c-Kit Receptor Signaling Regulates Islet Vasculature, β-Cell Survival, and Function In Vivo

Feng, Zhichao; Popell, Alex; Li, Jinming; Silverstein, Jenna; Oakie, Amanda; Yee, Siu‐Pok; Wang, Rennian

doi:10.2337/db15-0054

Cited by 26 publications

(32 citation statements)

References 46 publications

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“…c-kit + cells have been shown to be self-renewing, clonogenic, and multipotent both in vitro and in vivo in hearts, lungs, and other organs [22–24]. Furthermore, c-kit and its ligand, stem cell factor, are both expressed in the CNS and the peripheral nervous system [25–28], as well as in the retinas of humans and mice [29–32].…”

Section: Introductionmentioning

confidence: 99%

Grafted c-kit+/SSEA1− eye-wall progenitor cells delay retinal degeneration in mice by regulating neural plasticity and forming new graft-to-host synapses

Chen

et al. 2016

Stem Cell Res Ther

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BackgroundDespite diverse pathogenesis, the common pathological change observed in age-related macular degeneration and in most hereditary retinal degeneration (RD) diseases is photoreceptor loss. Photoreceptor replacement by cell transplantation may be a feasible treatment for RD. The major obstacles to clinical translation of stem cell-based cell therapy in RD remain the difficulty of obtaining sufficient quantities of appropriate and safe donor cells and the poor integration of grafted stem cell-derived photoreceptors into the remaining retinal circuitry.MethodsEye-wall c-kit+/stage-specific embryonic antigen 1 (SSEA1)− cells were isolated via fluorescence-activated cell sorting, and their self-renewal and differentiation potential were detected by immunochemistry and flow cytometry in vitro. After labeling with quantum nanocrystal dots and transplantation into the subretinal space of rd1 RD mice, differentiation and synapse formation by daughter cells of the eye-wall c-kit+/SSEA1− cells were evaluated by immunochemistry and western blotting. Morphological changes of the inner retina of rd1 mice after cell transplantation were demonstrated by immunochemistry. Retinal function of rd1 mice that received cell grafts was tested via flash electroretinograms and the light/dark transition test.ResultsEye-wall c-kit+/SSEA1− cells were self-renewing and clonogenic, and they retained their proliferative potential through more than 20 passages. Additionally, eye-wall c-kit+/SSEA1− cells were capable of differentiating into multiple retinal cell types including photoreceptors, bipolar cells, horizontal cells, amacrine cells, Müller cells, and retinal pigment epithelium cells and of transdifferentiating into smooth muscle cells and endothelial cells in vitro. The levels of synaptophysin and postsynaptic density-95 in the retinas of eye-wall c-kit+/SSEA1− cell-transplanted rd1 mice were significantly increased at 4 weeks post transplantation. The c-kit+/SSEA1− cells were capable of differentiating into functional photoreceptors that formed new synaptic connections with recipient retinas in rd1 mice. Transplantation also partially corrected the abnormalities of inner retina of rd1 mice. At 4 and 8 weeks post transplantation, the rd1 mice that received c-kit+/SSEA1− cells showed significant increases in a-wave and b-wave amplitude and the percentage of time spent in the dark area.ConclusionsGrafted c-kit+/SSEA1− cells restored the retinal function of rd1 mice via regulating neural plasticity and forming new graft-to-host synapses.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0451-8) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Grafted c-kit+/SSEA1− eye-wall progenitor cells delay retinal degeneration in mice by regulating neural plasticity and forming new graft-to-host synapses

Chen

et al. 2016

Stem Cell Res Ther

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“…We further evaluated whether up-regulation of Igf-2 and Akt signaling could enhance islet Vegf-a levels, a major factor associated with increased islet growth [22], and islet vascularization in the developing fetal pancreas. We found that MIP-βIRKO islets had elevated pancreatic Vegf-a protein levels as determined by immunofluorescence (Figure 5A) and western blotting ( p < 0.01 vs .…”

Section: Resultsmentioning

confidence: 99%

“…The loss of insulin receptor (IR) expression on pancreatic β-cells during 2 nd transition of the pancreatic development results in enhanced secretion of insulin growth factor-2 (Igf-2). B. Autocrine/paracrine activation of the insulin growth factor-1 receptor (Igf-1r) on pancreatic β-cell by Igf-2 promotes Akt phosphorylation, leading to: (1) suppressed phospho-p53 (S15) activation that prevents β-cell apoptosis, and (2) increased secretion of vascular endothelial growth factor-a (Vegf-a) through the Akt/HIF-1/Vegf-a signaling pathway in β-cells [22]. C. Together, Vegf-a-mediated hyper islet vascularization and upregulated Akt activity promotes exaggerated β-cell replication and cell survival, leading to an expanded β-cell population within the pancreas of MIP-βIRKO animals.…”

