Identification of a pancreatic stellate cell population with properties of progenitor cells: new role for stellate cells in the pancreas

Abstract

Numerous studies conducted in a diversity of adult tissues have shown that certain stem cells are characterized by the expression of a protein known as the ABCG2 transporter (where ABC is ATP- binding cassette). In the adult pancreas, although various multipotent progenitors have been proposed, the ABCG2 marker has only been detected in the so-called 'side population' (a primitive haematopoietic cell population with a multipotential capacity). In the present study we sought to identify new ABCG2+ pancreatic cell populations and to explore whether they exhibit the properties of progenitor cells. We isolated and expanded mitoxantrone-resistant cells from pancreata of lactating rats by drug selection. These cells were characterized and maintained in different stages of differentiation using several media 'cocktails' plus Matrigel (BD Biosciences). Differentiation was assessed by RT-PCR (reverse transcription-PCR), immunocytochemistry, electron microscopy and ELISA. The expanded cell population demonstrated a phenotype of PaSCs (pancreatic stellate cells). Spontaneous cell clusters occurred during cell expansion and they showed weak expression of the transcription factor Pdx1 (pancreatic and duodenal homeobox 1). Moreover, the presence of inductive factors in the Matrigel plus exendin-4 led to an increase in Pdx1 and endocrine genes, such as insulin, islet amyloid polypeptide, glucagon, the glucose transporter GLUT2, chromogranin A and the convertases PC1/3 and PC2 were also detected. Immunocytochemical analysis showed co-localization of insulin and C-peptide, whereas ultrastructural studies revealed the presence of granules. Insulin secretion from cell clusters was detected in the cell culture medium. We identified a population of PaSCs that express the ABCG2+ transporter and have the capacity to transdifferentiate into insulin-producing cells. Although the potential therapeutic application remains to be tested, PaSCs could represent a future option for insulin replacement in diabetes research.

Hepatic stem cell niches

“…Stellate cells are mainly known as the primary collagenproducing cells following liver injury, which are responsible for fibrogenesis in chronic liver disease (85). In addition to a role for stellate cells in fibrogenesis, evidence exists that stellate cells have properties of stem cells (86)(87)(88)(89)(90)(91)(92). The expression of stem/progenitor cell-associated genes such as nestin in stellate cells of the liver and pancreas (86,89,(92)(93)(94) and the potential of stellate cells to differentiate into hepatocyte-like cells in vitro (86,92) indicate that stellate cells have stem cell characteristics.…”

Bone marrow-derived pancreatic stellate cells in rats

“…Reports regarding the potential origin of insulin-producing cells are extremely controversial, including bone marrow (BM)-derived progenitors, pancreas-resident stem cells, transdifferentiation of acinar as well as duct cells and self-duplication of adult β-cells [5][6][7][8][9][10]. Recently, Mato et al [11] reported an in vitro-selected mitoxantrone-resistant cell pool from rat pancreas displaying characteristics of PSCs. These cells were reported to differentiate into insulin-producing cells upon adequate stimulation.…”

The Plasticity of Pancreatic Stellate Cells Could Be Involved in the Control of the Mechanisms that Govern the Neogenesis Process in the Pancreas Gland

“…However, most of the information about the activation mechanism has derived from in vitro studies of rodent PSC maintained in culture. These cultures, initially express the molecular markers of the quiescent cells and it is easy to observe the presence of the cytoplasmic lipid droplets by oil red stain (Apte MVet al, 1988, Mato E et al 2009. However, in a short amount of time, most of the cells in the culture showed a proliferative phenotype with -SMA and ECM protein expression.…”

“…These intermediary filaments present in cells of the epithelial origin, such as ductal cells, indicate that the cell could be involved in the mechanism to control the mesenchymal-epithelial transition (MET). This phenomenon consists of a promising source of cells for replacement therapies, but can also be involved in the carcinogenesis process (Mato E et al 2009). …”