Management of diabetes is a major health concern and recent research in pluripotent stem cells shows promise in effective therapy. We provide a comprehensive outlook in our three part series.
Diabetes mellitus is a metabolic disorder, widespread among the human population. The main characteristic of this disorder is the presence of high sugar or glucose in blood. However, there is nothing sweet or sugary about diabetes, as its long-term effects include morbidities and mortalities. In fact, the World Health Organization (WHO) predicts diabetes to be the seventh leading cause of death by 2030. The exact causes of diabetes is a matter of huge debate, and several contributing factors such as, diet, lifestyle and genetics have been identified (Fig 1.). Nevertheless, several research groups have focused in effective therapy of this disease. One of the approaches includes use of stem cells.
Pluripotent stem cells, which include induced pluripotent stem cells and embryonic stem cells are distinguished both by their ability for self-renewal and differentiation into all three germ layers. Induced pluripotent stem cells can be derived from somatic cells e.g. blood cells, hepatocytes, keratinocytes, stomach cells and fibroblasts. These pluripotent stem cells in turn can be differentiated into insulin secreting pancreatic β cells and in fact, recent studies have documented that pluripotent stem cells are an excellent resource for b cells. Transplantation of pancreatic β cells in patients suffering from diabetes offers a long-term therapeutic solution. Below, we describe the steps involved in differentiation of pluripotent stem cells to β cells.
Transfection of somatic cells with key transcription factors such as OCT4, SOX2, C-MYC, NANOG, SOX2 and KLF4 generates pluripotent stem cells and their identity is characterized by rapid and symmetrical cell division. Pluripotent stem cells in turn can be differentiated into pancreatic β cells in four-step protocol, whose success is based on culture conditions and the stimulation of central regulatory genes contributing to pancreas development (Fig 2.). The first step is the differentiation of stem cells to definitive endoderm (DE), which requires NODAL and WNT as essential signals. NODAL is activated by activin A and hence a high concentration of activin A (50-100 ng/ml), along with antagonists of PI3K pathway in absence of serum ensures DE induction. DE further differentiates into pancreatic progenitors (PDX1-positive) by addition of antagonists against BMP, FGF receptor, NOTCH and HEDGEHOG pathways. The next two steps involve inhibition of TGFβ type 1 receptor, vesicular monamine transporter 2 (VMAT2) and pancreatic β cell maturation by appropriate steroids and growth factors.
The four step process
Among the diverse sources of somatic cells, peripheral blood offers several advantages and HemaCare has well-established protocols for stem cell generation, which can be further customized to suit your research needs! For a comprehensive outlook of this field, please be sure to read this entire series. In Part II, we will discuss the state-of-art technology to derive patient specific stem cells and in the final part, part III, potential benefits and pitfalls of pluripotent stem cells in personalized medicine will be evaluated.
1. Essam M. Abdelalim, Amélie Bonnefond, Annelise Bennaceur-Griscelli, Philippe Froguel. Pluripotent Stem Cells as a Potential Tool for Disease Modelling and Cell Therapy in Diabetes. Stem Cell Reviews and Reports (2014) 129 (4):1102-15. doi.org/10.1007/s12015-014-9503-6