Diabetes Mellitus, Insulin-Dependent

 - Cell Therapy Approaches

Cell-based therapies for T1DM harness several therapeutic arms: generating transplantable glucose-responsive, insulin-producing cells (IPCs) and exploiting the immunomodulatory characteristics of the cells to reconstitute the immune system, thereby preserving the β cells.

Immunomudolation:

Many clinical trials have employed hematopeitic stem cell (HSCs) transplantations for reconstitution of the immune system and β-cell preservation. The cells are mobilized and collected by leukapharesis and transplanted following chemotherapy and immunotherapy aimed to terminate immune aggression against IPCs. Immunological tolerance was achieved by infusion of autologous non-myeloablative HSCs after immune ablation. Treatment resulted in a significant number of insulin-free patients, with no mortality and only mild adverse effects, after a mean follow-up period of 29.8 months. Thus, HSCs transplantation is considered by some to be the most effective therapy studied to date, for new onset T1DM. Autologous lymphocytes that were conditioned by cord blood-derived stem cells were infused to T1DM patients achieving reversal of autoimmunity, inducing increase in peripheral regulatory T (Treg) cells and reducing exogenous insulin requirements.

Mesenchymal stem cells (MSCs) can exert immunomodulatory effects on T cells by direct cell-to-cell contact and also by secretion of soluble immunomodulatory molecules. MSCs may interact with dendritic cells (DC) and induce their maturation and migration and are known to induce Treg cell expansion. Thus, MSCs derived from different sources, such as bone marrow, umbilical cord and adipocytes, might serve as a viable alternative to harmful immunosuppressive drugs deleterious to islets. Moreover, MSCs selectively migrate to sites of injury and participate in their repair. In T1DM patients MSCs modulate β cell regeneration by affecting gene expression and promote angiogenesis by secretion of angiogenic factors. The safety and efficacy of repeated administration of bone marrow-derived MSCs to regulate the immune system and promote some degree of disease control in newly diagnosed T1DM patients was assessed. No side effects were recorded and HbA1c and c-peptide values improved in patients treated with umbilical cord-derived MSCs. Remestemcel-L (Prochymal) is an intravenous formulation of MSCs, which are derived from the bone marrow of healthy adult donors and do not require that recipients be typed, matched or receive immunosuppression. Administration of Remestemcel-L in new-onset T1DM patients was well-tolerated and induced slightly fewer hypoglycemic events compared to controls.

Treg cells: Long-lasting antigen-specific tolerance by means of Treg cells is a goal to achieve in the treatment of T1DM. Encouraging results following delivery of Treg cells have demonstrated prevention of experimental diabetes. Intravenous infusion of autologous polyclonal Treg cells in T1DM patients is currently being assessed.

Cell replacement:

The main sources explored for b cell replacement are porcine islets (xenografts), expansion of autologous or allogeneic β cells, other pancreatic cell types (endocrine, acinar or ductal), embryonic stem cells and conversion of terminally differentiated cells, such as blood cells and liver cells. Controversy exists regarding the existence of β cell progenitor cells in the pancreas, which could serve as potential sources for cell therapy. Conclusions vary depending on the experimental model; either adult β cells replicate without progenitors or neogenesis of β cells exists in vivo.

Some strategies for increasing the abundance of donor material for transplantation include the use of islets from other species including pigs (xenografts) and the expansion of human β cells in vitro. However, xenotransplantation bears the potential risk of transferring disease across species, while β cell expansion in vitro is limited by senescence and dedifferentiation of the cells.

Embryonic stem cells (ESCs) and human pluripotent stem cells (hPSCs) can be induced to preferentially differentiate into IPCs by changing the composition of the culture medium and by expression of dominant transcription factor genes which are involved in pancreas development. However, apart from their potential tumorigenicity, disparity exists regarding the glucose sensing and insulin secreting abilities of the cells. Reprogramming of other cells, such as induced pluripotent cells (iPSCs), and conversion of terminally differentiated cell types (liver cells and blood cells) into IPCs, utilizing protocols that mimic the mechanism of in vivo pancreatic development to guide the differentiation, have been established. The conversion of other pancreatic cell types into IPCs has been primarily demonstrated in acute animal models and is still in early stages of development. IPCs derived from ESCs, hPSCs and iPSCs do not mature to functional monohormonal β cells in vitro. Moreover, the modes of delivering pancreatic transcription factors may introduce risk as some of them involve lentiviral infection. The efficiency and yield of these processes is low and though proven to normalize the blood glucose levels in vivo in mice models, have yet to be clinically proven. At the same time, most of these treatments provide autologous sources for IPCs that may reduce the necessity for immune suppression and may be transplanted into a non-endogenous site or into immunoprotective devices. A semipermeable barrier or encapsulation can be used in order to transplant xenogenous and allogeneic cells, enabling immuno-isolation.

There are several clinical trials employing different cell types for treatment of diabetes. Porcine islet cells in alginate microcapsules (DIABECELL®) were transplanted and found to be safe and induced a reduction in required insulin dose and circulating glycosylated hemoglobin. Embryonic porcine cells exhibit markedly little immunogenicity, providing an effective substitute to β cells in diabetic animal models. Endothelial progenitor cells co-transplanted with porcine-derived islets into STZ-treated mice enhanced revascularization of the transplanted islets. StemGenex™, adipose-derived stem cells combined with platelet-rich plasma, activated by specialized low laser light, are precursors to embryonic and islet stem cells that produce insulin and their safety and efficacy is under investigation.