Encouraging developments have been made in encapsulation and immunomodulation techniques, but many challenges still remain. Human islet transplantation "Teplizumab fdating" successful in restoring normal glycemia but is limited by the need for toxic immunosuppressive drugs, the scarcity of donors, and graft failure usually within a few years [ 2 ]. These areas of research, still being Teplizumab fdating experimental, will be addressed in this review.
Whether this represents a replication capacity, neogenesis, or resistance to apoptosis is unknown. Neogenesis has recently been a source of intense debate, with many lineage tracing studies in mice showing contradictory results [ 17 Teplizumab fdating. Controversy reached its climax when two recent reports obtained distinctly different results using similar tracing for Sox9-expressing populations [ 1819 ].
However, Furuyama et al. These results clearly underline technical limitations of current lineage tracing approaches. Neogenesis from ducts is influenced by the type and extent of pancreatic injury. This was highlighted in a recent study showing different regeneration depending on the affected cell type and the extent of diphtheria toxin-induced apoptosis [ 20 ]. Also, neogenesis from the ducts seems to happen by recapitulating pancreatic embryonic development as highlighted using a pancreatic duct ligation model in the mouse [ 21 ] and partial pancreatectomy in the rat [ 2223 ].
In the human pancreas, indirect evidence of neogenesis has been provided by showing cells coexpressing cytokeratin and insulin [ 24 ]. Many studies have demonstrated the presence of cells containing insulin within the ducts, either at autopsy [ 5 ] or in biopsy from organ donors [ 2425 ]. Currently, the general concept is
Teplizumab fdating, after birth, neogenesis from ducts occurs mostly in the neonatal period and, as shown in rodents, can be stimulated in the regeneration following injury [ 17 ].
Islet neogenesis associated protein-pentadecapeptide INGAP-PP generated interest after the report of its potential for stimulating neogenesis and reversing diabetes in streptozotocin STZ -treated Teplizumab fdating [ 30 ]. The therapeutic potential of such combinations or single agents in humans
Teplizumab fdating not been explored in enough detail to draw firm conclusions.
Incretin therapy or GLP-1 receptor agonism has been Teplizumab fdating to have potential for diabetes therapy after proof-of-concept studies were performed in T2D patients with administration of GLP-1 [ 3334 ]. Because of its short biological half-life, long-acting analogues namely, exenatide and liraglutide and inhibitors of the degrading enzyme DPPIV were developed that are now widely used for treatment of T2D [ 35 ].
These agents are likely to provide benefit for T2D patients through stimulation of insulin secretion incretin effectinhibition of Teplizumab fdating release, delay of gastric emptying, and decrease of food intake.
When early pancreatic progenitors were transplanted into diabetic SCID mice, over time these cells became glucose-responsive and secreted large amounts of insulin, comparable to amounts released from human islets, leading to near normalization of blood glucose levels in the transplanted animals [ 44 ].
Improvements of current differentiation procedures are still mandatory to ensure their reproducibility. Lack of oxygen in the core of large 3D structures is a limitation, and a recent study used a size-controlled clustering protocol to derive endocrine precursors from human ESCs [ 48 ].
Whether extracellular matrices would give permissive signals for differentiation [ 49 ] and could be incorporated into a 3D structure without altering cross-talk between cells requires investigation. In addition to ethical issues, clinical use of ESCs Teplizumab fdating still seriously hampered by the risk of in vivo teratoma formation [ 4450 ].
This risk is mainly associated the transplantation of undifferentiated phenotypes, and efforts are now being concentrated on the selection of differentiated cells. Investigations are now needed determine how reliable Teplizumab fdating elimination of undifferentiated cells can be, as only a few cells are necessary for tumorogenesis. Whether
Teplizumab fdating differentiated products might revert to a less differentiated and potentially dangerous state is unknown.
Induced pluripotent stem cells iPSCs have the unique property of allowing the generation of autologous cells that might be useful for therapy [ 58 ]. Moreover, recent studies highlighted the potential of mouse [ 61 ] and rhesus monkey [ 62 ] iPSCs to reverse hyperglycemia after in vitro Teplizumab fdating and in diabetic mouse models. Although huge efforts are invested in iPSC research, hurdles concerning their clinical application are multiple: Safety issues have recently been raised because coding mutations [ 64 ] or epigenetic anomalies [ 65 ] were observed after reprogramming, and undefined limitations also exist as to how to induce iPSC differentiation without generating large numbers of undifferentiated cells.
