Laminin-1 promotes differentiation of fetal mouse pancreatic beta-cells.

Abstract

Extracellular factors that regulate the growth and differentiation of cell lineages in the pancreatic primordia are poorly understood. Identification of these factors for pancreatic islet beta-cells could open new avenues for the treatment of insulin-dependent diabetes. We developed a low cell density serum-free culture system for dissociated pancreatic cells from the 13.5-day mouse fetus and investigated the effects of extracellular matrix proteins on differentiation of islet cells. After 4 days in culture, total cell number decreased by two-thirds, but insulin-positive beta-cell number increased 10-fold. Both of collagens I and IV inhibited cell survival (by >50%), whereas fibronectin had no effect. In the presence of soluble laminin-1, however, the number of beta-cells increased linearly by 60-fold without an increase in the total cell number; glucagon-positive cell number was unchanged, and somatostatin and pancreatic polypeptide-positive cells were not detected. The effect of laminin-1 was completely blocked by a monoclonal rat anti-laminin-1 antibody. In the presence of laminin-1, the thymidine analogue, BrdU, was incorporated into only 2.5% of cells, which were mainly insulin-negative at days 1-3. Laminin-1 appeared, therefore, to induce differentiation of beta-cells from precursor cells in day-13.5 fetal pancreas. Laminin-1 was shown to be expressed in the epithelial basement membrane of the 13.5- to 17.5-day fetal pancreas. These findings provide the first evidence of a role for laminin-1 to promote differentiation of pancreatic beta-cells.

Endothelial cell signalling supports pancreatic beta cell function in the rat

“…Likewise, there are indications that beta cells do not form their own basement membrane, but rely on endothelial cells to form a vascular basement membrane containing LMs next to the beta cell [14]. LM-111 has been demonstrated to promote differentiation of pancreatic precursor cells into beta cells in vitro [24] and to promote glucose-stimulated insulin secretion in vitro [15,25,26]. Prostaglandins exert a number of effects on islet beta cells, although mostly negative [27,28].…”

Sustained insulin secretory response in human islets co-cultured with pancreatic duct-derived epithelial cells within a rotational cell culture system

“…Soluble mediators such as IGF-1 and -2 and the epidermal growth factor (EGF) family have been implicated in beta cell survival and replication [38][39][40][41], and ductal epithelial cells may provide an additional source of these regulatory hormones in the post-isolation environment [41]. Additionally, components of the ECM are vital for appropriate pancreatic development, and several integrin receptors and their associated ligands, including laminin, fibronectin and collagen I, are produced in ductal cells [41][42][43]. Whether the actions of one or several of these factors underlie the improved beta cell function in our co-culture models will thus form the basis of future research.…”

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

“…Factorial design of experiments [6] was used to compare multiple candidate growth and differentiation factors simultaneously. Based on factors reported to influence the development or differentiation of beta cells, we examined the effects of glucose [7], nicotinamide [8], exendin 4 [9], insulin [10,11], IGF-1 [12], betacellulin [12], laminin-1 [13], epidermal growth factor [14], retinoic acid [15], gastrin17 [14], hepatocyte growth factor [16] and activin A [17]. To date, the effects of these factors and their interactions have not been systematically compared in one study.…”