Skin deep: from dermal fibroblasts to pancreatic beta cells

Abstract

Type I diabetes (T1D) is a chronic autoimmune disease caused by pancreatic β-cell destruction induced by autoantibodies and autoreactive T cells. After significant reduction of the β-cell mass, diabetes sets in and can cause significant complications. It is estimated that more than 3 million Americans have T1D, and its prevalence among young individuals is progressively rising; however, the reasons for this increase are not known. Islet transplantation is recognized as the ultimate cure for T1D, but unfortunately, the severe scarcity of available islets makes it necessary to establish alternative sources of β-cells. Our lab seeks to establish human-induced pluripotent stem cells as an unlimited, novel source of insulin-producing cells (IPCs) that are patient-specific, obviating the requirement for immunosuppression. Although several reports have emerged demonstrating successful derivation of IPCs from human pluripotent stem cells, the efficiencies of derivation are inadequate and these IPCs do not respond to glucose stimulation in vitro. We reasoned that the use of a growth factor sequestering bioscaffold and promotion of cell-cell signaling through 3D clustering would enhance the generation of functionally superior IPCs compared to those derived by 2D differentiation. Here, we discuss a novel 3D platform for the generation of highly efficient human IPCs.

Generation and function of glucose-responsive insulin producing cells derived from human induced pluripotent stem cells

“…Recently, a clinical trial was initiated using iPS cell-derived retinal pigment epithelial cells for the treatment of a debilitating eye disease known as macular degeneration 43 . Moreover, unlike ES cells that are fraught with controversy regarding their derivation from embryos, iPS cells are derived from pre-existing somatic cells and enable the possibility of developing patient-tailored therapies 6,9 . These characteristics of iPS cells allow a unique opportunity to engineer autologous Insulin Producing Cells (IPCs) that can be used to replace pancreatic β-cells destroyed in T1D 6,9,44,45 .…”

“…For therapy of T1D patients, relatively noninvasive procedures can be used to obtain somatic cells that can be reprogrammed into iPS cells, which upon conversion into IPCs would be transplanted back into the patient for effective and long-term maintenance of homeostatic blood glucose levels ( Figure 1B). Our rationale for differentiating IPCs from iPS cells is that these cells will be a superior source of therapeutic cells compared to cadaveric pancreatic islets in their 1) unlimited availability, 2) patient-tailored derivation, and most significantly, 3) poor expression of MHC complexes by these cells may allow for evasion of autoimmune detection, giving rise to cells that are permanently functional without the requirement for immunosuppression, encapsulation procedures or recurrent transplantation 6 .…”

“…Mirroring the organogenesis of the pancreas, the differentiation of iPSCs into IPCs involves several major lineage choices that must be managed correctly in order to efficiency give rise to IPCs. Modulation of the cell fate decisions involves reinforcement of positive signals toward particular cell types while inhibiting alternative lineage choices in tandem 6,47 . These lineage bifurcations are summarized in a simplified cartoon ( Figure 2).…”

“…In order to become IPCs, the iPSCs must first be instructed to differentiate into DE cells 6,[12][13][14][15][16]47,48 . The endoderm constitutes the innermost layer of cells of the three germ layers that form during gastrulation 49,54 .…”

“…Because of their high pancreatic β-cell content, islet transplantation is recognized as the most effective treatment for T1D 1,4,5 . Unfortunately, the source of cadaveric islets is extremely scarce and the possibility of immunological rejection precludes widespread matching of donors and recipients [5][6][7] . Mechanical insulin secreting technologies are being developed for automatic control of blood glucose levels and have met some success 8 .…”