Abstract
Pancreatic stellate cells (PaSCs) are cells that are located around the acinar, ductal, and vasculature tissue of the rodent and human pancreas, and are responsible for regulating extracellular matrix (ECM) turnover and maintaining the architecture of pancreatic tissue. This study examines the contributions of integrin receptor signaling in human PaSC function and survival. Human PaSCs were isolated from pancreata collected during the 2nd trimester of pregnancy and identified by expression of stellate cell markers, ECM proteins and associated growth factors. Multiple integrins are found in isolated human PaSCs, with high levels of β1, α3 and α5. Cell adhesion and migration assays demonstrated that human PaSCs favour collagen I matrix, which enhanced PaSC proliferation and increased TGFβ1, CTGF and α3β1 integrin. Significant activation of FAK/ERK and AKT signaling pathways, and up-regulation of cyclin D1 protein levels, were observed within PaSCs cultured on collagen I matrix. Blocking β1 integrin significantly decreased PaSC adhesion, migration and proliferation, further complementing the aforementioned findings. This study demonstrates that interaction of β1 integrin with collagen I is required for the proliferation and function of human fetal PaSCs, which may contribute to the biomedical engineering of the ECM microenvironment needed for the efficient regulation of pancreatic development.
Highlights
Pancreatic stellate cells (PaSCs) are non-endocrine, mesenchymal-like cells [1,2,3] that reside in the periacinar, peri-ductal and peri-vascular area and play a role in regulating extracellular matrix (ECM) turnover, which is important for maintaining the integrity of pancreatic tissues architecture [4]
We have isolated and purified human PaSCs from developing pancreata and have demonstrated that β1 integrin and its associated α3 subunit is highly expressed in human fetal PaSCs
The activation of α3β1 integrin by collagen I matrix protein plays an important role in mediating human fetal PaSC adhesion, migration, proliferation, and growth factor production
Summary
Pancreatic stellate cells (PaSCs) are non-endocrine, mesenchymal-like cells [1,2,3] that reside in the periacinar, peri-ductal and peri-vascular area and play a role in regulating extracellular matrix (ECM) turnover, which is important for maintaining the integrity of pancreatic tissues architecture [4]. Interactions between α3β1 and collagen I or IV activate both the MAPK/ERK and the PI3K/AKT signaling pathways, suggesting that they are critical for modulating islet cell differentiation, proliferation, and survival in the developing human pancreas [13]. Despite these previous studies, the functional role of β1 integrin directly affecting PaSCs in the developing human pancreas has yet to be examined. This study demonstrated that β1 integrin association with α3 integrin is required for the proliferation and proper function of human fetal PaSCs on a collagen I matrix, and provide a better understanding of PaSC-ECM interactions in the developing human pancreas
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