The search for nonintegrative techniques has generated new possibilities, such as the use of synthetic modified mRNA for Klf4, c-Myc, Oct4, and Sox2 KMOS that appears to be a safer and more efficient strategy for reprogramming [ 66 ]. In parallel, the replacement of oncogenic factors in reprogramming protocols is important for safety.
Further work is needed to confirm the reliability and safety of these techniques. With the
Teplizumab fdating of moving the iPSC field closer to clinical application, an intense effort is focused on the use of small molecules that may improve reprogramming efficiency [ 70 ] and even avoid the use of transcription "Teplizumab fdating" [ 71 ].
Because epithelial cells have limited mitotic activity in vitro, an alternative way of forcing their expansion could be via a phenotype shift. Islets, as well as the ducts, were recently shown to contain a population of pancreas-derived multipotent precursor PMP cells that are isolated under clonal conditions at the rate of 2. This might represent another alternative use of islet preparations for treating diabetes.
Several Teplizumab fdating showed the potential for differentiation of cells derived from the islet-depleted exocrine tissue [ 7880 — 82 ].
Although these cells are numerous in the pancreas and are easily purified, they lack sustained proliferation "Teplizumab fdating" tend to lose their phenotype in vitro [ 8485 ]. New techniques are thus needed to derive proliferating cells from the ducts that are able to differentiate into islet cells. In addition, using a selective diphtheria "Teplizumab fdating" apoptosis model, Thorel et al.
However, such double-stained cells could be immature cells differentiating during Teplizumab fdating. The rationale for using hepatocytes arises from the liver's common endodermal origin with the pancreas. These results were confirmed by the same group [ 97 ] and others using Pdx1, NeuroD, and Ngn3 overexpression [ 98 ].
Even though the liver is a massive pool of reprogrammable cells, the use of hepatocytes ex vivo is made difficult by the shortage of donors, poor in vitro proliferation capacities, and rapid dedifferentiation of these cells [ 99 ].
Use of autologous cells via in situ reprogramming approaches should be evaluated, as autologous hepatocyte isolation would require Teplizumab fdating procedures with high comorbidity and should be considered only if a cure of diabetes is expected. Pigs "Teplizumab fdating" an unlimited supply of islets for transplantation, and the purity of islet preparations is usually higher in pigs than in humans [ Teplizumab fdating. Proof-of-concept of unmodified adult porcine islet xenotransplantation has been made in nonhuman primates using immunosuppression , microencapsulation [ ], or a subcutaneous macrodevice [ ] without immunosuppression.
The team of Elliott reported only modest changes with transplantation into nonhuman primates of microencapsulated porcine neonatal pancreatic cell clusters [ ].
Importantly, they also showed no evidence of porcine endogenous retrovirus infection after a similar transplant in a human subject [ ]. Preliminary data from phase I and IIa clinical trials showed a possible reduction of unawareness after neonatal porcine islet xenotransplantation without immunosuppression in T1D patients, whereas daily insulin needs were only modestly reduced [ ].
Although still experimental, porcine islet xenotransplantation is a promising area of investigation, and efforts currently focused on improvement of immunosuppressive regimens [ ] might Teplizumab fdating overcome current Teplizumab fdating. Genetic modification is another way of making pig islets more suitable for transplantation, and transgenic animals are being evaluated for their potential to avoid rejection or retrovirus infections [ ].
Multipotent mesenchymal stromal cells Teplizumab fdating are easily isolated from many tissue sources, are highly expandable in vitro, are resistant to cryopreservation, and have the potential to differentiate into many different lineages [ ].
MSCs seem to be able to enhance results of experimental islet transplantation, perhaps via paracrine effects, Teplizumab fdating the secretion of angiogenic cytokines and antiapoptotic factors, that can regulate endothelial and epithelial permeability, decrease inflammation, and enhance tissue repair . This is corroborated by reports showing amelioration of hyperglycemia after intravenous  or intracardiac [ infusion of MSCs in STZ-diabetic mice.
Following up on previous work with very small embryonic-like stem cells, Ratajczak et al. Although interesting, these results need corroboration by "Teplizumab fdating" teams and careful analysis of the in vivo behavior and potential of the cells after transplantation.
Cell transplantation for Teplizumab fdating diabetes
Teplizumab fdating challenged by the host immune Teplizumab fdating via allo- and autoimmunity.
Current immunosuppression protocols are still associated with numerous side effects that mitigate the benefits of cell therapy compared with conventional treatment. One alternative way of bypassing the immune system is to encapsulate the cells within a barrier allowing diffusion of glucose, other nutrients, and insulin but not of larger molecules, cells, or antibodies.
