Abstract
Contrasting evidence is present regarding the contribution of stem/progenitor cell populations to pancreatic regeneration in diabetes. Interestingly, a cell compartment with stem/progenitor cell features has been identified in the pancreatic duct glands (PDGs). The aims of the present study were to evaluate pancreatic islet injury and regeneration, and the participation of the PDG compartment in type 2 diabetic mellitus (T2DM) and in an experimental model of diabetes. Human pancreata were obtained from normal (N = 5) or T2DM (N = 10) cadaveric organ donors. Experimental diabetes was generated in mice by intraperitoneal injection of 150 mg/kg of streptozotocin (STZ, N = 10); N = 10 STZ mice also received daily intraperitoneal injections of 100 µg of human recombinant PDX1 peptide (STZ + PDX1). Samples were examined by immunohistochemistry/immunofluorescence or RT-qPCR. Serum glucose and c-peptide levels were measured in mice. Islets in T2DM patients showed β-cell loss, signs of injury and proliferation, and a higher proportion of central islets. PDGs in T2DM patients had a higher percentage of proliferating and insulin+ or glucagon+ cells compared to controls; pancreatic islets could be observed within pancreatic duct walls of T2DM patients. STZ mice were characterized by reduced islet area compared to controls. PDX1 treatment increased islet area and the percentage of central islets compared to untreated STZ mice but did not revert diabetes. In conclusion, T2DM patients show signs of pancreatic islet regeneration and involvement of the PDG niche. PDX1 administration could support increased endocrine pancreatic regeneration in STZ. These findings contribute to defining the role and participation of stem/progenitor cell compartments within the pancreas.
Highlights
IntroductionType 1 diabetes mellitus (T1DM) is caused by an autoimmune destruction of pancreatic β-cells, while type 2 diabetes mellitus (T2DM) develops due to insulin resistance and can progress towards β-cell dysfunction (Mathieu et al, 2021)
Diabetes mellitus comprises metabolic diseases characterized by hyperglycemia
The percentage of proliferating cell nuclear antigen (PCNA) + islet cells was higher in type 2 diabetic mellitus (T2DM) (52.9 ± 4.2%) compared to normal pancreata (43.2 ± 2.3%; p < 0.01; Figure 1C); cells within pancreatic islets in T2DM patients showed an increase of γH2A.x (27.5 ± 3.5%) and cCasp3+ (52.6 ± 2.3%) expression compared to normal pancreatic islets (19.6 ± 4.9% and 34.4 ± 5.4%, respectively; p < 0.05 and p < 0.001; Figure 1D)
Summary
Type 1 diabetes mellitus (T1DM) is caused by an autoimmune destruction of pancreatic β-cells, while type 2 diabetes mellitus (T2DM) develops due to insulin resistance and can progress towards β-cell dysfunction (Mathieu et al, 2021) In these patients, regenerative processes can occur, attempting to compensate for the loss of β-cells (Yoneda et al, 2013). The biliary tree stem/progenitor cells (BTSCs) have been identified within the peribiliary glands (PBGs) of the larger intrahepatic and extrahepatic bile ducts, and represent a multipotent stem/progenitor cell compartment. Their capabilities to differentiate towards mature endocrine pancreatic cells have been evaluated both in vitro and in vivo (Lanzoni et al, 2016). We observed how PDX1 can trigger the expression of both intermediate and mature stage β-cell differentiation markers in BTSCs (Cardinale et al, 2015)
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