Signals from lateral plate mesoderm instruct endoderm toward a pancreatic fate

Abstract

During embryonic development, organs arise along the gut tube as a series of buds in a stereotyped anterior-posterior (A-P) pattern. Using chick-quail chimeras and in vitro tissue recombination, we studied the interactions governing the induction and maintenance of endodermal organ identify focusing on the pancreas. Though several permissive signals in pancreatic development have been previously identified, here we provide evidence that lateral plate mesoderm sends instructive signals to the endoderm, signals that induce expression of the pancreatic genes Pdx1, p48, Nkx6.1, glucagon, and insulin. Moreover, this instructive signal directs cells to form ectopic insulin-positive islet-like clusters in endoderm that would otherwise form more rostral organs. Once generated, endocrine cells no longer require interaction with mesoderm, but nonendocrine cells continue to require permissive signals from the mesoderm. Stimulation of activin, BMP, or retinoic acid signaling is sufficient to induce Pdx1 expression in endoderm anterior to the pancreas. Lateral plate mesoderm appears to pattern the endoderm in a posterior-dominant fashion as first noted in the patterning of the neural tube at the same embryonic stage. These findings argue for a central role of the mesoderm in coordinating the A-P pattern of all three primary germ layers.

Directed differentiation of human embryonic stem cells towards a pancreatic cell fate

“…Because we used a relatively high concentration (20%) of serum during EB formation (three-dimensional differentiation), the optimal range of serum concentrations for endodermal differentiation seems to vary depending on the culture conditions. RA generated from lateral plate mesoderm has recently been reported to control Pdx1 expression in early pancreatic development in mice and zebrafish [36][37][38]. Our study demonstrated that RA treatment at the end of EB formation efficiently upregulated PDX1 expression, together with FOXA2 and SOX17 expression, while strongly downregulating the expression of MIXL1 and T, both of which were previously used as markers of the mesendodermal differentiation of ESCs [35].…”

Pancreas organogenesis: From bud to plexus to gland

“…Transplantation of already specified prepancreatic endoderm to a more rostral endodermal location did not abolish Pdx1 expression, while more caudal engraftment led to its respecification towards a more caudal fate. Therefore, these instructive signals from the LPM, which might be BMP, RA, or activin, regionalize the endoderm in a posterior-dominant fashion (Kumar et al, 2003), the latter being a conserved theme in overall body plan patterning in many species.…”

Differentiation of Stem Cells into Insulin-Producing Cells: Current Status and Challenges

“…Differentiated cells secrete very low level of insulin, express multiple hormones and show very little response to glucose stimulation. A possible explanation for b cells maturation failure in vitro could be absence of mesenchyma-epithelium interactions, that occur during pancreatic embryogenesis (Kumar et al 2003). Another challenge is long term survival of IPCs grafts.…”