Section: Discussionmentioning

confidence: 99%

“…Igf-2 acts as a stimulatory ligand of both the Igf-1r and IR, and is therefore a critical factor for expansion of β-cell mass [37–39] and embryonic vasculogenesis by up-regulating Vegf levels via the Akt signaling pathway (Figure 7) [40]. Our recent study further determined that Vegf-a synthesis and secretion in the β-cell is regulated by the Akt/mTOR pathway, through increased HIF-1 expression, and is associated with increased β-cell mass and proliferation [22]. Since the endothelium and its associated blood supply are critical for maintenance of β-cell fate and proliferation, numerous studies have proposed that increased islet vascularization could result in enhanced β-cell replication through rapid and efficient exchange of nutrients and hormones [12, 41–44].…”

Section: Discussionmentioning

confidence: 99%

“…Both plasma and pancreatic insulin content were measured using an ultrasensitive (mouse) insulin ELISA kit (ALPCO, Salem, NH). Plasma insulin level was expressed as ng per ml, and pancreatic insulin content was normalized to protein and expressed as ng per mg protein [22]. …”

Section: Methodsmentioning

confidence: 99%

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β-cell insulin receptor deficiency duringin uterodevelopment induces an islet compensatory overgrowth response

et al. 2016

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The presence of insulin receptor (IR) on β-cells suggests that insulin has an autocrine/paracrine role in the regulation of β-cell function. It has previously been reported that the β-cell specific loss of IR (βIRKO) leads to the development of impaired glycemic regulation and β-cell death in mice. However, temporally controlled βIRKO induced during the distinct transitions of fetal pancreas development has yet to be investigated. We hypothesized that the presence of IR on β-cells during the 2nd transition phase of the fetal murine pancreas is required for maintaining normal islet development. We utilized a mouse insulin 1 promoter driven tamoxifen-inducible Cre-recombinase IR knockout (MIP-βIRKO) mouse model to investigate the loss of β-cell IR during pancreatic development at embryonic day (e) 13, a phase of endocrine proliferation and β-cell fate determination. Fetal pancreata examined at e19-20 showed significantly reduced IR levels in the β-cells of MIP-βIRKO mice. Morphologically, MIP-βIRKO pancreata exhibited significantly enlarged islet size with increased β-cell area and proliferation. MIP-βIRKO pancreata also displayed significantly increased Igf-2 protein level and Akt activity with a reduction in phospho-p53 when compared to control littermates. Islet vascular formation and Vegf-a protein level was significantly increased in MIP-βIRKO pancreata. Our results demonstrate a developmental role for the β-cell IR, whereby its loss leads to an islet compensatory overgrowth, and contributes further information towards elucidating the temporally sensitive signaling during β-cell commitment.

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The islet endothelial cell: a novel contributor to beta cell secretory dysfunction in diabetes

Hogan

Hull

2017

Diabetologia

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The pancreatic islet is highly vascularised, with an extensive capillary network. In addition to providing nutrients and oxygen to islet endocrine cells and transporting hormones to the peripheral circulation, islet capillaries (comprised primarily of islet endothelial cells) are an important source of signals that enhance survival and function of the islet beta cell. In type 2 diabetes, and animal models thereof, evidence exists of morphological and functional abnormalities in these islet endothelial cells. In diabetes, islet capillaries are thickened, dilated and fragmented, and islet endothelial cells express markers of inflammation and activation. In vitro data suggests that this dysfunctional islet endothelial phenotype may contribute to impaired insulin release from the beta cell. This review examines potential candidate molecules that may mediate the positive effects of islet endothelial cells on beta cell survival and function under normal conditions. Further, it explores possible mechanisms underlying the development of islet endothelial dysfunction in diabetes and reviews therapeutic options for ameliorating this aspect of the islet lesion in type 2 diabetes. Finally, considerations regarding differences between human and rodent islet vasculature and the potentially unforeseen negative consequences of strategies to expand the islet vasculature, particularly under diabetic conditions, are discussed.

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c-Kit Receptor Signaling Regulates Islet Vasculature, β-Cell Survival, and Function In Vivo

Cited by 26 publications

References 46 publications

Grafted c-kit+/SSEA1− eye-wall progenitor cells delay retinal degeneration in mice by regulating neural plasticity and forming new graft-to-host synapses

Grafted c-kit+/SSEA1− eye-wall progenitor cells delay retinal degeneration in mice by regulating neural plasticity and forming new graft-to-host synapses

β-cell insulin receptor deficiency duringin uterodevelopment induces an islet compensatory overgrowth response

The islet endothelial cell: a novel contributor to beta cell secretory dysfunction in diabetes

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