell types both
2.2. Differentiation of hESCs into embryoid bodies (EBs) and definitive endoderm (DE)
To differentiate hESCs into particular cell lineages
For the production of EBs, several methods have been designed. The first method: Methylcellulose (MC) method developed to form EB from single embryonic stem cell but has limitation to use EBs for medical application due to the contamination of methylcellulose. The second method, hanging drop (HD) method has been widely used to generate EBs, and further differentiate into a variety of cell types can be applied into other xenofree or chemically defined medium culture protocols that suitable for human therapeutic applications. However, it is a troublesome multiple steps methods. Moreover, it is hardly exchange that the medium for a drop and the observations of forming EBs in drops by direct microscopic is difficult . Therefore, the third method has been developed called suspension culture method—the obtained EBs tends to be more heterogeneous in size and shape because their self-organized aggregation in culture. The heterogeneity of EBs structures may influence cell fate differentiation [38, 39].
In fact, improvement of the definitive endoderm (DE) layer development will increase the successful rate of insulin-producing cell generation from pluripotent stem cells. Therefore, there are several factors have been used to activation of DE formation, for example, activin A, GDF8, Wnt3a, bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), inhibition of PI3K/Akt, and chemical inhibition of GSK3β . In addition, collagen type 1 could improve the differentiation of hESCs into definitive endoderm .
2.3. Differentiation of hESCs into insulin-producing cells
At present time, cell-based therapy for diabetes is mostly target to type I diabetes. It has been described that islet-like clusters derive hESCs differentiation can be achieved in multistep procedures (nestin-positive protocol): (i) formation of EBs (stage 1), (ii) selective differentiation of cell populations expressing nestin using fetal calf serum depletion and culture with ITSF (stage 2), (iii) proliferation and maintenance of precursor cells (stage 3), and (iv) the differentiation induction and maintenance of insulin-positive cells (stage 4). The resultant cells are positive for dithizone (DTZ), a zinc-chelating agent known to selectively stain pancreatic β-cells, and are immunoreactive for antibodies against insulin, glucagons, and C-peptide. Insulin and other pancreatic β-cell-related genes such as glucagon, somatostatin, KIR6.2 and SUR1, IAPP, Isl1, PC1/3, PC2, GK, Nkx6.1, GLUT2, and Pax4 are expressed in the differentiating cells. The results indicated that differentiated cells can express genes involved in the β-cell differentiation pathway .
Moreover, insulin-producing islet-like clusters (ILCs) are generated from hESCs according to the method (definitive endoderm-based protocols) developed by Jiang and colleagues  who culture hESC lines under feeder-free conditions and direct differentiation toward ILCs by using a multistep, serum-free protocol. The 36-day differentiation protocol consists of four stages which included definitive endoderm induction (stage 1), pancreatic endoderm formation (stage 2), endocrine induction (stage 3), and islet-like clusters maturation (stage 4). The hESCs generate definitive endoderm coexpressing CXCR4 and Sox17, and CXCR4 and Foxa2 when treated with sodium butyrate and activin A. The Pdx1-expressing pancreatic endoderm is then induced by the addition of bFGF, EGF, noggin, and B27 supplement. Following withdrawal of bFGF, these cells are allowed to develop pancreatic endocrine cells. Gene expression analysis shows that pancreatic endoderm cells also start to express other pancreas-related genes such as HlxB9, Ptf1a, Ngn3, and Nkx6.1. Upon further differentiation of Pdx1-positive cell clusters to day 36, immunocytochemical-staining data demonstrated that the C-peptide-, glucagon-, and somatostatin-positive cells were predominantly localized in the small bud-like clusters as well as in some of the smaller ILCs. In addition, the ILCs generated by this protocol are able to secrete C-peptide in response to 20 mM glucose .
