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Diabetes is a common life-long condition and the number of children being diagnosed with type 1 diabetes is increasing. We've worked with scientists and doctors to answer some of your most frequently asked questions about stem cell science and potential therapies.
If yes, then why don't you try other treatments to help control your blood glucose levels - apart from medical treatment? According to the American Diabetic Association, there are four types of suitable physical activities for diabetes. Activities that do not require very high amounts of strenuous activity, is actually good for patients such as walking, jogging, using the stairs, and moving around throughout the day. Strength training has the potential to strength your bones together along with your muscles. Stretching exercises are a kind of gentle exercises that most people use for a warm up prior to starting harder exercises and as a way to cool down after as well. In this 2005 segment, NOVA scienceNOW explores the promise and potential of the emerging field of stem cell research, as well as the maelstrom of emotion and politics that engulfs it. Three separate teams overcome a biomedical hurdle: creating stem cells without the use of human embryos.
A fraudulent South Korean researcher is unmasked, and scientists find a new technique for easing ethical concerns.
Microphotographs show step-by-step how scientists create a cloned mouse embryo to generate embryonic stem cells.
Unfertilized egg cells that spontaneously develop into blastocysts offer an approach to stem cell research. National corporate funding for NOVA is provided by Google and Cancer Treatment Centers of America. Surrounding the arteries and veins of the cord is a gelatinous connective tissue called Whartona€™s Jelly. Benefits of banking the cord tissue, while prevalent now, will be overwhelmingly prominent in the future with more treatments and trials coming every day.
When banking cord tissue, many parents will also choose to bank the cord blood for additional stem cells.
Stem Cells from Cord Blood have been used in the treatment of nearly 80 life-threatening diseases. Freezing stem cells provides a form of "Life Insurance" for your child and your extended family.
Science, Technology and Medicine open access publisher.Publish, read and share novel research. Induced Pluripotent Stem Cells: Therapeutic Applications in Monogenic and Metabolic Diseases, and Regulatory and Bioethical ConsiderationsAntonio Liras1, 2, Cristina Segovia1 and Aline S. In February 2004, South Korean scientists create a worldwide media sensation by announcing that they have successfully isolated stem cells from a cloned human embryo. Cord Blood has been successfully preserved and used for two decades, saving many lives from cancers, leukemia, immune disorders and other serious diseases. Generation of human induced pluripotent stem cells for use in cell therapy, in vitro human pathology modelling and in drug discovery. Induced pluripotent stem cells application to the treatment of haemophilia and diabetes mellitus. Gaban1, 3[1] Department of Physiology, School of Biology, Complutense University of Madrid, and Cell Therapy and Regenerative Medicine Unit, La Paz University Hospital Health Research Institute-IdiPAZ. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.
Strategies and new developments in the generation of patient-specific pluripotent stem cells. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. For many, diabetes means living with daily insulin injections and the possibility of long-term damage to their health. You can start from a few simple minutes a day and increase that time to until about 30 minutes a day! Stem cell extracts can potentially replace your damaged cells that were caused by diabetes. NOVA goes inside the Harvard labs of Doug Melton and his colleagues, who are trying to replicate the South Korean experiment. Autologous transplantation of healthy differentiated cells, obtained from iPSCs, into an animal model with haemophilia or diabetes mellitus type 1, normalizes the corresponding altered function by in vivo production of the deficient protein or hormone.5.
Insulin is made by cells in the pancreas called beta cells that are arranged into clusters together with other pancreas cells. As a result, your body can develop newer and healthier cells so that they can function better. IntroductionThe potential use of stem cells in advanced therapies such as tissue engineering, regenerative medicine, cell therapy and gene therapy by virtue of their significant therapeutic potential and clinical applications has aroused keen interest among scientists [1,2].
Cell therapy is based on the transplantation of living cells into an organism with a view to repairing tissue or restoring a lost or deficient function.
Insulin is needed for the uptake of glucose by cells (for example, muscle cells) so that it can be used as energy.There are several types of diabetes. Stem cells are the most frequently used cells for such purposes given their ability to differentiate into other more specialized cells [3]. The chief defining feature of stem cells is their capacity for self-renewal and their ability to differentiate into cells of various lineages.
They can be found in virtually any kind of tissue including bone marrow, trabecular bone, periosteum, synovium, muscle, adipose tissue, breast gland, gastrointestinal tract, central nervous system, lung, peripheral blood, dermis, hair follicle, corneal limbus, etc.
