Biology of pancreatic stellate cells-more than just pancreatic cancer

Abstract

Pancreatic stellate cells, normally quiescent, are capable of remarkable transition into their activated myofibroblast-like phenotype. It is now commonly accepted that these cells play a pivotal role in the desmoplastic reaction present in severe pancreatic disorders. In recent years, enormous scientific effort has been devoted to understanding their roles in pancreatic cancer, which continues to remain one of the most deadly diseases. Therefore, it is not surprising that considerably less attention has been given to studying physiological functions of pancreatic stellate cells. Here, we review recent advances not only in the field of pancreatic stellate cell pathophysiology but also emphasise their roles in physiological processes.

Keywords: Calcium; Fibrosis; Myofibroblasts; Pancreatic cancer; Pancreatic stellate cells; Pancreatitis.

Fig. 1

Schematic illustration of the pancreas. The exocrine part of the organ predominantly consists of acinar lobules. Pancreatic stellate cells (shown in bright green-yellow-red pseudocolours, lower panel) form a three-dimensional network in between those lobules (dark purple)

Fig. 2

Pancreatic stellate cells have the capacity to store retinoids. Cultured human PSCs quickly become activated and lose most of their stored retinol (upper panel). In the presence of 100 μM retinol (24 h treatment), lipid vesicles appear in the cytosol of PSCs (lower panel, red pattern), which is revealed by excitation with UV light

Fig. 3

Expression of α-smooth muscle actin (α-SMA), and thus the number of activated PSCs (aPSCs), increases as a result of tissue inflammation. In the healthy mouse pancreas (upper panel) α-SMA-positive staining (red) is only present in the vascular smooth muscle cells in the blood vessels and is labelled as vascular smooth muscle actin (VSMA). Induction of pancreatitis (by ethanol and fatty acids) leads to a sudden appearance of α-SMA-positive cells—aPSCs—scattered within the parenchymal tissue

Fig. 4

Mouse pancreatic stellate cells, in their native environment of pancreatic lobules, respond to pathophysiological stimuli with intracellular Ca²⁺ signals as well as generation of NO. a Sample traces recorded in mouse pancreatic lobules loaded with a Ca²⁺-sensitive dye Fluo-4 AM. Pancreatic stellate cell (PSC, red trace) responds to 10 nM bradykinin (BK) but pancreatic acinar cell (PAC, blue trace) does not, which confirms the stellate phenotype. The PSC subsequently responds to 5 mM taurocholate (TC) with a large elevation of intracellular Ca²⁺, whereas the neighbouring PAC generates only modest Ca²⁺ oscillations. For more information, the reader is referred to a study by Ferdek et al. [30]. b Individual images from the recording shown in (a). The red circular regions mark the PSC that responded to bradykinin and then to taurocholate with increases in intracellular Ca²⁺ concentration. The blue circular regions indicate the PAC that did not respond to bradykinin and produced only transient Ca²⁺ elevations in response to treatment with taurocholate. c Sample traces recorded in a PSC embedded in a mouse pancreatic lobule loaded with both Fura-2 AM (Ca²⁺-sensitive dye) and DAF-2 (NO-sensitive dye). The cell responds to 20 nM BK with an elevation of intracellular Ca²⁺ concentration (red trace) and a simultaneous increase in intracellular NO (purple trace). For more information, the reader is referred to a study by Jakubowska et al. [58]. d Sample images show a mouse pancreatic lobule, loaded with DAF-2, before and after treatment with 500 μM hydrogen peroxide (H₂O₂). PSCs are indicated with white arrowheads. Treatment with H₂O₂ increases intracellular NO in these cells (shown as a shift in the pseudocolour spectrum)

Fig. 5

Schematic illustration of a pancreatic lobule. Pathophysiological stimuli (e.g. bile acids, bradykinin, H₂O₂) induce stress responses in pancreatic stellate cells (PSC, red), manifested as an increase in the cytosolic Ca²⁺ concentration and NO generation. Stress in PSCs further escalates pathophysiological responses in adjacent pancreatic acinar cells (PAC, blue) leading to premature activation of zymogen granules, exacerbated inflammation and necrotic cell death (pink), associated with loss of the cellular content