Based on the differentiation protocol, the nestin-positive progenitor-based and definitive endoderm-based protocols are successful in generating insulin-producing cells from hESCs. However, there is still some debate on the therapeutic potential between the cells obtained from these two protocols. Therefore, other approaches are developed. Bruin and colleagues implemented an approach in which hESCs were differentiated into fetal-like pancreatic cells
The strategies for differentiation of hESCs into insulin-producing cells also have been demonstrated by many research groups. They demonstrated that the insulin-producing cells are expressed the markers associated with pancreatic β-cell differentiation pathway, able to produce and secrete insulin in response to glucose concentration [42, 45–49]. The spontaneous differentiation of insulin-producing cells can also be observed with undifferentiated hESCs colonies when hESCs are propagated on a feeder layer of MEFs . It has been demonstrated that
Recently, it has been shown that maturation of stem cell into beta-cells can be driven by the expression of peptide hormone called urocortin 3 which also served as islet cell maturation marker . In addition, the scalable differentiation protocol also able to generate several millions of glucose-responsive β-cells from hESCs . Interestingly, it has been revealed that acceleration of Cdk4-cyclin D complex in the cell cycle of hESCs also play a potential key role in cell fate decision of hESCs differentiation into insulin-producing cell .
Although several authors achieved to demonstrate the rapid progress for possible treatment of diabetes using insulin-producing cells generated from hESCs, there are some crucial aspects need to be concerned. Based on this regard, the culture should be performed in xeno-free system in order to further develop potential medical applications. Moreover, the contamination of undifferentiated hESCs in the culture of insulin-producing cell induction needs to be removed before it can be applied for therapeutic purposes to eliminate the teratoma formation. The immune rejection aspect is also need to be assessed. For examples, during differentiation stage, the major histocompatibility complex (MHC) is up-regulated, leading to the non-self-proteins expression on the graft cells which may result in immune rejection of the graft in the absence of immunosuppressive therapy . In addition, the expression of high level of telomerase activity can lead to teratoma formation after injection which should be noted . Furthermore, prolonged growth of hESCs and differentiation of these cells into any stages of beta-cells development
2.4. Transplantation of hESC-derived insulin-producing cells
In order to gain insights into the human condition, the function of hESC-derived insulin-producing cells should be achieved
3. Induced pluripotent stem cells
3.1. The generation of iPSCs
The induced pluripotent stem cells (iPSCs) also provided an alternative approach to produce autologous cell-based therapy (Figure 2). The iPSCs have been shown the properties similar to hESCs including morphology, self-renewal capacity, gene expression profiles, and retained a normal karyotype. The differentiation potential of these cells would allow researchers to study disease mechanisms, drug screening and provide another autologous cell sources for transplantation [59–61].
Based on the knowledge of transcriptional regulators that maintain the stem cell state, researchers have been developed a technique that can be reprogrammed adult cells into pluripotent stage. In 2006, Takahashi and Yamanaka discovered that the introduction of four transcription factors (Oct4, Sox2, c-Myc, and Klf4) could induce pluripotency in mouse embryonic or adult fibroblasts. These iPSCs exhibited the morphology and growth properties of ESCs and expressed ESC marker genes. The resultant cells resulted in tumors containing a variety of tissues from all three germ layers when transplantation into nude mice. Consequently, Yu and colleagues designed a reprogramming strategy in which a set of four factors (Oct4, Sox2, Nanog, and Lin28) were sufficient to induce pluripotency in human somatic cells. These cells displayed normal karyotypes, expressed telomerase activity, expressed the hESC surface markers/genes, and maintained the developmental potential to differentiate into advanced derivatives of all three primary germ layers . Additionally, it has been found that the miR-302 family is specifically expressed in undifferentiated ESCs. The miR-302 has a role in regulating ESC pluripotency and differentiation [63, 64]. Also, several studies have demonstrated that miR-302 can directly reprogram somatic cells. Lin et al. reported that miR-302 inhibits stem cell tumorigenicity by enhancing G1 phase arrests pathway . This evidence suggests that the miR-302-reprogrammed iPSCs may provide the potential applications of iPSC technology.
