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Cardiovascular effects of cell therapy on type 1 diabetes, an overview on basic research

. Escrito en Número 1

Gustavo Monnerat Cahli, Jennifer Schroder, Emiliano Medei

Laboratório de Eletrofisiologia Cardíaca, Instituto de Biofísica Carlos Chagas Filho, Brazil.
Laboratório de Cardiologia Celular e Molecular, Instituto de Biofísica Carlos Chagas Filho, Brazil.

Abstract. Diabetes Mellitus is a metabolic disease characterized by high level of serum glucose. It is a serious health problem that can lead the patient to several physiological complications. According to The American Heart Association, in 2006 Diabetes mellitus killed 72,449 people in the United States along with 17,200,000 U.S. adults have physician-diagnosed diabetes. According to World Health Organization, at least 171 million people have a medical condition of diabetes, or 2.8% of the population. Its occurrence is increasing quickly, and it is estimated that by 2030, this number will be approximately 366 million people. The present review discusses the use of cell therapy as a new treatment to cardiovascular problems of type I diabetes, on basic research.

Introduction

Diabetes Mellitus is a metabolic disease characterized by high level of glucose [(fasting plasma glucose ? 7.0mmol/l (126mg/dl)]1. According to the International Diabetes Federation (IDF), there are two main types of diabetes. Type 1 diabetes is caused by an auto-immune reaction in which insulin-producing beta cells in the pancreas are destroyed. The reason why this occurs is not fully understood. People with type 1 diabetes produce very little or no insulin. Type 2 is the most common type of diabetes and accounts for 90-95% of all diabetes. It is characterized by insulin resistance and relative insulin deficiency.
It is a serious health problem that can lead the patient to several physiological complications. According to The American Heart Association in 2006, Diabetes mellitus killed 72,449 people in the United States along with 17,200,000 U.S. adults have physician-diagnosed diabetes. According to World Health Organization at least 171 million people have a medical condition of diabetes, or 2.8% of the population. Its occurrence is increasing quickly, and it is estimated that by 2030, this number will be approximately 366 million people1.
Besides that, the continue hyperglycemia is responsible for the appearance of numerous organs and tissues complications. In this context, the cardiovascular system is one of the most damaged. At least 65 percent of people with diabetes mellitus die of some form of heart disease or stroke. In addition, several studies, as Framingham Study, have established diabetes mellitus (DM) as a strong risk factor for cardiovascular morbidity and mortality2-5, especially in women3.

Cardiac complications

The presence of diabetes is associated with a significantly increased risk for developing cardiovascular disease. Comparing patients with cardiovascular disease, the morbidity and mortality are worse in those who also have diabetes4. Concerning the cardiac complications more specifically, many epidemiological studies have shown for almost 4 decades the association between diabetes and heart failure5. The prevalence of HF in diabetic patients is 12%, confronting with 1-4% among the patients without diabetes6. More than 30% of the patients that required hospitalization for HF during the year 2000 in Alabama were diabetics7.
Many associated pathologies contribute to this elevated incidence of HF in diabetic patients. Diabetes is associated with most known risk factors for cardiac failure, including obesity, dyslipidemia, thrombosis, infarction, hypertension, activation of multiple hormone and cytokine systems, autonomic neuropathy, endothelial dysfunction and coronary artery disease8. Besides that, there is a diabetic cardiomyopathy, term firstly introduced in 1972 by Rubler et al.9.
Diabetic cardiomyopathy affects mainly the myocardium, is not necessarily associated with vascular and valvular pathology or high blood pressure and occurs in approximately 30% of type 1 diabetic patients10, 11. The pathology of diabetic cardiomyopathy includes interstitial fibrosis, apoptosis of cardiomyocyte, abnormal energy utilization, small vessel disease and cardiac neuropathy10. It is believed that diabetic cardiomyopathy is induced by metabolic abnormalities, as hyperlipidemia, hyperinsulinemia and hyperglycemia, and cardiac alterations. These alterations can cause oxidative stress and impairment of intracellular traffic of ions, especially reducing calcium availability. The altered cardiac biochemistry and structure result in clinical symptoms. Initially, it is possible to detect asymptomatic diastolic dysfunction, and then can be observed symptoms of cardiac insufficiency. The systolic dysfunction is usually observed late10, 11.

