The receptor tyrosine kinase c-Kit plays an integral role in maintaining b-cell mass and function. Although c-Kit receptor signaling promotes angiogenesis in multiple cell types, its role in islet vasculature is unknown. This study examines the effects of c-Kit-mediated vascular endothelial growth factor isoform A (VEGF-A) and islet vascularization on b-cell function and survival using in vitro cell culture and in vivo mouse models. In Increasing evidence suggests that c-Kit and its ligand, stem cell factor (SCF), are implicated in the regulation of angiogenesis.
Progenitor expansion during development is a highly regulated process dictating the final organ size, while expansion of specific progenitor populators can adjust the final cellular composition of the organ. Understanding factors involved in these pathways is required to develop cell-based therapies such as β-cell transplantation for conditions such as diabetes mellitus. One versatile factor controlling both processes as well as a network of other proteins involved in pancreatic and duodenal development is the transcription factor SOX9. This review will focus on a comparison of SOX9 function during progenitor expansion and differentiation in the developing pancreas and duodenum with specific focus on endocrine development. During human pancreatic development, SOX9 functions in a dose-dependent manner to regulate epithelial progenitor expansion and endocrine differentiation. SOX9 expression is eventually limited to a subset of ductal and centroacinar cells, hypothesized to be the pancreatic stem cell compartment. Similarly, during duodenal development, SOX9 is expressed in most early epithelial progenitors and becomes gradually restricted to proliferative progenitors in the lower crypts, as well as mature Paneth and enteroendocrine cells indicating some differences in functional roles. However, in both developmental contexts, SOX9 is involved in pathways responsible for cellular proliferation and differentiation, such as Notch and Wnt. With its adaptable and central function in progenitor control, SOX9 represents an attractive target for manipulation for in vitro progenitor expansion and differentiation meriting further investigation.
Our findings indicate that ALDH1(+) cells represent a pool of endocrine precursors in the developing human pancreas and that ALDH1 activity is required during endocrine cell differentiation. Inhibition of ALDH1-mediated retinoid signalling impairs human fetal islet cell differentiation and survival.
Insulin secretion from pancreatic β-cells is initiated through channel-mediated depolarization, cytoskeletal remodeling, and vesicle tethering at the cell membrane, all of which can be regulated through cell surface receptors. Receptor tyrosine kinases (RTKs) promote β-cell development and postnatal signaling to improve β-cell mass and function, yet their activation has also been shown to initiate exocytotic events in β-cells. This review examines the role of RTK signaling in insulin secretion, with a focus on RTKs c-Kit and insulin receptor (IR). Pathways that control insulin release and the potential interplay between c-Kit and IR signaling are discussed, along with clinical implications of RTK therapy on insulin secretion.
The enzyme aldehyde dehydrogenase (ALDH) is found in developing and multipotent cell populations, and is important for the production and regulation of retinoic acid, which controls β-cell differentiation in the pancreas. The role of ALDH-expressing cells in the formation of endocrine-like cells and co-localization with the putative stem cell marker CD133 has not been examined during human pancreatic development. This study focuses on the co-expression of CD133 on ALDH cells from the human fetal pancreas (18-22 weeks of fetal age) with transcription factors (TFs) central to endocrine cell development. Fluorescence-activated cell sorting demonstrated that cells with high ALDH activity (ALDH) had increased co-expression of CD133 and endocrine-lineage TFs when compared with cells with low ALDH (ALDH) expression. Hormone-expressing (insulin, somatostatin) and ductal cells (CK19) were noted in the ALDH population, while mesenchymal (vimentin) and endothelial (CD31) markers were predominantly found in ALDH cells. Culture of sorted ALDH or ALDH/CD133 cells resulted in loss of endocrine TF, insulin, and CK19 expression. The formation of cell clusters from cultured ALDH or ALDH/CD133 cells led to restored CK19 expression and showed endocrine TFs and insulin expression. In summary, pancreatic ALDH cells contain a heterogeneous CD133-enriched population with a subset of β-cell associated markers in the developing human pancreas.
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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