Signals from the neural crest regulate beta-cell mass in the pancreas

Nekrep, Nada; Wang, Juehu; Miyatsuka, Takeshi; German, Michael S.

doi:10.1242/dev.015859

Cited by 97 publications

(92 citation statements)

References 45 publications

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“…1b). NCSCs indeed have a strong capacity to migrate in vivo and in vitro [8,10] and thus are able to migrate into the islets, making cell-cell contacts.…”

Section: Resultsmentioning

confidence: 99%

“…The endocrine pancreas is normally richly innervated with sympathetic, parasympathetic, sensory, peptidergic and nitric oxide synthase containing neurons that help to modulate hormone secretion [1][2][3]. In rodent models, signals from the neural crest are important in regulating beta cell mass during development [7,8] and neural signals are involved in the adaptive increase of beta cell mass in obesity [37]. There are several studies suggesting that neurotrophins, such as nerve growth factor and brain-derived neurotrophic factor, may affect the growth of both nerves and beta cells in Fig.…”

Section: Discussionmentioning

confidence: 99%

“…In BioBreeding (BB) rats, an experimental model for type 1 diabetes, these nerves disappear even before beta cells are lost [6]. Recent studies have demonstrated that neural crest stem cells (NCSCs), from which all neurons that innervate the islets are derived, play an important role in regulating beta cell mass during early development [7,8] and during islet maturation [9]. We previously showed that mature sensory neurons influence insulin release by adult islets in vitro [10].…”

Section: Introductionmentioning

confidence: 99%

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Differentiating neural crest stem cells induce proliferation of cultured rodent islet beta cells

et al. 2012

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Aims/hypothesis 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. Methods 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.Results 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. Conclusions/interpretation 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.

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“…1b). NCSCs indeed have a strong capacity to migrate in vivo and in vitro [8,10] and thus are able to migrate into the islets, making cell-cell contacts.…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differentiating neural crest stem cells induce proliferation of cultured rodent islet beta cells

et al. 2012

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“…Recently, it has been proposed that nonmesodermal-derived stem cells support beta-cell replication. Different studies found that beta-cell growth may be affected by neurotrophins [51,52], and that neural crest stem cells (NCSC) have an important role in beta-cell differentiation by regulating beta-cell mass during development [53]. On the basis of these observations, Olerud et al investigated whether co-transplantation of islets and neurospheres derived from NCSC is beneficial for survival, growth, and function of transplanted beta-cells [54].…”

Section: Mechanism Of Diabetes Reversal Through Co-transplantation Ofmentioning

confidence: 99%

Mesenchymal Stem Cells as Feeder Cells for Pancreatic Islet Transplants

Sordi¹,

Piemonti²

2010

Rev Diabet Stud

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■ AbstractAllogeneic islet transplant serves as a source for insulinsecreting beta-cells for the maintenance of normal glucose levels and treatment of diabetes. However, limited availability of islets, high rates of islet graft failure, and the need for life-long non-specific immunosuppressive therapy are major obstacles to the widespread application of this therapeutic approach. To overcome these problems, pancreatic islet transplantation was recently suggested as a potential target of the "therapeutic plasticity" of adult stem cells. In fact, new results suggest that stem/precursor cells, and mesenchymal stem cells in particular, co-transplanted with islets can promote tissue engraftment and beta-cell survival via bystander mechanisms, mainly exerted by creating a milieu of cytoprotective and immunomodulatory molecules. This evidence consistently challenges the limited view that stem/precursor cells work exclusively through beta-cell replacement in diabetes therapy. It proposes that stem cells also act as "feeder" cells for islets, and supporter of graft protection, tissue revascularization, and immune acceptance. This article reviews the experience of using stem cell co-transplantation as strategy to improve islet transplantation. It highlights that comprehension of the mechanisms involved will help to identify new molecular targets and promote development of new pharmacological strategies to treat type 1 and type 2 diabetes patients.