Although Type 2 diabetes can often be at least partially controlled by a healthy diet and regular exercise, Type 1 diabetes cannot. People with Type 1 diabetes must test their blood sugar levels several times a day and administer insulin when it is needed (through injections or a pump). The clinical application of this type of cell is associated with potentially better prospects than that of embryonic stem cells since use of adult stem cells does not raise any ethical conflicts nor does it involve immune rejection problems in the event of autologous implantation. The possibility to generate induced pluripotent stem cells (iPSCs) by reprogramming somatic stem cells through the introduction of certain transcription factors [7-12] is radically transforming received scientific wisdom. Over time, high blood sugar levels can cause serious damage to the heart, eyes, blood vessels, kidneys and nerves, whilst injecting too much insulin can lead to a blood sugar level that is too low (hypoglycaemia) which can be fatal.It is possible to treat Type 1 diabetes by transplanting isolated islet cells, containing beta cells or even a whole pancreas into the patient from a donor. The pluripotency of these cells, which enables them to differentiate into cells of all three germ layers (endoderm, mesoderm, and ectoderm), makes them an extremely valuable tool for the potential design of cell therapy protocols. Transplants can enable the body to regain control of blood sugar levels so that administrating insulin is no longer needed. Furthermore, unlike embryonic stem cells, iPSCs are not associated with bioethical problems and are considered a "consensus" alternative that does not require use of human oocytes or embryos and is therefore not subject to any specific regulations. The immune suppressing drugs leave the recipient vulnerable to infection and often have side-effects. Today only a limited number of type 1 diabetic patients are suited for transplantation due to these side effects.Even with immune suppressing drugs the transplant is eventually destroyed by the immune system and further transplants are needed. Researchers have also looked into the application of iPSCs to toxigological and pharmacological screening for the presence of toxic and teratogenic substances [20].Stem cell therapy is emerging as a new concept of medical application in pharmacology.
As the immune system has developed to destroy these types of cells from the first transplant, it recognises foreign cells more quickly and easily.
For all practical purposes, human embryonic stem cells are used in 13% of treatments, whereas fetal stem cells are used in 2%, umbilical cord stem cells in 10%, and adult stem cells in 75% of cases. The most significant treatment indications for gene and cell therapy have so far been cardiovascular and ischemic diseases, diabetes, hematopoietic diseases, liver diseases and, more recently, orthopaedics [21]. On the right glucagon is highlighted in purple, produced from alpha cells.How could stem cells help?There are currently no proven treatments for diabetes using stem cells.
For example, over 25,000 transplants of hematopoietic stem cells are performed every year for treatment of lymphoma, leukemia, immunodeficiency disorders, congenital metabolic defects, hemoglobinopathies, and myelodysplastic and myeloproliferative syndromes [22].Each type of stem cell has its own advantages and disadvantages, which vary depending on the different treatment protocols and the requirements of each clinical condition. Thus, embryonic stem cells have the advantages of being pluripotent, easy to isolate and highly productive in culture, in addition to showing a high capacity to integrate into fetal tissue during development. By contrast, their disadvantages include immune rejection and the possibility that they may spontaneously and uncontrollably differentiate into inadequate cell types or even induce tumors.
Researchers have recently succeeded in producing cells from human pluripotent stem cells that respond to glucose in a similar way to normal beta cells both in the laboratory and in diabetic mice after being transplanted. Adult stem cells have a high differentiation potential, are less likely to induce an undesirable immune response and may be stimulated by drugs. Their disadvantages include that they are scarce and difficult to harvest, grown slowly, differentiate poorly in culture and are difficult to handle and produce in adequate amounts for transplantation. It is not known whether stem cells exist in the pancreas but beta cell progenitors have been found.
In addition, they behave differently depending on the source tissue, show telomere shortening, and may carry the genetic abnormalities inherited or acquired by the donor. Researchers hope they may be able to find drugs that can activate the progenitor cells in the body of a diabetes patient, or reprogramme other mature pancreas cells to produce more beta cells. Reprogramming other cells, for example, skin cells or liver cells, to make beta cells in the lab is also a possibility.
The first one is stimulation of endogenous stem cells by growth factors, cytokines, and second messengers, which must be able to induce tissue self-repair.
The second alternative is direct administration of the cells so that they differentiate at the damaged or non-functional tissue sites. The third possibility is transplantation of cells, tissues, or organs taken from cultures of stem cell-derived differentiated cells.
The US Food and Drug Administration defines somatic cell therapy as the administration to humans of autologous, allogeneic or xenogeneic living non-germline cells, other than transfusion blood products, which have been manipulated, processed, propagated or expanded ex vivo, or are drug-treated.
The most significant applications of cell therapy as a whole are expected to be related to the treatment of organ-specific conditions such as diabetes —a typically metabolic disease—, liver and cardiovascular conditions, immunological disorders and hereditary monogenic diseases such as haemophilia. Progenitor cells are being placed in a credit card-like case and transplanted into the body. As one of the key advanced therapies —together with gene therapy and tissue engineering— cell therapy will require a new legal framework that affords generalized patient accessibility to these products and that allows governments to discharge their regulatory and control duties. The hope is that similar to in mice the progenitor cells will spontaneously mature into insulin producing cells in the body, with the case allowing for the dispersal of insulin whilst preventing the immune system from attacking the cells.


