Bone marrow-derived stem cell transplantation for the treatment of insulin-dependent diabetes

Abstract

The bone marrow is an invaluable source of adult pluripotent stem cells, as it gives rise to hematopoietic stem cells, endothelial progenitor cells, and mesenchymal cells, amongst others. The use of bone marrow-derived stem cell (BMC) transplantation (BMT) may be of assistance in achieving tissue repair and regeneration, as well as in modulating immune responses in the context of autoimmunity and transplantation. Ongoing clinical trials are evaluating the effects of BMC to preserve functional beta-cell mass in subjects with type 1 and type 2 diabetes, and to favor engraftment and survival of transplanted islets. Additional trials are evaluating the impact of BMT (i.e., mesenchymal stem cells) on the progression of diabetes complications. This article reviews the progress in the field of BMC for the treatment of subjects with insulin-dependent diabetes, and summarizes clinical data of pilot studies performed over the last two decades at our research center by combining allogeneic islet transplantation with donor-specific BMC. Clinical data is summarized from pilot studies performed at our research center over the last two decades.

Figure 1. Schematics of the different cell subsets present in the bone marrow and their potential therapeutic application in the context of diabetes

Hematopoietic stem cells (HSC) give rise to hematopoietic lineages. Autologous HSC may be used in combination with lymphodepletion preconditioning to restore self-tolerance in the context of autoimmune diabetes. Whereas, allogeneic HSC may be used to achieve mixed chimerism in recipients of donor-specific insulin-producing cells. The high plasticity of mesenchymal stem cells (MSC) may be exploited to induce tissue repair and modulation of inflammation, leading to the recovery of functional islet cell competence, and to the improvement of diabetes complications. MSC may also contribute to the engraftment of insulin-producing cells by providing trophic factors and/or stimuli in the local microenvironment. Also, it may be possible to reprogram MSC into insulin-producing cells ex vivo from a patient's own cells or from allogeneic donors. Endothelial progenitor cells (EPC) are present in the bone marrow and may be mobilized, or obtained from aspirates, and used to improve tissue repair in islets or diabetic complications. They may also be used to enhance the engraftment of insulin-producing cells.

Figure 2

Cumulative graft survival of allogeneic islet grafts combined with donor-specific BMSC transplantation in single, center pilot clinical trials performed at the Diabetes Research Institute of Miami, USA. Graft function was defined as measurable C-peptide.

Figure 3

Metabolic control and insulin requirements in a clinical trial of autologous bone marrow stem cell transplantation and hyperbaric oxygen therapy in 25 subjects with T2D (adapted from [59]).