Pancreatic ductal cells may have a negative effect on human islet transplantation

PLoS One. 2019 Jul 19;14(7):e0220064. doi: 10.1371/journal.pone.0220064. eCollection 2019.

Abstract

Aim: To evaluate the effect of pancreatic ductal cells on experimental human islet transplantation.

Materials and methods: Isolated islets were additionally purified by handpicking. Ductal cells were purified by magnetic cell sorting and then clustered into ductal pancreatospheres (DPS). Islets, DPS, and islets + DPS (100 islets + 75 DPS, or 100 islets + 200 DPS) were cultured and glucose-stimulated insulin secretion, β-cell apoptosis, and gene expression was determined. Islets and islets + DPS preparations (800 islets + 600 DPS) were transplanted to streptozotocin-treated immunodeficient mice and glycemia, graft morphometry, and gene expression were determined.

Results: Insulin stimulation index was higher in islets than in islets co-cultured with DPS (5.59 ± 0.93 vs 4.02 ± 0.46; p<0.05). IL1B and CXCL11 expression was higher in 100 islets + 200 DPS than in islets (p<0.01), and IL-1β was detected in supernatants collected from DPS and islets + DPS preparations, but not in islets. Hyperglycemia developed in 33% and 67% of mice transplanted with islets or with islets + DPS respectively. β-cell mass was 26% lower in islets + DPS than in islets grafts (p>0.05), and the ratio β-/endocrine non-β-cell mass was lower in islets + DPS grafts (islets: 2.05 ± 0.18, islets + DPS: 1.35 ± 0.15; p<0.01). IL1B and IL1RN expression was significantly higher in islets + DPS grafts.

Conclusions: Islet preparations enriched with ductal cells have a lower insulin stimulation index in vitro and achieved a worse metabolic outcome after transplantation. Inflammation may mediate the deleterious effects of ductal cells on islet cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Apoptosis
  • Biomarkers
  • Female
  • Gene Expression
  • Glucose / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin-Secreting Cells / metabolism
  • Islets of Langerhans / cytology
  • Islets of Langerhans / metabolism*
  • Islets of Langerhans Transplantation* / adverse effects
  • Islets of Langerhans Transplantation* / methods
  • Male
  • Mice
  • Middle Aged
  • Pancreatic Ducts / cytology*

Substances

  • Biomarkers
  • Insulin
  • Glucose

Grants and funding

This work was supported by grants from Instituto de Salud Carlos III (ISCIII) (PI13/00108 and PI16/00462); the European Community under the ERDF operational program (European Regional Development Fund) “a way to build Europe”; and Laboratorios Meranini. CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM) is an initiative from ISCIII. CERCA Program / Generalitat de Catalunya provided institutional support. SMC was supported by a doctoral grant for Agència de Gestiò d’Ajuts Universitaris i de Recerca (AGAUR) from the Government of the Generalitat of Catalonia under the European Social Fund program (European Community).