In this respect, the main advantage of iPSCs lies in the fact that their use does not raise bioethical questions, which means that regulatory provisions governing their use need not be overly stringent.
Induced pluripotent stem cells technology and general clinical applicationsiPSCs are obtained through the reprogramming of an individual's somatic stem cells by the introduction of certain transcription factors.
Their chief value is based on their pluripotency to differentiate into cells of all three germ layers, which makes them an useful tool for the discovery of new drugs and the establishment of cell therapy programs. Moreover, unlike embryonic stem cells, they are not associated with any ethical controversies and therefore regulatory conditions governing their use are much less stringent. Induced pluripotent stem cells were generated for the first time by Shinya Yamanaka's team [8] from murine and human fibroblasts by transfecting certain transcription factors (Oct4, Sox2, c-Myc, and Klf4) by means of retroviral vectors. Nonetheless, it was later reported that only two transcription factors (Oct4 and Klf4) are needed for generating the iPSCs from neural stem cells that endogenously express high Sox2 concentrations [24].All of these strategies require transfection through retroviral vectors and integration for in vitro and in vivo modeling, which precludes their clinical use because of the potential risks involved.
This is the reason why several research teams have looked into the reprogramming of cells using plasmid vector rather than viral vector transfection [10-12]. Although reprogramming efficacy with plasmid vectors is lower ?as is also the case with non viral gene therapy? this method significantly increases the safety of the procedure, which makes it clinically applicable and also constitutes a source of valuable cell material that can be used for research into reprogramming and pluripotency.Another promising strategy consists in the direct release of reprogramming proteins through modified versions of reprogramming factors in some of their molecular domains. These protein-induced pluripotent stem cells (piPSCs) bind to the membrane of cells reaching their nucleus [25]. On the one hand, this reduces the risk of immune rejection in autologous transplantations by virtue of gene identity. On the other, it provides treatment that is customized to the specific characteristics of each patient and takes into account the etiology and severity of the condition. Moreover, induction of pluripotency has been developed for a great variety of tissue types [9,24,27] as it is a relatively straightforward procedure and —as mentioned above— subject to fewer regulatory constraints [28].Important as these advantages are, there are still a few uncertainties that need to be resolved.
One of the most pressing ones is related to determining the likelihood that these iPSCs may undergo genetic aberrations further to the reprogramming process [29]. In order for the clinical application of these cells to become a reality both for diagnostic purposes and for the design of cell therapy protocols, a few methodological hurdles must still be resolved in connection, as is often the case with pharmacological products, with their safety profile [30].
This means basically that efforts must be directed at removing the genome in the integrating viral vectors, eliminating the risk of tumor formation and establishing more efficient reprogramming and differentiation protocols.
Clearly our knowledge on the reprogramming mechanisms leading to pluripotency are still insufficient to understand and more importantly control the adverse events that could potentially occur.
Therefore the most important goal for research in this field will be to study genetic modifications in animal models by means of large-scale genome sequencing programs. This task will require sharing cell lines with other researchers, with appropriate confidentiality protections and, eventually, patenting scientific discoveries and developing commercial tests and therapies. It will also be necessary to fully ascertain and confirm that pluripotency confers iPSCs with functions similar to those of embryonic stem cells regardless of the initial source of somatic cells used [14,15].Undoubtedly, the most attractive application of this type of strategy is the production of patient-specific or healthy individual-specific iPSCs for replacement of damaged non-functional tissue. Thus for example skin fibroblast-derived iPSCs have been shown to possess a high potential to differentiate into islet-like clusters and to release insulin, which is highly relevant for diabetes [16].
In fact, since they were discovered in 2008, almost one-hundred-and-fifty iPSCs have been established from nearly thirty fibroblast cell lines related to over a dozen conditions, including some complex diseases such as schizophrenia and autism and other genetic or acquired disorders such as cardiovascular or infectious diseases. However, it is still necessary to optimize iPSC protocols, particularly with respect to the possible modifications to their genome, and to increase the efficacy of the transfection process leading to iPSC reprogramming [36,37]. Advanced therapies for monogenic and metabolic diseasesThe progression of the different areas of biology, biotechnology and medicine leads to the development of highly innovative new treatments and pharmacological products.
The different schools of thought that advocate the emerging concept of advanced therapies agree that the latter must be used for the treatment of diseases (both hereditary and non-transmissible) caused by the anomalous behavior, or complete lack of function, of a single gene (also called monogenic hereditary diseases) or by an anomaly in several genes (polygenic diseases).
