Local growth factors are beneficial for the autonomic reinnervation of transplanted islets in rats.
ABSTRACT Transplanted islets, being avascular and denervated, receive blood vessels and nerves from the recipient. Reinnervation may account in part for the normalization of islet function in islet transplants. Whether reinnervation is possible to augment is not known.
To explore whether reinnervation of transplanted islets is augmented by local addition of growth factors to the graft, syngeneic islets were transplanted to the pancreas of streptozotocin-diabetic Lewis rats with or without pellets locally releasing nerve growth factor (NGF) and vascular endothelial growth factor (VEGF), alone or in combination. The pellets released growth factors for 14 days at a rate of 20 ng/day. After 7 weeks, pancreatic tissue was processed for immunofluorescence of insulin and the neural markers neuropeptide Y (NPY) and tyrosine hydroxylase (TH).
Islets were larger and more numerous after treatment with NGF (p = 0.024) and with NGF in combination with VEGF (p = 0.044). Similarly, immunostaining for TH and the C-terminal flanking peptide of NPY (C-PON) was more pronounced after treatment with NGF in combination with VEGF than in controls (both p < 0.05).
Local growth factor treatment has a beneficial effect on autonomic reinnervation as well as islet integrity and survival of the graft after islet transplantation in rats.
- SourceAvailable from: Mark Van de Casteele[Show abstract] [Hide abstract]
ABSTRACT: Efficient stimulation of cycling activity in cultured beta cells would allow the design of new strategies for cell therapy in diabetes. Neural crest stem cells (NCSCs) play a role in beta cell development and maturation and increase the beta cell number in co-transplants. The mechanism behind NCSC-induced beta cell proliferation and the functional capacity of the new beta cells is not known. We developed a new in vitro co-culture system that enables the dissection of the elements that control the cellular interactions that lead to NCSC-dependent increase in islet beta cells. Mouse NCSCs were cultured in vitro, first in medium that stimulated their proliferation, then under conditions that supported their differentiation. When mouse islet cells were cultured together with the NCSCs, more than 35% of the beta cells showed cycle activity. This labelling index is more than tenfold higher than control islets cultured without NCSCs. Beta cells that proliferated under these culture conditions were fully glucose responsive in terms of insulin secretion. NCSCs also induced beta cell proliferation in islets isolated from 1-year-old mice, but not in dissociated islet cells isolated from human donor pancreas tissue. To stimulate beta cell proliferation, NCSCs need to be in intimate contact with the beta cells. Culture of islet cells in contact with NCSCs induces highly efficient beta cell proliferation. The reported culture system is an excellent platform for further dissection of the minimal set of factors needed to drive this process and explore its potential for translation to diabetes therapy.Diabetologia 05/2012; 55(7):2016-25. · 6.49 Impact Factor
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ABSTRACT: Background Significant functional decrease and sclerosis of the pancreas graft in late delays cannot only be related to chronic rejection. Any transplantation leads to graft denervation, which may be an important cause of dysfunction. Studies concerning graft reinnervation were controversial. Purpose of the Study The purpose of this study was to investigate the feasibility and pertinence of a surgically directed reinnervation (SDR) of denervated/neuro-reflex isolated (NRI) or autotransplanted (aTx) pancreas. Basic Procedures Anatomy of the nerves penetrating into the pancreas was studied in humans, dogs, cats, and rats. Surgery and physiological investigations were performed in dogs, cats, and rats. Nervous conductivity between NRI, NRI+SDR pancreas, and brain was tested. Load tests with glucose, insulin, and adrenalin were performed; amylase and lipase were determined in fasted and not fasted animals to evaluate the influence of NRI and SDR on pancreatic function. Histology was provided. Observation delays were 6 months. Main Findings Anatomic feasibility of SDR in humans and animals was proved. Models of pancreatic tail NRI and surgical reconstitution of the interrupted nervous pathways (SDR) were elaborated in animals. The restoration of the pancreas-brain reflex axis after SDR was electro physiologically proved. As blood glucose curves after load test, exocrine amylase and lipase determination have shown that pancreas NRI or aTx leads to an exaggerated reaction to usual stimulations that may cause the observed graft functional exhaustion in late delays. SDR shortened the period of the graft neuro-reflex isolation, contributed to a quick normalization of its function, and prevented its late degradation. Conclusion SDR was shown to be a simple surgical technique, easily performed after the graft surgical revascularization. Its functional and morphological efficiency was tested and proved. Thus, SDR may be recommended in human pancreas transplantation as pertinent.Transplantation Proceedings 08/2014; 46(6):2010–2018. · 0.95 Impact Factor
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ABSTRACT: Nerve growth factor (NGF) belongs to the family of neurotropic proteins NGF is markedly expressed in proteinuric renal diseases and in end-stage renal disease; it might be involved in kidney physiopathology. To date, little is known about NGF concentrations in kidney transplant recipients (KTRs). Because NGF exerts its action on cell survival and differentiation, tissue repair, and inflammatory responses, it may also be implicated in the pathogenesis of chronic allograft nephropathy. The aim of this study was to determine circulating NGF concentrations in KTRs and to ascertain their use as a prognostic marker for kidney transplant outcomes. Using enzyme-linked immunosorbent assay, we performed quantification of NGF in the serum of 40 prevalent KTRs at baseline and at 6 months. NGF concentrations in KTRs averaged 1.16 ± 0.67 ng/mL. They negative-linearly correlated with recipient age. Logistic multivariate regression analysis showed NGF to be independently associated with increased proteinuria over the 6-month follow-up. Our data demonstrated that serum concentrations of NGF in KTRs were elevated and that they could be considered to be a prognostic marker in kidney transplantation.Transplantation Proceedings 09/2013; 45(7):2654-6. · 0.95 Impact Factor