Adult Stem Cell Plasticity, Hype or Hope?

University dissertation from Clinical Research Center Islet pathophysiology UMAS, Malmö Lund University

Abstract: Several studies have reported that bone marrow (BM)-derived stem cells have the capacity to give rise to cells of different type of tissue; an ability termed stem cell plasticity or transdifferentiation. Controversies exist as to how frequent this phenomenon is, or if it may be explained by alternative mechanisms. Here we have used different mouse models to study the potential plasticity of BM-derived stem cells. In the first two studies aiming at defining how BM transplantation may contribute to generation of pancreatic beta-cells, we first demonstrated that BM cells readily engraft recipient pancreas in normal and diabetic mice. Engrafted cells expressed the hematopoietic marker CD45 (CD45+), but no beta-cell markers, e.g. insulin or transcription factors pdx 1 or Nkx6.1. However, a subset of engrafted BM cells also expressed endothelial markers von Willebrand factor (vWF) and CD31/PECAM. In mice treated with different dosages of the beta-cell toxin streptozotocin (STZ) to induce diabetes, the fraction of CD45+vWF+ cells increased with the STZ dose. This coincided with increased proliferation BrdU+ cells in both vWF+ and insulin+ cells. In a third study evaluating BM plasticity in mouse models of myocardial infarction, we showed that BM-derived stem cells efficiently engraft the infarcted myocardium, without any signs of transdifferentiation. A very small population (0.75%) of the BM-derived cells exhibiting a cardiomyocyte phenotype was observed outside the infarcted myocardium. Further analysis showed that these cells were derived through cell fusion. In summary, this thesis challenges the view that BM-derived stem directly transdifferentiate into cardiomyocytes or pancreatic beta-cells. However, BM cells may stimulate pancreatic ?-cell proliferation indirectly, possibly by adopting an endothelial phenotype. These results underline the importance of thorough studies at the cellular level before initiation of clinical BM transplantation trials.

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