Mesenchymal Stem Cells and Islet Cotransplantation in Diabetic Rats: Improved Islet Graft Revascularization and Function by Human Adipose Tissue-Derived Stem Cells Preconditioned with Natural Molecules

Abstract

Hypoxia plays an important role in limiting the engraftment, survival, and function of intrahepatically transplanted islets. Mesenchymal stem cells (MSCs) were recently used in animal models of islet transplantation not only to reduce allograft rejection but also to promote revascularization. Among different possible origins, adipose tissue represents a novel and good source of MSCs. Moreover, the capability of adipose tissue-derived stem cells (ASCs) to improve islet graft revascularization was recently reported after hybrid transplantation in mice. Within this context, we have previously shown that hyaluronan esters of butyric and retinoic acids can significantly enhance the rescuing potential of human MSCs (hMSCs). Here we evaluated whether ex vivo preconditioning of human ASCs (hASCs) with a mixture of hyaluronic (HA), butyric (BU), and retinoic (RA) acids may result in optimization of graft revascularization after islet/stem cell intrahepatic cotransplantation in syngeneic diabetic rats. We demonstrated that hASCs exposed to the mixture of molecules are able to increase the secretion of vascular endothelial growth factor (VEGF) as well as the transcription of angiogenic genes, including VEGF, KDR (kinase insert domain receptor), and hepatocyte growth factor (HGF). Rats transplanted with islets cocultured with preconditioned hASCs exhibited a better glycemic control than rats transplanted with an equal volume of islets and control hASCs. Cotransplantation with preconditioned hASCs was also associated with enhanced islet revascularization in vivo, as highlighted by graft morphological analysis. The observed increase in islet graft revascularization and function suggests that our method of stem cell preconditioning may represent a novel strategy to remarkably improve the efficacy of islets-hMSCs cotransplantation.

The β-Cell/EC Axis: How Do Islet Cells Talk to Each Other?

“…The ideal candidate should be able to migrate to the required site, deliver supportive factors, and persist for the appropriate time. Mesenchymal stem cells stimulate vessel ingrowth into islets in vitro (71), and their cotransplantation improves islet transplant outcomes in rats (72). While somewhat efficacious, concerns linger regarding the potential invasiveness and pluripotency of mesenchymal stem cells, especially in the immune-compromised transplant population.…”

In situ application of hydrogel-type fibrin–islet composite optimized for rapid glycemic control by subcutaneous xenogeneic porcine islet transplantation

“…To prevent hypoxia-induced beta-cell damages and thereby improve islet engraftment, many studies have attempted to improve the graft vascularization by addition of extracellular matrix or by constructing pre-vascularized device with synthetic bio-compatible materials [14][15][16]. In addition, stem cell co-transplantation, maintenance in a low-temperature, hypoxia-resistant gene transfer and use of oxygen-supplying system have been tried in experimental mouse models [17,18]. However, the clinical application of these techniques has been limited because of the multiple surgeries that are required, the complex manipulations and biosafety concerns.…”

Cancer Stem Cells: Foe or Reprogrammable Cells for Efficient Cancer Therapy?

“…Among these agents, hyaluronic acid (HA), butyric acid (BA) and retinoic acid (RA) have long and consistently been shown to modulate growth and differentiation even at the stem cell level (see below for detailed references). A combination of HA, BA, and RA has been shown to increase the survival and differentiation potential in human adipose tissue-derived mesenchymal stem cells (ADhMSCs) [32]. To this end, ex vivo stem cell preconditioning with a mixture of these molecules followed by stem cell co-transplantation with beta-pancreatic islets in syngeneic diabetic rats also resulted in the optimization of islet engraftment and survival, and normalization of glycemic control [32].…”

“…A combination of HA, BA, and RA has been shown to increase the survival and differentiation potential in human adipose tissue-derived mesenchymal stem cells (ADhMSCs) [32]. To this end, ex vivo stem cell preconditioning with a mixture of these molecules followed by stem cell co-transplantation with beta-pancreatic islets in syngeneic diabetic rats also resulted in the optimization of islet engraftment and survival, and normalization of glycemic control [32]. BA and RA have also been grafted within a synthetic molecule in the form of HA mixed esters (HBR) [33].…”