Surface Coating of Pancreatic Islets with Neural Crest Stem Cells Improves Engraftment and Function after Intraportal Transplantation

Abstract

The present study aimed to develop techniques for surface coating of islets with neural crest stem cells (NCSCs) in order to enable cotransplantation to the clinically used liver site and then investigate engraftment and function intraportally of such bioengineered islets. Mouse islets were coated during incubation with enhanced green fluorescent protein (EGFP)-expressing mouse NCSCs and transplanted into the portal vein to cure diabetic mice. An intravenous glucose tolerance test was performed at 1 month posttransplantation. Islet grafts were retrieved and evaluated for vascular density, nerves, and glial cells. NCSCs expressed a vast number of key angiogenic and neurotrophic factors. Mice transplanted with NCSC-bioengineered islets responded better to the glucose load than recipient mice with control islets. NCSCs remained present in the vicinity or had often migrated into the NCSC-coated islets, and an improved islet graft reinnervation and revascularization was observed. Transplanted NCSCs differentiated into both glial and neural cells in the islet grafts. We conclude that bioengineering of islets with NCSCs for intraportal transplantation provides a possibility to improve islet engraftment and function. Pending successful establishment of protocols for expansion of NCSCs from, for example, human skin or bone marrow, this strategy may be applied to clinical islet transplantation.

Boundary Cap Neural Crest Stem Cells Promote Survival of Mutant SOD1 Motor Neurons

“…The improved SOD1 G93A MN survival coincided with the presence of direct contacts between bNCSCs and SOD1 G93A MNs, suggesting that the positive effect of bNCSCs might be mediated through intercellular connections, as was shown previously in bNCSC-beta-cell cultures [29]. We have also shown that bNCSCs produce a broad range of trophic factors, as well as Wnt-1 and matrix metalloproteinases [35]. This trophic capacity, in co-operation with direct cell-cell interaction, may explain the survival promoting effects of bNCSCs on SOD1 G93A MNs under stressful conditions in vitro .…”

“…However, the presence of GFP + MNs at a distance from bNCSCs and in the vicinity of the central canal one week after implantation indicates that some implanted SOD1 G93A MN precursors rapidly become independent of close contact with bNCSCs. Survival of migrated SOD1 G93A MNs may be supported by bNCSC-derived diffusible molecules, such as vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), and ciliary neurotrophic factor (CNTF) [35], all of which have trophic effects on MNs [37]. bNCSC-derived matrix metalloproteinase-2 and -9 (MMP-2 and -9) [36], which have been implicated in cell migration [38, 39], may contribute to the migratory capacity of implanted SOD1 G93A MNs to the spinal cord parenchyma and in some cases towards the central canal (Supplemental Fig.…”

Tissue‐engineering approaches in pancreatic islet transplantation

“…Finally, neural crest stem cells ( NCSCs ) are other supporting cells that have been used to improve islet transplantation, increasing both islet reinnervation and revascularization (Lau, Vasylovska, Kozlova, & Carlsson, ).…”

“…Dendritic cells (DCs) are potent antigen-presenting cells that play an important role in innate and adaptive immunity by inducing and modulating T cell activation. DC-based immunotherapeutic approaches have been developed to prevent and reverse T1D (Mukherjee & Dilorenzo, 2010 Finally, neural crest stem cells (NCSCs) are other supporting cells that have been used to improve islet transplantation, increasing both islet reinnervation and revascularization (Lau, Vasylovska, Kozlova, & Carlsson, 2015).…”

Effect of scaffold properties on adhesion and maintenance of boundary cap neural crest stem cells in vitro

“…In addition to their robust survival and broad differentiation potential, they display a remarkable ability to promote survival and support the function of different types of co-cultured cells. Thus, bNCSCs stimulate proliferation of co-cultured (Grouwels et al, 2012;Ngamjariyawat, Turpaev, Vasylovska, Kozlova, & Welsh, 2013;Ngamjariyawat, Turpaev, Welsh, & Kozlova, 2012;Wang et al, 2016) and co-implanted insulinproducing pancreatic beta-cells (Lau, Vasylovska, Kozlova, & Carlsson, 2015;Olerud et al, 2009). Co-transplantation of bNCSCs and human pancreatic islets increased islet vascularization and innervation, most likely mediated by diffusible factors released from the bNCSCs (Grapensparr et al, 2015;Lau et al, 2015).…”