Vascular complications

Vascular complications in DM can be caused by micro and macro-angiopathy. Patients with type 1 diabetes mellitus represent 10% of the diabetic patients12. However, diabetes mellitus microvascular complications present high prevalence in this group of patients. With regard to this pathology, it is the leading cause of blindness, end-stage renal disease, and non-traumatic amputations in the developed world13. About 50% of lower limbs amputations are related to diabetes and this risk is 8 times higher in diabetic people14. In about 72% of normotensive diabetic patients was observed evident small vessel disease, whereas in non-diabetic patients this finding was only 12%15. These complications represent significant morbidity for the patient, but they do not represent the main cause of mortality among those with diabetes.
The presence of diabetes mellitus is an independent risk factor for coronary artery disease, cerebrovascular accident, peripheral vascular disease and heart failure. These macrovascular complications, specifically cardiovascular and cerebrovascular, remain the leading cause of death among those with diabetes13.
By the age of 55 years, in patients with type 1 diabetes mellitus, the cumulative mortality rate due to coronary artery disease has been reported to be 30 to 40%16, which is much higher than the overall mortality rate of 4% in non-diabetic subjects17. In fact, in type 1 diabetic patients, the mortality risk by coronary artery disease is increased 4 to 9 fold in men and 4 to 29 fold in women18. 5,148 type 1 diabetic patients were followed for more than 10 years and it was observed that once chronic renal failure occurs, coronary artery disease develops earlier and much more often19.
Concerning cerebrovascular disease, an increased risk of stroke has been linked to the physiopatological changes seen in the cerebral vessels of individuals with diabetes20. In a 24-year follow-up study, both type 1 and type 2 diabetes were associated with a significantly higher risk of stroke and its subtypes in women, but the association with type 1 diabetes was stronger21. The incidence of total stroke was fourfold higher in women with type 1 diabetes and twofold higher among women with type 2 than for nondiabetic women. The multivariate relative risk of ischemic stroke was increased six fold in type 1 diabetes and twofold in type 2 diabetes. Type 1 diabetes was also significantly associated with the risk of hemorrhagic stroke, but type 2 diabetes was not21.