Metabolic diseases, or congenital metabolic errors, are conditions highly amenable to be treated by the new advanced therapies as such treatments have been shown to restore mutation-induced alterations of gene products. Proteins are the most commonly affected gene products, although messenger RNA is also a usual victim.
Of particular interest are the proteins that participate in homeostasis and exert their functions outside the cells that synthesize them.
This is the case of coagulation factors VIII and IX (FVIII and FIX), whose deficiency results in the development of haemophilia A or B, respectively. Another member of this class of proteins is antitrypsin, also of hepatic origin and secreted into the bloodstream, whose function is to prevent the digestion of pulmonary alveoli by proteolytic enzymes. Lastly, mention should be made of proteins with such diverse functions as transcription factors, oncogenes, tumor-suppressing genes and even some hormones and their receptors, the latter being specifically related with diabetes mellitus, a typically metabolic disease.The nature of the monogenic or metabolic disease is the main factor that determines whether a treatment that can eradicate or at least mitigate its clinical consequences is possible or not. In this context, induced pluripotent stem cells can play a very significant role and hold an enormous therapeutic potential in the fields of cell therapy and tissue engineering.4.
Advanced therapies and induced pluripotent stem cells in the treatment of haemophiliaHaemophilia is a recessive X-linked hereditary disorder caused by a deficiency of coagulation factor VIII (haemophilia A) or IX (haemophilia B). The disease is considered to be severe when factor levels are below 1% of normal values, moderate when they are between 1 and 5% and mild when levels range between 5% and 40%. Haemophilia A is four times more common than haemophilia B and, in terms of severity for both types, 35% of patients have the severe form, 15% the moderate form and 55% have mild haemophilia. The clinical characteristics of both types of haemophilia are very similar: spontaneous or traumatic hemorrhages, muscle hematomas, haemophilic arthropathy resulting from the articular damage caused by repetitive bleeding episodes in the target joints, or hemorrhages in the central nervous system. In the absence of appropriate replacement treatment with exogenous coagulation factors, these manifestations of the disease can have disabling or even fatal consequences thus negatively impacting patients' quality of life and reducing their life expectancy [39].At present, patients with haemophilia benefit from optimized treatment schedules based on the intravenous systemic delivery of exogenous coagulation factors, either prophylactically or on demand. The current policy in developed countries is in general to administer a prophylactic treatment (2 or 3 times a week) from early childhood into adulthood [39]. Such prophylactic protocols result in a clear improvement in patients' quality of life on account of the prevention of haemophilic arthropaty and other fatal manifestations of the disease as well as a reduction in the long-term costs of treatment because of a decrease in the need of surgical procedures such as arthrodesis, arthroplasty or synovectomy [40].Conventional treatment of haemophilia [41,42] is currently based on the use of plasma-derived or recombinant high-purity coagulation factor concentrates. The former are duly treated with heat and detergent to inactivate lipid-coated viruses [43], and the latter are a recently developed product that does not contain proteins of human or animal origin [44,45].
Both kinds of factor boast high efficacy and safety profiles, at least for the inactivation-susceptible pathogens known to date. The choice of one product over the other is usually based on the clinical characteristics of the patient and on cost and availability considerations [46,47].Now that infections by pathogenic viruses (HIV, HCV) that were common a few decades ago have been eradicated, the most distressing adverse effect observed when using either product is the development of antibodies (inhibitors) against the perfused exogenous factors [48,49].
The appearance of inhibitors renders current treatment with factor concentrates inefficient, increasing morbidity and mortality, leading to the early onset of haemophilic arthropathy and disability and to a consequent reduction in patients' quality of life. Lastly, inhibitors result in higher costs as treatment must be provided both for bleeding episodes and inhibitor eradication (immune tolerance induction). They are directed at certain regions in the factor molecule that interact with other components of the coagulation cascade and, depending on their titre level and on whether they are transient or persistent, will bring about greater or lesser alterations in the said cascade. Whether the factor concentrate used is plasma-derived or recombinant does not have a significant influence on the inhibitor incidence rate [51].Short and medium-term perspectives for the treatment of haemophilia strongly rely on the current research efforts directed at increasing the safety levels of (especially) plasma-derived factors.
Such research focuses on the detection and subsequent inactivation of emerging blood-borne pathogens in donors such as the prions causing variant Creutzfeldt-Jakob disease, or other potential emerging agents [52-54]. It is also important to increase the efficiency of recombinant factors increasing their half-life (by PEGylating the factor molecule or using fusion proteins [55-58] and attenuating their immunogenic capacity to produce inhibitors, by chemically modifying them [59] or by developing recombinant factors of human origin [60].In the long term, efforts must be directed at the development of advanced therapies, particularly strategies in the field of gene therapy (using of adeno-associated viral vectors) and cell therapy (using of adult stem cells or induced pluripotent stem cells).