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“…In both type 1 and type 2 diabetes, dysregulation of glucose homeostasis and b-cell function and loss of b-cells are responsible of hyperglycemia (1). b-cells are neuroendocrine cells arising from precursor cells of the embryologic neural crest (2,3). Pancreatic b-cells regulate a large variety of body functions through paracrine and endocrine actions via dedicated amines and peptides, including the neurotransmitter serotonin.…”

mentioning

confidence: 99%

¹¹C-Hydroxytryptophan Uptake and Metabolism in Endocrine and Exocrine Pancreas

et al. 2012

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Determination of the residual b-cell mass using noninvasive tools might help to follow up the efficacy of new treatments in both type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus, including islet transplantation. b-cells are neuroendocrine cells that can take up and metabolize the serotonin precursor 5-hydroxytryptophan. The serotonin pathway may therefore be an attractive target for the development of an imaging tracer for residual b-cell mass. The aim of this study was to evaluate the uptake mechanism and the retention of the PET tracer 11 C-hydroxytryptophan in endocrine and exocrine pancreas in vitro and in vivo. Methods: The exocrine human pancreas carcinoma cell line (PANC-1) and the endocrine human insulinoma cell line (CM) were applied for in vitro 11 Chydroxytryptophan accumulation/efflux experiments and blocking studies using inhibitors of key enzymes and transporters involved in the serotonin pathway. Animal experiments were performed on normal Wistar rats and on rats pretreated with the monoamine oxidase (MAO) inhibitor clorgyline. After intravenous injection of 11 C-hydroxytryptophan, a 60-min dynamic PET scan was acquired followed by an ex vivo biodistribution study. Autoradiography and hematoxylin-eosin staining were performed on the dissected pancreas to localize the radioactivity within the pancreatic tissue. Results: 11 C-hydroxytryptophan accumulated rapidly in both endocrine CM cells and exocrine PANC-1 cells. In the exocrine cells, a rapid efflux of radioactivity was observed, whereas most radioactivity remained trapped in the endocrine cells. PET images showed clear accumulation of 11 C-hydroxytryptophan in the pancreas in both animal groups, but with a significant 3-fold higher retention of the radiopharmaceutical in clorgyline-treated animals. Ex vivo biodistribution studies confirmed the results obtained by PET. Autoradiographs did not discriminate between the exocrine and endocrine pancreas in control animals, whereas autoradiographs showed intense radioactive spots colocalized with the islets of Langerhans in clorgyline-treated animals. The islets of Langerhans represent only 2%-3% of the total pancreas and consist of about 80% b-cells. In both type 1 and type 2 diabetes, dysregulation of glucose homeostasis and b-cell function and loss of b-cells are responsible of hyperglycemia (1). b-cells are neuroendocrine cells arising from precursor cells of the embryologic neural crest (2,3). Pancreatic b-cells regulate a large variety of body functions through paracrine and endocrine actions via dedicated amines and peptides, including the neurotransmitter serotonin. As a consequence, b-cells have an efficient mechanism for the uptake and metabolism of the amine precursors L-3,4-dihydroxyphenylalanine and 5-hydroxytryptophan through specific receptors (4,5).5-hydroxytryptophan and its precursor tryptophan are taken up in b-cells by the L-type amino acid transporter (LAT). Tryptophan is converted to 5-hydroxytryptophan by tryptophan hydroxylase (TPH). Subsequently,...

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Signals from the neural crest regulate beta-cell mass in the pancreas

Cited by 97 publications

References 45 publications

Differentiating neural crest stem cells induce proliferation of cultured rodent islet beta cells

Differentiating neural crest stem cells induce proliferation of cultured rodent islet beta cells

Mesenchymal Stem Cells as Feeder Cells for Pancreatic Islet Transplants

¹¹C-Hydroxytryptophan Uptake and Metabolism in Endocrine and Exocrine Pancreas

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Signals from the neural crest regulate beta-cell mass in the pancreas

Cited by 97 publications

References 45 publications

Differentiating neural crest stem cells induce proliferation of cultured rodent islet beta cells

Differentiating neural crest stem cells induce proliferation of cultured rodent islet beta cells

Mesenchymal Stem Cells as Feeder Cells for Pancreatic Islet Transplants

11C-Hydroxytryptophan Uptake and Metabolism in Endocrine and Exocrine Pancreas

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Product

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¹¹C-Hydroxytryptophan Uptake and Metabolism in Endocrine and Exocrine Pancreas