Activation of Pancreatic Stellate Cells Is Beneficial for Exocrine but Not Endocrine Cell Differentiation in the Developing Human Pancreas

Abstract

Pancreatic stellate cells (PaSCs) are non-endocrine, mesenchymal-like cells that reside within the peri-pancreatic tissue of the rodent and human pancreas. PaSCs regulate extracellular matrix (ECM) turnover in maintaining the integrity of pancreatic tissue architecture. Although there is evidence indicating that PaSCs are involved in islet cell survival and function, its role in islet cell differentiation during human pancreatic development remains unclear. The present study examines the expression pattern and functional role of PaSCs in islet cell differentiation of the developing human pancreas from late 1st to 2nd trimester of pregnancy. The presence of PaSCs in human pancreata (8–22 weeks of fetal age) was characterized by ultrastructural, immunohistological, quantitative RT-PCR and western blotting approaches. Using human fetal PaSCs derived from pancreata at 14–16 weeks, freshly isolated human fetal islet-epithelial cell clusters (hIECCs) were co-cultured with active or inactive PaSCs in vitro. Ultrastructural and immunofluorescence analysis demonstrated a population of PaSCs near ducts and newly formed islets that appeared to make complex cell-cell dendritic-like contacts. A small subset of PaSCs co-localized with pancreatic progenitor-associated transcription factors (PDX1, SOX9, and NKX6-1). PaSCs were highly proliferative, with significantly higher mRNA and protein levels of PaSC markers (desmin, αSMA) during the 1st trimester of pregnancy compared to the 2nd trimester. Isolated human fetal PaSCs were identified by expression of stellate cell markers and ECM. Suppression of PaSC activation, using all-trans retinoic acid (ATRA), resulted in reduced PaSC proliferation and ECM proteins. Co-culture of hIECCs, directly on PaSCs or indirectly using Millicell® Inserts or using PaSC-conditioned medium, resulted in a reduction the number of insulin+ cells but a significant increase in the number of amylase+ cells. Suppression of PaSC activation or Notch activity during the co-culture resulted in an increase in beta-cell differentiation. This study determined that PaSCs, abundant during the 1st trimester of pancreatic development but decreased in the 2nd trimester, are located near ductal and islet structures. Direct and indirect co-cultures of hIECCs with PaSCs suggest that activation of PaSCs has opposing effects on beta-cell and exocrine cell differentiation during human fetal pancreas development, and that these effects may be dependent on Notch signaling.

Activated Stellate Cell Paracrine HGF Exacerbated Pancreatic Cancer Cell Ferroptosis Resistance

“…Additionally, reversing activated PSCs back to a quiescent state might also sensitize pancreatic cancer ferroptosis. It has been indicated that ATRA could keep PSCs in a quiescent state and reduce pancreatic fibrosis [ 25 ]. Combining ATRA with ferroptosis inducers may be able to mitigate the effects of the dense microenvironment of pancreatic cancer on treatment resistance [ 26 ] and provide a therapeutic effect.…”

Pancreatic Stellate Cells and Metabolic Alteration: Physiology and Pathophysiology

“…The antioxidant N-acetylcysteine (NAC) attenuates this effect, suggesting that hypoxic PSCs increase oxidative stress ( Kim et al, 2020 ). The presence of activated PSCs also inhibits differentiation of fetal islet–epithelial cell clusters into insulin-positive cells, indicating suppressive effects on islet cells ( Li et al, 2021b ). High glucose conditions, derived from DM, activate PSCs by elevating oxidative stress ( Ryu et al, 2013 ).…”

Development of the human pancreas and its exocrine function

“…Pancreatic stellate cells secrete extracellular matrix proteins and seem to have a significant function in the first trimester of human pancreatic development by enhancing differentiation to exocrine cell lineages ( 14 ).…”