The chief goal of these new strategies will be to address some of the shortcomings associated with current treatment options such as the short in vivo half-life of administered factors, the impending risk of a pathogen-induced infection and the development of inhibitors. Another goal of the advanced therapies (cell therapy) will be palliative treatment of the articular consequences derived from haemophilic arthropathy [40].Haemophilia is optimally suited for advanced therapies as it is a monogenic condition and does not require very high expression levels of a coagulation factor to reach moderate disease status (Figure 2). For this reason, significant progress has been possible with respect to these kinds of therapies: cell therapy has broken new ground with the use of several types of target cells and gene therapy has shown particular promise with the use of viral and non-viral vectors. The studies published so far have, in the most part, not reported any severe adverse effect resulting from the application of such strategies in the clinical trials performed.Specifically, gene therapy trials in haemophilic patients have shown adeno-associated vectors to represent the most promising treatment option given their excellent safety profile, even if on occasion they may create immune response problems. Efforts are currently centered on minimizing the incidence of immune rejection and increasing efficacy and expression time. In this connection, several studies have been published with a view to optimizing the use of this type of viral vectors. Among them, in a landmark study on patients with severe haemophilia B (<1% FIX), Nathwani et al. Significant as they may seem, these results must be considered with caution as the expression levels achieved rather than normalize the patient's phenotype convert it to a mild-to-moderate form. Also, concomitant treatment with glucocorticoids is needed to prevent immune rejection and elevation of liver transaminase levels. Due account must also be taken of the fact that the adeno-associated vector has the potential to induce hepatotoxicity. Autologous transplantation of healthy differentiated cells, obtained from iPSCs, into an animal model with haemophilia or diabetes mellitus type 1, normalizes the corresponding altered function by in vivo production of the deficient protein or hormone.Non-viral strategies also have a role to play in the treatment of haemophilia as they could in the long term provide a safer alternative than viral vectors which, as we have seen, are fraught with significant biosafety and efficacy-related problems, which have so far limited their clinical application. This non-viral strategy has made it possible to obtain stable factor VIII secretion in vitro. Xenoimplantation of these protein-secreting cell lines into immunocompetent haemophilic mice corrects the severe form of the disease. Such implantation could prove extremely useful as a bioimplant in the context of monogenic diseases such as haemophilia. Our laboratory has advanced the use of nucleofection as a non-viral transfection method to obtain factor IX expression and secretion in adult adipose tissue-derived mesenchymal stem cells [68].
Although it is certainly true that expression efficacy with these types of protocols is lower than when viral vectors are used, it must be underscored that these protocols do offer much higher safety levels, with the additional advantage that increasing factor activity to above 5% of normal values already places the patient in the mild phenotype group.The use of cell therapy in the treatment of haemophilia has to date consisted mainly in the transplantation of healthy cells in an attempt to repair or replace a coagulation factor deficiency.
These procedures have been conducted mainly with adult stem cells and, more recently, with progenitor cells partially differentiated from iPSCs, albeit in most cases the mechanisms by which transplanted cells (to a greater or lesser extent) engraft and go on to proliferate and function remain unknown.Aronovich et al. These results would seem to indicate that transplantation of a fetal spleen (obtained from a developmental stage prior to the appearance of T-cells) may potentially be used to treat some genetic disorders. This resulted in a restoration of factor VIII plasma levels and in the correction of the bleeding phenotype. These iPSC-derived cells express specific membrane markers for these cells such as CD31, CD34 and Flk1, as well as factor VIII.
Following transplantation of these cells into mice with haemophilia A, the latter survived the tail-clip bleeding assay by over 3 months and their factor VIII plasma levels increased to 8%-12%.
These transplanted cells were injected into the liver parenchyma where they integrated functionally and made correction of the haemophilic phenotype.
High levels of FVIII mRNA were detected in the spleen, heart, and kidney tissues of injected animals with no indication of tumor formation or any other adverse events in the long-term. Induced pluripotent stem cells in the treatment of diabetes mellitusDiseases caused by the destruction or loss of function of a limited number of cells are good candidates for cell therapy. Diabetes mellitus (DM) is classified into two broad categories: type 1 DM, which is a genetic disease, and type 2 DM, a more generalized variety related with insulin resistance. DM, especially the type 1 form, is associated with microvascular complications, such as retinopathy, neuropathy or nephropathy, as well as cardiovascular problems. Type 1 DM is a T-cell mediated autoimmune disease specifically aimed against pancreatic beta cells, which results in insulin deficiency [75,76].


