El-Badawy A1, El-Badri N1.
- 1Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt.
Stem cell therapy is a promising therapeutic modality for advanced diabetes mellitus (DM). This study presents a meta-analysis of relevant clinical trials to determine the efficacy of stem cell therapy in DM. We aim to critically evaluate and synthesize clinical evidence on the safety and efficiency of different types of stem cell therapy for both T1DM and T2DM.
METHODS AND FINDINGS:
We pooled participant-level data from twenty-two eligible clinical trials that satisfied our inclusion criteria, with a total of 524 patients. There were significant differences in the outcome based on the type and source of the infused cells. Out of all T1DM patients who received CD34+ hematopoietic stem cell (HSC) infusion, 58.9% became insulin independent for a mean period of 16 months, whereas the results were uniformly negative in patients who received umbilical cord blood (UCB). Infusion of umbilical cord mesenchymal stem cells (UC-MSCs) provided significantly beneficial outcome in T1DM, when compared to bone-marrow mesenchymal stem cells (BM-MSCs) (P<0.0001 and P = 0.1557). Administration of stem cell therapy early after DM diagnosis was more effective than intervention at later stages (relative risk = 2.0, P = 0.0008). Adverse effects were observed in only 21.72% of both T1DM and T2DM stem cell recipients with no reported mortality. Out of all poor responders, 79.5% were diagnosed with diabetic ketoacidosis.
Stem cell transplantation can represent a safe and effective treatment for selected patients with DM. In this cohort of trials, the best therapeutic outcome was achieved with CD34+ HSC therapy for T1DM, while the poorest outcome was observed with HUCB for T1DM. Diabetic ketoacidosis impedes therapeutic efficacy.
Stem Cell Therapy in Diabetes Mellitus: The Gap Between the Bench and the Clinic
Diabetes mellitus is one of the top causes of chronic illness, affecting people worldwide in epidemic proportions and causing substantial morbidity and mortality . Type 1 DM (T1DM) is caused by autoimmune destruction of the pancreatic beta cells, while T2DM develops secondary to several factors including family history, poor diet, and inactive life style. While patients suffering from T1DM require administration of insulin for life, T2 patients can initially benefit from dietary control and oral medications. Eventually however, about 27% become insulin dependent (reviewed by El-Badri et al, 2012). The ultimate goal of therapy for advanced diabetics and patients who are insulin-dependent, is to ensure a continued production of insulin in response to fluctuation in glucose levels. Currently, this is provided by islet replacement. Successful application of islet transplantation following the Edmenton protocol  revolutionized treatment for T1DM and improved endogenous β cell reserves and physiologic insulin production. Islet transplantation however, suffers the limitation of availability of fresh cadaveric donors, and the requirement of life long immune suppression.
Stem cell therapy is evolving as a viable alternative to islet transplantation; however, many hurdles remain to be overcome. Animal studies demonstrated the potential advantages of using stem cells to treat DM and its complications. Efforts to engineer insulin-producing cells from stem cells have been achieved with remarkable success from embryonic stem cells (ESCs), induced pluripotent stem cells (iPS cells) and mesenchymal stem cells (MSCs) derived from a variety of adult tissues . However, given the ethical debates on ESCs and the complexities associated with the applications of iPSCs, just a few studies moved to the clinic. Published clinical trials utilizing stem cells in treatment of both T1 and T2 DM have used adult stem cells including autologous HSCs, marrow MSCs, cord blood mononuclear cells, umbilical cord mesenchymal cells placental cells and adipose stem cells . The Food and Drug Administration (FDA) has recently approved an Investigation New Drug application (IND) for the treatment of type I DM, in which encapsulated pancreatic progenitor cells derived from a human ESCs are allowed to grow in vivo after transplantation.
Critical evaluation of the literature on published clinical trials in treatment of DM revealed several findings. Most importantly, there is sufficient evidence that adult stem cell therapy represents a viable and efficacious approach for treatment of DM. However, the application of stem cells in almost all of the published trials lacked consistency and adequate follow up. Careful analysis of published trials revealed several factors that may account for the large gap between the bench-top and the clinic in applying stem cell therapy for DM. While literature search, for example, on stem cell therapy in diabetes mellitus resulted in thousands of entries, the clinical trials on uncomplicated DM did not exceed 25 . The disproportionality between the prolific experimental data, and the limited number of clinical trials is not restricted to DM, but extends to stem cell therapy for most of chronic diseases of non-hematopoietic origin. The list of more than 70 diseases now cured with stem cells includes mostly malignancies of the blood and the lymphoid system, diseases of the immune system such as severe combined immune deficiency, and metabolic disorders such as Hunter’s syndrome. For solid organ diseases, the list is limited to breast cancer, Wing Sarcoma, Neuroblastoma and renal cell Carcinoma. Evidently, DM is not included in this list.
