Human Mesenchymal Stem Cells Protect Human Islets from Pro-Inflammatory Cytokines

Abstract

Transplantation of human islets is an attractive alternative to daily insulin injections for patients with type 1 diabetes. However, the majority of islet recipients lose graft function within five years. Inflammation is a primary contributor to graft loss, and inhibiting pro-inflammatory cytokine activity can reverse inflammation mediated dysfunction of islet grafts. As mesenchymal stem cells (MSCs) possess numerous immunoregulatory properties, we hypothesized that MSCs could protect human islets from pro-inflammatory cytokines. Five hundred human islets were co-cultured with 0.5 or 1.0×106 human MSCs derived from bone marrow or pancreas for 24 hours followed by 48 hour exposure to interferon-γ, tumor necrosis factor-α and interleukin 1β. Controls include islets cultured alone (± cytokines) and with human dermal fibroblasts (± cytokines). For all conditions, glucose stimulated insulin secretion (GSIS), total islet cellular insulin content, islet β cell apoptosis, and potential cytoprotective factors secreted in the culture media were determined. Cytokine exposure disrupted human islet GSIS based on stimulation index and percentage insulin secretion. Conversely, culture with 1.0×106 bMSCs preserved GSIS from cytokine treated islets. Protective effects were not observed with fibroblasts, indicating that preservation of human islet GSIS after exposure to pro-inflammatory cytokines is MSC dependent. Islet β cell apoptosis was observed in the presence of cytokines; however, culture of bMSCs with islets prevented β cell apoptosis after cytokine treatment. Hepatocyte growth factor (HGF) as well as matrix metalloproteinases 2 and 9 were also identified as putative secreted cytoprotective factors; however, other secreted factors likely play a role in protection. This study, therefore, demonstrates that MSCs may be beneficial for islet engraftment by promoting cell survival and reduced inflammation.

Novel Immunomodulatory Markers Expressed by Human WJ-MSC: an Updated Review in Regenerative and Reparative Medicine

“…Authors reported that culture of MSC with transplanted islets prevented β-cell apoptosis after cytokine treatment. Hepatocyte growth factor, MMP-2 and MMP-9 were suggested as the secreted cytoprotective factors [111].…”

IGF2: an endocrine hormone to improve islet transplant survival

“…Exposure of rat islets to IL1b in vitro decreases islet insulin content, suppresses glucose-stimulated insulin secretion, induces DNA damage and leads to islet destruction (Bendtzen et al 1986, Comens et al 1987, Sandler et al 1987, Wachlin et al 2003. Recently, Yeung et al (2012) have described morphological alterations in human islets following pro-inflammatory cytokine exposure in vitro and these changes are consistent with the cells undergoing apoptosis (i.e. cell shrinkage and chromosomal condensation).…”

Murine Insulinoma Cell-Conditioned Medium with ΒETA2/Neurod1 Transduction Efficiently Induces the Differentiation of Adipose-Derived Mesenchymal Stem Cells into β-Like Cells both In Vitro and In Vivo

“…Several studies have already found that MSCs have an immunomodulatory effect by both contact-dependent and -independent mechanisms [19][20][21][22][23][24], and they secrete or release many substances into the surrounding medium. This phenomenon stimulated researchers to use conditioned medium (CM) of MSCs to reduce the toxic effects of ischemia reperfusion injury [25].…”