Symptoms of DM include episodes of lethargy and fatigue, polyuria, enuresis, nocturia, polydipsia, polyphagia, weight loss and abdominal pain.
The disorder has a strong genetic component related with the susceptibility to inherit and develop the disease through the HLA complex (HLA-DR and HLA-DQ genotypes) and other loci involved in immunologic recognition and cell-to-cell signaling in the immune system (graft compatibility) [77,78].Abnormal T-cell activation in susceptible individuals results in both an inflammatory response within the Langerhans islets and a humoral immune response involving the production of antibodies against insulin-specific beta cell antigens, decarboxylase glutamic acid or the protein tyrosine phosphatase [79]. The presence of one or more types of antibodies may precede the appearance of type 1 diabetes and its subsequent development [80,81].
In any case, the final result is the destruction of beta cells and progressive impairment of the blood glucose metabolism [82].
Some patients with type 1 diabetes may show a higher susceptibility to other conditions such as thyroiditis, Graves disease, Adisson disease, celiac disease, myasthenia gravis or to degenerative skin conditions such as vitiligo [83-85].The greatest incidence of type 1 DM occurs during childhood and in the early years of adulthood with significant variations across different geographies. Diagnosis is usually made before the age of 20 (between 16 and 18 in 50-60% of cases) [75]. The factors involved in the development of type 1 DM include the so-called familial predisposing factors, gestational status, age and other iatrogenic causes. Type 2 DM is characterized by a functional deficiency of insulin per se or by a resistance to the hormone resulting from an alteration of the function or structure of the insulin receptor at the level of the membrane or of any of the molecules involved in the intracytoplasmic signal transduction cascade [86]. The metaboilic effects of insulin vary depending on the action of the molecules that participate in signaling pathways to regulate gene expression in striated muscle cells, adipocytes, hepatocytes and in pancreatic beta cells [87-90]. Thus, for example, insulin resistance caused by the impairment of glucose transporter GLUT4 initially results in a metabolic syndrome, type 2 diabetes, lipodystrophy, hypertension, polycystic ovary syndrome or atherosclerosis. In general, the morbidity and mortality of DM is related with the different long-term cardiovascular complications associated with the disease, also taking into account other proactivating factors such as smoking, obesity, a sedentary lifestyle, hypertension, early onset and prolonged duration of type 1 DM, genetic predisposition and hyperglycemia.Nephropathy, retinopathy and diabetic neuropathy are the most common microvascular complications of DM.
As regards diabetic neuropathy, this can be a focal complication associated with diabetic amyotrophy or with cranial nerve III oculomotor palsy, or a more generalized occurrence that can take the form of a sensorimotor polyneuropathy affecting the autonomic nervous system, gastric motility and cardiac function. Peripheral neuropathy together with peripheral vascular disease may lead to a diabetic foot syndrome, characterized by ulcerations and poor healing in the lower limbs [91]. As a macrovascular complication, cardiovascular disease accounts for 70% of mortality in individuals with type 2 DM, with the incidence of coronary artery disease being higher in women than in men suffering from type 1 DM [92]. Atherosclerotic processes are in turn more common in patients with type 1 DM [93].Although treatment and diagnosis of diabetes is well-established, there is a constant quest for new drugs that may be more effective at lowering blood glucose levels, controlling their therapeutical management —especially in younger patients—, and preserving patients' long-term quality of life by reducing the incidence of complications resulting from the disease. Current research is centered on unveiling the structure and function of glucose transporters, which may offer significant therapeutic advantages [86], as well as on the development of new fast-acting insulin analogs and more accurate subcutaneous pumps [94-98]. Commendable as these initiatives are, it is difficult to anticipate and control factors that exert a variable influence upon glucose levels such as nutrition, physical activity or stress.
These factors alter the glycemic environment and consequently the amount of insulin required at each point in time, which reinforces the need to establish sophisticated artificial pumping systems that may simulate the natural endocrine pancreas. The continuous advancement of our understanding of the mechanisms that govern the physiopathology of diabetes and gene susceptibility together with the multiple possibilities currently offered by biotechnology have fuelled the researchers' interest in the development of all three types of advanced therapies: gene therapy, cell therapy and tissue engineering. In this regard, although we are still at a very incipient stage [99,100], procedures based on transplantation of insulin-secreting cells or islets obtained from stem cell differentiation may hold valuable hope for the future.
The need to justify the human and financial investment made in the development of new advanced therapies is as strong in diabetes as it is in haemophilia. However, in the case of the former justification is even more compelling taking into account that an optimal and efficient treatment is already available for the disease.
