Endothelial Progenitor Cell Cotransplantation Enhances Islet Engraftment by Rapid Revascularization

Abstract

Impaired revascularization of transplanted islets is a critical problem that leads to progressive islet loss. Since endothelial progenitor cells (EPCs) are known to aid neovascularization, we aimed to enhance islet engraftment by cotransplanting EPCs with islets. Porcine islets, with (islet-EPC group) or without (islet-only group) human cord blood–derived EPCs, were transplanted into diabetic nude mice. The islet-EPC group reached euglycemia by ∼11 days posttransplantation, whereas the islet-only group did not. Also, the islet-EPC group had a higher serum porcine insulin level than the islet-only group. Islets from the islet-EPC group were more rapidly revascularized at the early period of transplantation without increment of final capillary density at the fully revascularized graft. Enhanced revascularization rate in the islet-EPC group was mainly attributed to stimulating vascular endothelial growth factor-A production from the graft. The rapid revascularization by EPC cotransplantation led to better graft perfusion and recovery from hypoxia. EPC cotransplantation was also associated with greater β-cell proliferation, probably by more basement membrane production and hepatocyte growth factor secretion. In conclusion, cotransplantation of EPCs and islets induces better islet engraftment by enhancing the rate of graft revascularization. These findings might provide a directly applicable tool to enhance the efficacy of islet transplantation in clinical practice.

Human blood outgrowth endothelial cells improve islet survival and function when co-transplanted in a mouse model of diabetes

“…Interestingly, while the proliferative capacity of beta cells has been questioned for many years, recent lineage-tracing studies have revealed the remarkable capacity of adult beta cells to support beta cell mass maintenance and regeneration through replication [19][20][21]. Our data underscore the potential of beta cells to replicate in an islet-transplantation setting and are in line with a beneficial effect of co-transplantation of EPC on the replication rate of the engrafted beta cells [8]. Unlike Kang et al [8], the current report shows the effect of adult human outgrowth endothelial cells with autologous potential rather than the effect of cord-blood-derived EPC.…”

“…Previous reports have shown that endothelial (progenitor) cells of different origin can improve transplanted beta cell survival and function [7,8,16]. Nevertheless, in contrast to these studies, which evaluated the effect of non-human and/or human cord-blood-derived cells, the present study pioneers co-transplantation of adult human peripheral BOEC with a marginal-islet graft and reports a significant BOEC-specific increase in plasma C-peptide levels and improvement in blood glucose control.…”

“…When cotransplanted, rat aortic endothelial cells have been shown to support beta cell function and/or survival [7]. Human cord-blood-derived endothelial progenitor cells (EPC) are beneficial to porcine islet graft transplantation via rapid graft revascularisation [8]. Nevertheless, the possibility of using adult human endothelial cells derived from the diabetic islet recipient has not yet been examined.…”

Reversal of hyperglycemia in diabetic mice by a marginal islet mass together with human blood outgrowth endothelial cells is independent of the delivery technique and blood clot-induced processes

“…Although we cannot exclude that the observed improvement in blood glucose control and increased insulin content is due to an increased insulin content per cell, our previous report 4 illustrated that BOEC co-engraftment resulted in an increased β-cell volume via a reduction in β-cell death and stimulation of β-cell proliferation. While others have reported that endothelial (progenitor) cells of different origins can improve survival and function of transplanted islets, [16][17][18] our study is, to our knowledge, the first to illustrate the beneficial effect on islet transplantation of adult, human, peripheral blood derived endothelial cells. As we were previously able to mimic the observed beneficial glycometabolic effect with BOEC derived from a type 1 diabetic individual, 4 we further confirmed the autologous transplantation potential of BOEC.…”

“…As we were previously able to mimic the observed beneficial glycometabolic effect with BOEC derived from a type 1 diabetic individual, 4 we further confirmed the autologous transplantation potential of BOEC. Moreover, while some research groups reported an effect of endothelial (progenitor) cells on rapid graft revascularization, 17 BOEC co-engraftment did not affect islet vessel density but rather resulted in an increased graft-vessel and β-cell volume at day 28 PTx. Although we cannot exclude that BOEC, like other primary human endothelial cells, 16 do have a potential benefit on IBMIR-related islet damage, our previous and current report illustrates that BOEC provide other, presumably trophic, support to promote the outcome of islet transplantation and subsequently reverse hyperglycemia.…”