New strategies for diabetes treatment

For decades, controlled diet, physical exercise and some medications, as insulin, have been the most common treatment for diabetes. However, in some patients these are not enough to avoid or reverse the cardiovascular complication of this disease22-24. In this context, the cell therapy, that use cells, biomaterials, and different grow and proliferation factors to repair organs and tissues, have emerged as alternative. However, this kind of therapy still have important aspects to be defined as: 1- prove whether the cell therapy is able to improve cardiovascular function; 2- which kind of stem cells should be more effective to improve metabolic and cardiovascular profile; 3- the best pathway and the number of cells for injection; and 4- when the cells should be injected to obtain the best results.
One of the cells that have been used in the cell therapy in the animal model of the streptozotocin (STZ) induced pancreatic damage is the hematopoietic stem cell (HSC). HSCs are multipotent stem cells, found in the bone marrow25, 26, that give rise to all the blood cells types including myeloid and lymphoid lineages. This kind of cell is one of the most used in the clinical trials, as a consequence of the good results obtained when used in different animal models of disease in basic research. In addition, other advantages of these cells are the facility to obtain and the possibility of autologous injection. In this context, Voltarelli et al (2009) showed that in most patients with early onset type 1 diabetes mellitus, caused by autoimmune disorder, high dose immunosuppression followed by autologous hematopoietic stem cell transplantation was able to induce complete remission (insulin independence). The success of this therapy depends mainly on the integrity of the rest of the pancreatic tissue and the response of the immune system.
While some groups try to treat the cause of diabetes by resetting the immunological system (Voltarelli et al 2009, Haller et al 2009), others are exploring the possibility of create the insulin-secreting cells to restore the pancreatic tissue using HSCs. However, the transdifferentiation of HSCs to pancreatic beta cells is rarely evidenced (Choi et al 2003; Palma et al 2008). In fact, Wu et al (2009) showed that treatment with HSCs can improve the cardiovascular system of diabetic rats decreasing the apoptosis rates and increasing the NO content but not by transdifferentiation27. This transdifferentiation would promote a regeneration of the injured tissue, but subsequent studies indicate that this capacity of the stem cells is very low or absent in vivo, as described by Murruy et al.28. More recent studies indicate that the fusion of the cells could explain how this cell therapy acts; however, this hypothesis, also, was denied. In spite of stem cell having the capacity to fuse with other cell, the number of this episode is very low, and after some months they are not found anymore, as proved by Nygren and coworkers29.
At the present time, at least in our knowledge, the most accepted hypothesis of the favorable results observed with HSCs is mediated by paracrine, and angiogenic effects30,31. Many studies have shown that stem cells can mediate a paracrine effect, with cytokines and other factors, inducing antiapoptose, angiogenese32 and regeneration of some inflamed tissues. According to these studies, inflammatory areas modify their extracellular structure, attracting the HSCs, which would benefit, through paracrine effect, the injured tissue33.
Mesenchymal stem cells (MSCs) are multipotent stem cells with the potential to differentiate into a variety of cell types, as bone, cartilage, fat and muscle cells. They are also found in bone marrow and can grow in culture maintaining their multipotency. This lineage was first described by Pittenger and coworkers34, in 1999. Since with this type of cell can be done an autologous transplantation and it has more capacity to differentiate in many types of cell, they are prominent tool to use in cell therapy.
Some recent works used MSC in the model of diabetes induced by STZ. In spite of low or none differentiation into cardiomyocytes, the improvement of cardiovascular system was observed by some mechanic evaluations. The fusion of MSC was observed with cardiomyocytes, as well as angiogenesis, myogenesis, fibroses and apoptosis inhibition, probably by paracrine effects of the MSC35-39. A more recent detailed analysis by Abdel and coworkers38 showed that the transplantation of MSCs can improve the cardiac function in the animal model of diabetes. The results are about the heart rate, left ventricular developed pressure, LV dp/dt (left ventricular delta pressure/delta time, contractility index) and Systolic blood pressure.
In vitro studies, as showed by Di Gioacchino and coworkers40, indicated the potency of generation of beta cells lineage, being a prominent possibility to solve many complications about pancreatic degeneration. Hence, Dong et al41 demonstrated that after the transplantation of MSCs, these cells can transdifferentiate in insulin producing cells in the pancreas of recipient rats, consequently reduce blood glucose level. Unfortunately the percentage of transdifferentiated cells is very low, with this kind of cells and way of application.
Other kinds of cells proposed, to revert/repair the diabetic disease, are the embryonic stem cells (ESCs). Evans and Kaufman originally described these in mice in 198142. Embryonic stem cells were described in human seventeen years later, by Thomson et al.43. They are pluripotent stem cells that can be obtained from the inner cell mass of the blastocyst, an early-stage embryo. This kind of cells are able to differentiate into all derivatives of the three primary germ layers: ectoderm, endoderm, and mesoderm. These include each of the more than 220 cell types in the adult body, as described by Odorico et al (2001)44. The ethical concerns of stem cell therapy and graft-versus-host disease associated with allogeneic stem cell transplantation are some limiting factors for research and clinical trials. In spite of these limiting factors some groups work with this lineage, finding some interesting results. As they could differentiate in cardiomyocytes, the diabetic cardiomyopathy could be improved with ESC therapy; however, other important problem is the formation of many teratomas after the injection of undifferentiated ESC. To solve this problem, the differentiation to ESC derived cardiomyocytes is done in vitro and after the purification, the ESC derived cardiomyocytes are injected. After that, the cardiomyopathy was improved, but a decrease in the conexines could lead to an electric remolding, conducting to some arrhythmias, as showed by Kolossov and coworkers in 200645.
The ESCs are the most prominent lineage to be used to regenerate the insulin producing cells in the pancreas. A very recent study made by Champeris and Jones46 showed that pancreatic beta cells could be done in vitro, manipulating the signaling pathways of the ESC colony. Since the type one diabetes is caused by a degeneration of beta cells, the transplantation of differentiated ESC could solve the disease of the patients.

Conclusion

Many works were done, but the primary focus is about the regeneration of insulin producing cells; however, the benefits of cell therapy on the cardiovascular system, are inconclusive. In this context more works are necessary to understand which kind of cells could really help to ameliorate the consequence of diabetes.

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