Human islet-derived precursor cells can cycle between epithelial clusters and mesenchymal phenotypes.

Area of Science:

• Cell Biology
• Stem Cell Research
• Endocrinology

Background:

• Human islet precursor cells (hIPCs) are mesenchymal stem/stromal cells (MSCs) that differentiate into endocrine cells in vitro and in vivo.
• Previous studies showed inconsistent differentiation of hIPCs in vivo, suggesting potential de-differentiation.
• The potential for de-differentiation to a mesenchymal phenotype was investigated in implanted hIPCs.

Purpose of the Study:

• To investigate the de-differentiation of human islet precursor cells (hIPCs) and adult human islets after implantation in mice.
• To determine the role of serum factors and proliferation in the epithelial-to-mesenchymal transition (EMT) of hIPCs.
• To assess the implications of EMT for cell replacement therapy in diabetes.

Main Methods:

• Implantation of hIPCs cultured as epithelial cell clusters (ECCs) under mouse kidney capsules.
• In vitro culture of ECCs with various sera (fetal bovine serum, mouse serum, human serum) to induce de-differentiation.
• Treatment of hIPCs with mitomycin to inhibit proliferation and assess its role in EMT.
• Analysis of cell phenotypes in grafts and in vitro cultures.
• Examination of grafts from adult human islets implanted in mice.

Main Results:

• Mesenchymal cells were found in grafts of implanted hIPCs, indicating de-differentiation.
• Exposure to fetal bovine serum and mouse serum induced a transition from epithelial cell clusters (ECCs) to de-differentiated mesenchymal cells in vitro.
• Mouse serum and fetal bovine serum were more effective than human serum in stimulating mesenchymal hIPC migration.
• Proliferation was not required for the transition from ECCs to de-differentiated cells, as shown by mitomycin-treated cells.
• Mesenchymal cells were also observed in grafts of adult human islets implanted in mice.

Conclusions:

• Epithelial-to-mesenchymal transition (EMT) occurs in human islet precursor cells (hIPCs) and potentially in adult human islets after implantation in mice.
• Serum factors, particularly from non-human sources, can induce EMT in hIPCs.
• The potential for EMT in cells used for cell replacement therapy needs careful consideration for successful diabetes treatment.