The approach to reprogram somatic cells involved the use of genome-integrating retroviruses to transfer transcription factors. However, the usage of integrating retroviral vector has major limitation due to the potential risk relating to tumor formation. Thus, researchers have also used the different strategies with non-integrating system that provided the solution to make it clinically applicable . Although the reprogramming efficiencies with non-integrating method are lower (~0.001%) than those achieved with integrating method (0.1–1%), this method increases the safety of generating and using iPSCs . Alternative methods have been developed to avoid genetic modification as the reprogramming proteins, or mRNA was delivered directly into the cells. This has been successfully demonstrated that high reprogramming efficiencies, however, can be more complicated to perform .
Interestingly, iPSCs technology has been possible to create disease-specific cells from individual patients that could be analyzed the disease pathology, provided treatment methods and drug development . In addition, it has been documented that iPSCs can be generated into the desired cell types, which hold great promise for treating many diseases. There have been reported in iPSC-derived cells in clinical applications in several types of disease including neurological, immune system, endocrinology/metabolism, muscle skeletal, genetic, hematological, and inherited liver disease .
3.2. Differentiation of iPSCs into insulin-producing cells and transplantation
The achievement of hESCs differentiation into insulin-producing cells has raised up the possibility of generation of iPSCs-derived insulin-secreted cells by adopted the same protocols that have been used in hESCs works into iPSCs studies with or without modification the protocols. Recently, researchers have also been differentiated iPSCs into functional insulin-producing cells
These findings suggested that iPSC-derived insulin-producing cells will provide a potential therapeutic source for treating diabetes. It should be noted that iPSC technology is a possible alternative to induce patient-derived iPSCs for autologous cell transplantation therapy.
3.3. The limitations of hESCs and iPS cells
The potential application of hESCs has been extensively studied due to their high differentiation capacity. However, the use of hESCs to generate functional cells raises the problems associated with technical limitations and ethical issues. These limitations including
(1) the ethical controversies associated with the use of fresh human embryos, (2) developing xenogeneic products-free culture systems both for culturing hESCs and insulin-producing cell differentiation, (3) teratoma formation has become a critical obstacle for the therapeutic applications of hESCs, and (4) destruction of transplanted cells
The ethical controversies represent another issue associated the use of fresh human embryos. There is concern about guidelines on the use of fresh embryos as a source of new hESC lines. In this regard, induced pluripotent stem cells (iPSCs) technology provides a solution to the ethical debate surrounding hESCs since it does not require both the destruction of an embryo and the use of human oocytes .
It is generally believed that highly purified progenitors or terminally differentiated cell types derived from hESCs results in prevention of teratoma formation . While subpopulations of hESCs have been characterized by the expression of distinct surface markers, their fates have provided a valuable tool for generating tissue-specific reagents for cell-based therapy . Moreover, the combined gene transfer/hESCs therapies can generate a pure population of genetically modified differentiated cells with the selection using lineage-specific markers . Furthermore, the encapsulation procedure has the potential to prevent the formation of tumors .
The possible destruction of transplanted hESCs derivatives by the patient’s immune system should also be considered before the transplantation of these cells. Some solutions to prevent the rejection of hESC-derived cells are the use of hematopoietic chimerism for tolerance induction and the creation of universal donor cell line [79, 80] and encapsulation technology .
The great promise of iPSCs is based on their properties of self-renewal capacity and differentiation into specialized cell types. In addition, the possibility to obtain patient-specific or disease-specific pluripotent stem cells is a promising approach for medical applications. Moreover, iPSCs are not associated with ethical issues as hESCs regarding the use of human oocytes or embryos in research. However, there are still some limitations including inadequate cell number, immune rejection, and teratoma formation upon transplantation.
3.4. Encapsulation technology: a power tool for hESCs and iPS cells applications
In the context of therapeutic applications, the encapsulation technology represents a powerful tool toward the implementation of hESCs and iPSCs in clinical and industrial applications. Generally, there are two types of encapsulation technologies available at the present time including microencapsulation and macroencapsulation. Microencapsulation technology aims to generate a small size semipermeable bag which popularly made of hydrogel polymers to cover small group of cells. On the other hand, macroencapsulation technology has been used to generate semipermeable membrane and hydrogel sheets to hold large scale cell quantity. In the aspect of oxygen diffusion into the encapsulated environment, the microencapsulated sphere allows higher oxygen diffusion capacity than macroencapsulated sphere.