The discovery of insulin as a therapeutic tool for DM constituted an important milestone in the history of medicine even if administration of this hormone does not fully compensate for the function lost. Moreover, both coagulation factor and insulin treatment are only palliative, never curative, which is the basic idea underlying treatment of DM and haemophilia. Moreover, it is also important to take into account the potential adverse effects of these therapies, and particularly the complications associated with DM, which derive from the fact that it is a long-term disease. In addition, advances in terms of the clinical transplantation of Langerhans islets have not met with the expected success as a result of the inadequate number of donors available and the incidence of immune rejection of the newly transplanted beta cells [101]. Built upon the knowledge gained from studies on embryonic cells about the differentiation process, the first studies on iPSCs, whereby human cells were reprogrammed to become in vitro differentiated insulin-producing cells, showed great promise [105,106]. However, as only partial cell differentiation was achieved, those studies failed in their attempt to enrich insulin-producing cell lines or assess their function. These authors established a quantitative cytometric method to evaluate the efficacy of cell differentiation. In addition, they increased the level of precision in the assessment of the competence and function of the iPSCs from a rhesus monkey by means of transplantation into immunodeficient mice. These cells were induced to form endodermal structures, pancreatic and endocrine progenitors and insulin-producing cells.
By means of a TGF-? inhibitor, generation of endocrine precursor cells capable of generating insulin-producing cells that respond to glucose stimulation in vitro was undertaken. Transplantation of these cells into a type 1 DM murine model decreased blood glucose levels in 50% of the mice. These results show the high efficacy that can be achieved by obtaining iPSCs from a superior animal model as well as the capacity of iPSCs to be transformed into insulin-producing cells, which opens up the possibility for carrying out autologous transplantations in the future.Along the same lines, Jeon et al. The insulin-producing cells obtained in this way express different pancreatic ? cell markers and secrete insulin in response to glucose stimulation. Transplantation of these cells into non-obese diabetic mice (a model of autoimmune type 1 DM very similar to the human form) results in a kidney graft with a functional response to glucose stimulation and a consequent normalization of blood glucose levels (Figure 2).Until recently, iPSC generation from patients with type 2 DM had not been reported in the literature. These cells were reprogrammed by lentiviral transduction with human transcription factors OCT4, SOX2, KLF4 and cMYC, telomere elongation, and down-regulation of senescence and apoptosis-related genes, and were subsequently differentiated into insulin-producing islet-like cells. Reprogramming of keratinocytes from elderly type 2 DM patients produces efficient iPSCs with a "privileged" senescence status that allows them to transform into insulin-producing islet-like cells, which may lead to the development of a versatile strategy for modeling the disease as well as an advanced therapy for treating it.Generally speaking, several problems must yet be resolved before iPSCs can be applied clinically, specifically to the treatment of haemophilia or diabetes.
In the first place, it is essential to optimize the reprogramming process so that it provides maximum safety assurances against the potential risks derived from undesirable genetic changes in iPSCs [111]. Recent studies have revealed significant chromosomal changes that take place during the long-term culture of iPSCs as well as variations in the number of copies of certain genes and point mutations, which could clearly be related with the reprogramming of somatic cells and result in damage to the DNA [112-115].The second hurdle that must be overcome is the high variability that exists between the different cell lines in the context of differentiation into pancreatic lineages [16].
The epigenetic and functional trials that should be performed in this respect are complicated by the fact that iPSCs have a high epigenetic content [116].
The third obstacle has to do with the purification of iPSC-derived ? cells to prevent the transplantation of undifferentiated cells, which could result in the formation of teratomas.
Moreover, it is necessary to develop new reagents to make direct differentiation of pancreatic progenitors into functional ? cells more efficient and to design highly specific surface markers for these cells so that a more precise fluorescence analysis can be performed in order to isolate homogeneous populations of this kind of cell so that their function can be rigorously controlled.
General regulatory and bioethical issuesCell therapy, as one of the bedrocks of the advanced therapies —together with gene therapy and tissue engineering—, requires a new legislative framework in order to guarantee that patients can avail themselves of the products they need and provide governments with a robust protection, control and regulation mechanism. The existing framework regulating advanced therapies will have to be adapted fast in order to keep pace with the proliferation of new knowledge in this rapidly developing field. However, desirable that this may be, the pace of legislative reform is unfortunately slow and inevitably lags behind the development of new science. For any product based on cells or on tissue, it should be made compulsory to verify that the desired physiological functions are preserved after the preparation process, both in isolation and in combination with other non-biological components, as many of these products will be used with a metabolic purpose [119,120].