Advances in stem cell therapy in DM:
In evaluating 22 clinical trials in which stem cell therapy was applied to treat uncomplicated DM, substantial discrepancies were observed, and issues with standardization of therapy and valid controls were reported. For example, in all analyzed studies, the route of injection, number of cells, type of stem cells, source of stem cells, follow up period, and metrics for improvement have not been standardized. This makes it difficult to make valid comparisons, or to provide reliable guidelines. Putting forth valid recommendations for stem cell therapy in DM, based on clinical trials is thus premature, due to the scarcity and the modest quality of available data.
Preclinical data on the other hand are based on better-controlled studies, large sample sizes and more robust analysis. Preclinical studies show that ESCs and iPSCs have achieved the highest ability to differentiate into insulin-producing cells, compared to adult stem cells [6,7]. Issues related to safety and sustainability of the graft were addressed by different laboratories. When adult stem cells were used as source for cell therapy, such as hematopoietic stem cells (HSCs) and mesenchyaml stem cells (MSCs), immune reactions, immune reconstitution, and graft rejection have been the most formidable issues. Similar to organ transplantation, post-operative complications related to graft stability and infection control have accounted for the most reported adverse reactions.
The large gap between animal experimentations and applications in human trials in regenerative therapy for DM can be attributed to several factors. First, when considering stem cell therapy for DM, the disease is treated as one single disorder. However, there are substantial differences between the pathology of T1DM and T2DM, and these differences are seldom considered when designing stem cell therapeutic approaches. While T1DM is caused by autoimmune destruction of the beta cells, and affects predominately young patients who are not obese, T2DM is a metabolic disorder. It is usually of adult onset, and is secondary to obesity, poor eating habits and sedentary life style. T1 diabetic patients often suffer episodes of hypoglycemia, while T2 patients rarely suffer this pathology. The compromised immune system of T1 diabetic patients is the cause of the disease, while T2 patients are immune-compromised later in the disease, as a result of the sustained hyperglycemia. Other significant differences exist in the genetic makeup, status of the beta cells of the pancreas, and onset and extent of complications. These significant differences are not taken into consideration when designing clinical trials for regenerative therapeutic approaches
Regenerative therapies employ different approaches than traditional therapies, in T1DM the aim is to replace non-functioning beta cells, and produce sufficient levels of insulin. Nevertheless, interestingly, in most of the clinical trials employing stem cell therapy for DM, none employed or examined the insulin producing function by stem cells. In these trials, insulin independence, and not insulin levels was used to measure the efficacy of the transplant, in addition to the levels of HBAc and C-peptid.
In clinical trials that applied marrow stem cell transplantation to treat T2DM [6-8], overall better efficacy of the treatment was achieved when HSC were transplanted, compared to marrow MSCs. Transplanted cells were not manipulated in vitro, or pre-differentiated into insulin-producing cells. Patient improvement was thus clearly not related to replacing non-functioning beta cells, or increasing insulin production. Improved clinical symptoms and insulin independence were thus mediated by other factors, which we propose to include immune reconstitution of the diabetic milieu, and not cell differentiation into beta cells.
Stem cell therapy has not been fully exploited for DM, partially due to the incipient, chronic and protracted course of the disease. Despite the high morbidity and mortality caused by DM, the ability to control the disease with diet, medications and insulin thwarted patients and health care professionals from considering stem cell therapeutic approach. Alternative therapies provided by new technological advances are effective and attractive for most diabetic patients and care givers. The development of insulin biosensors, batches, and the applications of nanotechnology in drug delivery all promise delivering the magic bullet, in this case insulin, in much easier, better controlled ways. Stem cell therapy thus must prove superior to the tough competition of novel insulin devices that could respond to fluctuation in insulin levels, and promise equally safe and convenient application.
Advanced diabetic patients who are resistant to medications are the real candidates for the stem cell transplant. Nevertheless, even when the stem cell infusion is autologous, patients require immune suppressive medications (9,10). The immune fragility of advanced diabetic patients renders the transplant of higher risk. Considering that data from clinical trials have also indicated that advanced patients who suffer from ketoacidosis are not considered good candidate for the transplant, selecting the best candidates and the best type of therapeutic approach become more complicated.
The role of immune suppressive regimens has not been given similar consideration in recipients of stem cell transplants, similar to solid organ transplant. Survival of the graft in solid organ transplants is dependent on the appropriate MHC matching between the donor and the recipient, and the efficacy and safety of the immune suppressive approach. This rigor in combining a regimen that is less toxic, and better tolerated by the patients was not applied to stem cell recipients. Stem cell scientists for example tout some cells such as MSCs as being immune suppressive. Randomized clinical trials need to address how these suppressive qualities translate into designing safe and effective immune suppressive regimen. To achieve progress towards applications of stem cell therapy in DM, all these factors should be taken into consideration: the type of the disease, standardization of the parameters of the stem cell infusion, and a well designed immune suppressive regimen that is safe and effective.
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