The loss of insulin-producing β-cells is central to the pathogenesis of type 1 diabetes (T1D). More recently, the contribution of the exocrine pancreatic cellular components is becoming evident in determining the β-cells well-being. Other pancreatic cell types could be acting by reducing β-cell resistance to the autoimmune attack or inducing a stressful condition that will lead to neo-antigen expression or modulate the autoimmune response favoring β-cell damage.
The pancreatic stellate cells (PSCs) reside in the exocrine pancreas in the peri-acinar space, but also in perivascular and periductal locations. They are implicated in the pathobiology of major exocrine pancreatic disorders such as chronic pancreatitis and pancreatic cancer. Activated PSCs lose their vitamin A content and are responsible for organ fibrosis, promote extracellular matrix deposition, release factors that promote an inflammatory state, interfere with acinar cell function, and reduce the insulin secretory capacity. The PSC activity known in other diseases leads to hypothesize that they could have a role either in determining the exocrine pancreas alterations seen in T1D and favoring β-cell function decline. In spite of the multiple possible causative mechanisms, the role of PSCs in the pathogenesis of T1D has not been investigated, and this proposal aims to close this knowledge gap.
A preliminary analysis of a subset of HPAP single-cell data showed that PSCs from organ donors with T1D have an immune-activated phenotype as described by Baron et al. in other conditions. They overexpress in fact multiple chemokines and IL-6. This evidence supports our hypothesis that a dysfunctional and proinflammatory PSC activation in T1D contributes to and maintains β-cell stress accelerating β-cell functional decline. It is hypothesized that this interaction is mediated by PSC-secreted factors directly acting on the islets which promote a pro-inflammatory gene expression. In this study, we will investigate the role of activated PSC-secreted factors on islet function.