In stem cell research, the encapsulated hESC results in high expansion ratio and high cell recovery yields after cryopreservation. This method also improves the culture of hESC aggregates by protecting cells from hydrodynamic shear stress, controlling aggregate size, and maintaining cell pluripotency . It has been demonstrated that hESCs encapsulated in alginate hydrogels maintain the undifferentiated state and retain their pluripotent capabilities without any enzymatic treatment, mechanical expansion, or manipulation in a feeder-free environment. This approach is well-suited for providing automated culture scale-up process and the opportunity of long-term culture, feeder-free, and non-labor-intensive culture of hESCs .
Alginate encapsulation systems have been shown to support the ability of ES cells to differentiate into specific cell types. The researchers use an alginate encapsulation process for the proliferation and growth of mESC aggregates, which further supports the differentiation of insulin-positive cells from mESCs . In addition, the other group demonstrates 3D model to culture and differentiate hESCs that are encapsulated in calcium alginate microcapsules. This system promotes cellular interactions that are essential for both maintaining pluripotency and differentiation. In addition, encapsulated hESCs are separated from feeder cells during the process of differentiation, which mimics
Cell encapsulation has been proposed to be a solution for treatment of diabetes since it potentially allows the cell protection from host immune system by a concept of immunoisolation. In particular, the microcapsules of islets provide a delicate balance of characteristics including physical strength, immunocompatibility, and selective permeability that will block large immune components. Additionally, its membrane allows the passage of smaller molecules such as oxygen, glucose, water, and insulin . In addition, encapsulated islets in a biocompatible alginates have protected the islets against immune rejection, which is confirmed by prolonged survival of encapsulated islet allografts up to 200 days . Furthermore, Schneider et al.  have developed a microcapsule system that protects adult rat and human islets against xenogeneic rejection in immunocompetent diabetic mice without immunosuppression.
3.5. Mechanism of insulin secretion by glucose stimulation
Glucose in the blood is the strong stimulator for the insulin secretion from the islets pancreatic beta cells. Besides glucose, amino acids, ketones, some nutrients, gastrointestinal peptides, and neurotransmitters can also influences the insulin secretion from the beta cells. The glucose-regulated insulin secretion is the complex process and involved several key proteins. Normally, the blood glucose level of more than 70 mg/dl (3.9 mmol/L) enhances insulin production by promoting protein translation and processing. This stimulatory process starts with the binding of glucose to the GLUT2 glucose transporter on the cell membrane of the beta cells. The cytoplasmic glucose is subjected to metabolic process by the action of glucokinase to produce glucose-6-phosphate, which is the rate-limiting step of insulin secretory pathway. Further glycolysis of glucose-6-phosphate finally produces ATP, which is the key molecule for inhibition of the ATP-sensitive K+ channel protein on the beta cell membrane. The inhibition of ATP-sensitive K+ channel protein results in beta cell membrane depolarization. This depolarization of the cell membrane induces the opening of voltage-dependent calcium channels with subsequently influx of calcium. High level of cytoplasmic calcium will drive the secretion of insulin from the secretory granules. Insulin secretory profile shows pulsatile pattern of insulin release, with small bursts occurring about every 10 min. Superimposed upon greater amplitude oscillations of about 80–150 min. This glucose-induced insulin secretion can be enhanced by incretins, released from the neuroendocrine cells of the gastrointestinal tract following food ingestion (Figure 3) [89, 90]. However, the mechanism of secretion of insulin with regard to the concentration of glucose from insulin-producing cells derived from hESCs and iPSCs remains unclear.
To date, the researchers have discovered a process that can generate insulin-producing cells from both hESCs and iPSCs. The step toward generating the insulin-producing cells required a differentiation protocol in a manner that mimics differentiation
However, current prospects for hESC- and iPSCs-based therapy for diabetes treatment still be requires to investigated further more in early phase and subsequent trials in animal models to generate more safety and effective treatment prior to apply to human therapy.
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