Mesenchymal stromal cell secretory factors induce sustained improvements in islet function pre- and post-transplantation

Cytotherapy. 2018 Dec;20(12):1427-1436. doi: 10.1016/j.jcyt.2018.07.007. Epub 2018 Oct 27.


Background aims: Mesenchymal stromal cells (MSCs) enhance islet function both in vitro and in vivo, at least in part by secreting ligands that activate islet G-protein coupled receptors (GPCRs). We assessed whether pre-treatment with a defined "cocktail" of MSC-secreted GPCR ligands enhances islet functional survival in vitro and improves the outcomes of islet transplantation in an experimental model of diabetes.

Methods: Isolated islets were cultured for 48 h with ANXA1, SDF-1 or C3a, alone or in combination. Glucose-stimulated insulin secretion (GSIS) and cytokine-induced apoptosis were measured immediately after the 48 h culture period and at 24 h or 72 h following removal of the ligands from the culture media. Islets were syngeneically transplanted underneath the kidney capsule of streptozotocin-induced diabetic C57BL/6 mice and blood glucose levels monitored for 28 days.

Results: Pre-culturing islets with a cocktail of ANXA1/SDF-1/C3a potentiated GSIS and protected islet cells from cytokine-induced apoptosis in vitro. These effects were maintained for up to 72 h after the removal of the factors from the culture medium, suggesting a sustained protection of islet graft functional survival during the immediate post-transplantation period. Islets pre-treated with the cocktail of MSC secretory factors were more effective in reducing blood glucose in diabetic mice, consistent with their improved functional survival in vivo.

Discussion: Pre-culturing islets with a cocktail of MSC secretory products offers a well-defined, cell-free approach to improve clinical islet transplantation outcomes while avoiding many of the safety, regulatory and logistical hurdles of incorporating MSCs into transplantation protocols.

Keywords: diabetes; islet transplantation; mesenchymal stromal cells; secretome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Annexin A1 / genetics
  • Annexin A1 / metabolism
  • Annexin A1 / pharmacology
  • Apoptosis / physiology
  • Cell Survival / physiology
  • Cells, Cultured
  • Chemokine CXCL12 / genetics
  • Chemokine CXCL12 / metabolism
  • Chemokine CXCL12 / pharmacology*
  • Complement C3a / genetics
  • Complement C3a / metabolism
  • Complement C3a / pharmacology*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / therapy
  • Glucose / metabolism
  • Insulin Secretion
  • Islets of Langerhans / cytology
  • Islets of Langerhans / drug effects
  • Islets of Langerhans Transplantation / methods*
  • Male
  • Mesenchymal Stem Cells / metabolism*
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Receptors, G-Protein-Coupled / metabolism


  • ANXA1 protein, human
  • Annexin A1
  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • Receptors, G-Protein-Coupled
  • Complement C3a
  • Glucose