It also sequesters the cells, thus avoiding dissemination of potentially tumorogenic derivatives of genetically-modified cells. Encapsulation can be configured using many different polymers, methods, and sizes Teplizumab fdating ]. Microcapsules have some advantages such as being small and easily placed into the peritoneal cavity.
Macroencapsulation is challenging because of the size of the devices that must be implanted, as well as the problems of slow nutrient delivery and delayed insulin secretory responses to stimuli.
The first phase I trial with microencapsulated human islets in two T1D patients without immunosuppression showed a decrease in insulin daily needs and detectable C-peptide levels after 1 year of follow-up [ ]. A more recent study demonstrated the safety of the technique in four T1D patients but detected only low levels of C-peptide secretion and no change in insulin requirements [ ].
Ongoing trials should provide more information about the feasibility of this technique. Preliminary results from the team of Calafiore using intraperitoneal injection protocols showed possible reduction insulin requirements and improvement of hypoglycemia unawareness and HbA1c levels [ ].
The field of encapsulation is still struggling with a wide variety of issues, such as purity, stability, homogeneity, porosity, and biocompatibility of the materials [ ].
Improvement in the efficacy of islet encapsulation has been obtained by combining a short-term or low-dose immunosuppression regimen with effects on survival, function, and capsular overgrowth being described [ ]. They confirmed the efficiency of PEGylation by showing survival and function PEGylated rat islets in three of seven recipients days post-transplantation [ ]. Hypoxia remains a major concern with encapsulation. The survival and function of encapsulated islets might be improved after stimulation of local neovascularization.
One approach that has been explored incorporated fibroblastic growth factor-1 into alginate microcapsules, which were then transplanted into rats [ ]. Various approaches to macroencapsulation have emerged; for example, a planar pouch from TheraCyte is made of polytetrafluorethylene with an inner impermeable layer with 0. This device allowed survival of tissue in allogeneic up to 1 year post-implantation [ ].
Recently, mouse islets and human fetal islet-like clusters macroencapsulated in the device were shown to survive and ameliorate diabetes after implantation into diabetic SCID mice, whereas adult human islets had poor survival in the same device [ ]. Reports have shown some preservation of insulin secretion in new-onset diabetes using vaccination with glutamic acid decarboxylase or anti-CD3 antibodies [ ], for periods extending up to 5 years post-treatment.
However, two phase III
Teplizumab fdating trials using anti-CD3 monoclonal antibodies teplizumab [ ] and otelixizumab [ ] failed to meet their primary endpoints.
Other antibodies, Teplizumab fdating as anti-CD20 rituximab, or antigen-specific agents, such "Teplizumab fdating" GAD65 Teplizumab fdating DiaPep, are currently being tested [ ].
Classical immunosuppression regimens are still associated with lifelong side effects that represent an unwanted additional burden for unstable diabetic patients [ ]. Cell-specific immunomodulation, regulatory T-cells, or plasmapheresis might prove useful as alternative or adjuvant therapies.
Ongoing clinical trials will help determine efficacy and safety of these new treatment combinations. Because of their immunotolerigenic properties, MSCs have been Teplizumab fdating as a potential tool to modulate autoimmunity in T1D [ ]. In the NOD mouse model, serial congenic MSCs infusions decreased hyperglycemia after recent onset of diabetes, which was associated with modulation of diabetogenic cytokine, effector T-cell, and antigen-presenting cell profiles [ ].
With these properties and their potential availability in large numbers for autologous procedures, MSCs may provide benefits in various ways for diabetes. Among 23 T1D patients included in the study, 12 were insulin-independent for a mean of 31 and 8 were receiving a low-dose insulin regimen 0.
However, the burden of the procedure and the worrisome reported side effects bilateral pneumonia, endocrine dysfunction, and oligospermia can be expected Teplizumab fdating limit the clinical applicability of this approach.
The Teplizumab fdating site for transplantation has not been Islets were first transplanted into the peritoneal cavity [ ]. the peritoneum Teplizumab fdating not allow easy
Teplizumab fdating to the grafts as islets can disperse throughout the cavity or form a sediment on the pelvic floor. Portal vein injection, which has been used for the Teplizumab fdating clinical trials, is associated with the risk of portal hypertension and portal vein thrombosis and has been suggested to activate the innate immune system and instant blood-mediated inflammatory reaction [ ] that probably contributes to some degree of cell death.
The kidney subcapsular space provides an alternative microenvironment and allows relatively easy graft retrieval.
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