No abstract

Although both endocrine and the exocrine pancreas display a significant capacity for tissue regeneration and renewal, the existence of progenitor cells in the adult pancreas remains uncertain. Using a model of cerulein-mediated injury and repair, we demonstrate that mature exocrine cells, defined by expression of an Elastase1 promoter, actively contribute to regenerating pancreatic epithelium through formation of metaplastic ductal intermediates. Acinar cell regeneration is associated with activation of Hedgehog (Hh) signaling, as assessed by up-regulated expression of multiple pathway components, as well as activation of a Ptch-lacZ reporter allele. Using both pharmacologic and genetic techniques, we also show that the ability of mature exocrine cells to accomplish pancreatic regeneration is impaired by blockade of Hh signaling. Specifically, attenuated regeneration in the absence of an intact Hh pathway is characterized by persistence of metaplastic epithelium expressing markers of pancreatic progenitor cells, suggesting an inhibition of redifferentiation into mature exocrine cells. Given the known role of Hh signaling in exocrine pancreatic cancer, these findings may provide a mechanistic link between injury-induced activation of pancreatic progenitors and subsequent pancreatic neoplasia. In addition to its well-established role in directing the patterning of embryonic tissues, 9 the Hedgehog (Hh) pathway has been implicated in the maintenance of stem or progenitor cell number in a growing list of adult tissues. 10-15 Mature tissue homeostasis at these sites appears to be a consequence of Hh-mediated stem or progenitor cell self-renewal within the organspecific stem cell niche. In addition to this observed role in "baseline" states, more recent work suggests that the Hh pathway also plays a critical role in regenerative responses to tissue injury. For example, Hh pathway activity is required for androgen-triggered regeneration of prostate epithelium in male mouse castrates, 14 as well as in the course of pulmonary epithelial regeneration in a napthalene-induced model of acute pulmonary injury. 15 Based on observations that inhibition of Hh signaling is associated with diminished tissue repair, these studies have suggested that up-regulated Hh signaling is a prerequisite for the stem/progenitor cell expansion that occurs in response to injury.The aim of the current study was to determine the role of Hh signaling in the process of exocrine regeneration following cerulein-induced pancreatitis. Recent empiric studies in archived human specimens of chronic pancreatitis have demonstrated aberrant expression of Hh components, 16,17 but these studies have not explored the functional implications of Hh blockade in the setting of exocrine injury. Confirming previous observations, we demonstrate by using lineage tracing experiments that pancreatic regeneration is mediated by mature acinar cells through the formation of transient metaplastic epithelium, expressing markers of pancreatic progenitor cells (nestin, P...