Nevertheless, many things remain to be learned about the procedures that should be followed to guarantee the safety and efficacy of cell therapy products, especially with respect to the biology of stem cells, their self-renewal and differentiation potential and, above all, the evaluation and prediction of potential risks.Most cell therapy products are not controversial from a bioethical point of view. The exception to this is therapy with human embryonic stem cells, which raises moral and bioethical problems [121,122]. Such consideration refer to the donor's informed consent and to problems associated with the harvesting of oocytes and the destruction of human embryos. In this regard, the guidelines used by the different countries range from total prohibition to regulated authorization. In general, there is an international consensus that the results obtained in stem cell research should be applied to humans without prior bioethical scrutiny, with the understanding that scientific research and the use of scientific knowledge must respect human rights and the dignity of the individual in accordance with the Universal Declaration of Human Rights and the Universal Declaration of the Human Genome [123].The main advantage of induced pluripotent stem cells is that their use, unlike that of embryonic stem cells, does not raise moral or bioethical issues as the scientific community, as well as society at large, consider it a valid alternative for the generation of pluripotent stem cells without the need to use human oocytes or embryos. Furthermore, these cells have shown themselves to be functionally and molecularly similar to embryonic cells, but without their bioethical problems, which means that their use in humans will not require an overly stringent regulatory framework. The importance of this cannot be overstated as, in many instances, and in some countries more than in others, legislation can hinder the development of science and, consequently, the application of new knowledge and new therapeutic strategies. Concluding remarksiPSCs offer an unprecedented alternative for basic, clinical and applied biomedical research. The most significant applications of these cells to the field of cell therapy are related to the treatment of such organ-specific conditions as diabetes ?a typically metabolic disease?, hepatic and cardiovascular diseases, immunological disorders and monogenic hereditary conditions in general such as haemophilia.However, many aspects remain to be unveiled about the safety of iPSCs and about their reprogramming mechanisms, although no-one denies that this technology offers new, until-recently-unimaginable possibilities for correcting alterations in a large number of conditions, particularly in monogenic and metabolic diseases [124]. Also, some technical problems will also have to be resolved such as finding a way to produce these cells using risk-free viral vector transfection as well as safer alternative methods such as viral vector-mediated reprogramming. In the longer term, once the challenges mentioned above have been overcome, both cell and gene therapy will become plausible alternatives.
As far as haemophilia is concerned, the first article discussing the benefits of gene therapy for the treatment of the disease was published a decade ago. At that time, experts in the field anticipated that a cure for haemophilia would be found by the first decade of the 21st century [125], a prediction that did not come true because of multiple problems related to biosafety. Although many steps have been taken in the right direction with respect to gene therapy, cellular reprogramming of iPSCs and the safety of transfer vectors, efforts must continue in order to resolve problems related to immune response, insertional mutagenesis, efficacy and expression time, the collateral (particularly hepatotoxic) damage caused by viral vectors and the risk of teratoma and neoplasia derived from the application of certain cell types. Sight should not be lost of the difficulties inherent in recruiting patients for clinical trials and in the large-scale production of vectors and cell lines, needed to facilitate optimal and efficient implementation in the clinical setting.
One of the first things that must be addressed when doing research into advanced therapies is whether the expected benefits of such therapies will be able to offset the investment needed. In the case of haemophilia, the answer is clearly in the affirmative as it is a chronic disease that requires high-frequency life-long treatment, very costly in patients on prophylaxis, and which poses a potential risk of infection by emerging pathogens. In this regard, application of strategies that are less demanding in terms of efficacy, i.e. As regards diabetes as a typically metabolic disease, advances in the understanding of its physio- and etiopathology, together with the greater biotechnological possibilities available, have made new alternatives possible as a result of the development of advanced therapies to treat it.
Transplantation of insulin-secreting cells or of islets obtained a from differentiation of stem cells could hold some hope in the long term.As in haemophilia, in diabetes it is also necessary to justify the investment of human and financial resources required for the development of new advanced therapeutical strategies, taking account of the fact that patients with this condition also benefit from an optimal and efficient treatment at present. The justification for the said investment is that diabetes gives rise to vascular and neurological complications in the long term and that transplantation of Langerhans islets has not achieved the success that scientists hoped for because of the dearth of donors and the high rate of immune rejection that characterizes diabetic patients.
In a nutshell, iPSCs technology has the potential to produce an about-face in the way we conceive cell behavior as iPSCs can be induced to form hormone-producing differentiated cells. In this regard, several authors have reported on the generation of insulin-producing pancreatic cells from iPSCs from rhesus monkey and murine models which, after transplantation, are capable of producing insulin in vivo in response to glucose stimulation. Nonetheless, some general issues affecting iPSCs remain to be resolved before these cells can be used clinically in the treatment of diabetes. Prominent among these are optimizing the reprogramming process as well as their genetic safety, controlling the high differentiation variability of the different pancreatic lines by means of epigenetic trials and enhancing the purification, isolation and characterization of homogeneous populations of iPSC-derived insulin-producing ? cells.NaN.



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