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Anandwardhan A Hardikar

Publications and source records attributed to Anandwardhan A Hardikar.

6 recordsLinked to original sources
PubMed2005

Are better islet cell precursors generated by epithelial-to-mesenchymal transition?

To generate cells for replacement therapy for patients with diabetes, preclinical research is being conducted to establish in vitro systems that generate large numbers of human islets of Langerhans (or insulin-expressing beta cells). Based on the concept that undifferentiated precursor cells can expand exponentially and then be induced to differentiate into mature cells, researchers are using islet (or beta cell) precursor cells for this purpose. The cells being used include embryonic stem cells, bone marrow-derived stem cells, pancreatic stem cells and cells derived from epithelial-to-mesenchymal transition of insulin-expressing cells. Transdifferentiation of another epithelial cell type is being studied also. Herein, we review our data of epithelial-to-mesenchymal-to-epithelial transition of human insulin-expressing cells and present our hypothesis that precursor cells obtained from insulin-expressing cells by epithelial-to-mesenchymal transition, after expansion, more easily differentiate into insulin-expressing cells (by mesenchymal-to-epithelial transition) than other precursor cells or by transdifferentiation.

Animals↗
PubMed2004

Epithelial-to-mesenchymal transition generates proliferative human islet precursor cells.

Insulin-expressing beta cells, found in pancreatic islets, are capable of generating more beta cells even in the adult. We show that fibroblast-like cells derived from adult human islets donated postmortem proliferate readily in vitro. These mesenchymal-type cells, which exhibit no hormone expression, can then be induced to differentiate into hormone-expressing islet-like cell aggregates, which reestablishes the epithelial character typical of islet cells. Immunohistochemistry, in situ hybridization, and messenger RNA measurements in single cells and cell populations establish the transition of epithelial cells within islets to mesenchymal cells in culture and then to insulin-expressing epithelial cells.

Adolescent↗
PubMed2004

Generating new pancreas from old.

Pancreas regeneration after tissue damage is a key response to pancreatic injury, involving pancreatic duct progenitor cells and intra-islet precursor cells. Surgical removal of the pancreas, duct obstruction by cellophane wrapping and bone marrow-derived stem cell transplantation act as inductive stimuli, leading to pancreas regeneration. The exact role of growth and differentiation factors regulating pancreatic beta-cell mass remains unknown. Here, I will attempt to integrate recent findings and speculate on the factors that trigger this fascinating response, wherein the pancreas responds to a deficit in cell mass and undergoes new islet formation, leading to restoration of normal beta-cell mass. I will also discuss recent advances in regenerating endocrine pancreatic cells, which could affect stem cell-based approaches to treating diabetes mellitus.

Animals↗
PubMed2003

Human pancreatic precursor cells secrete FGF2 to stimulate clustering into hormone-expressing islet-like cell aggregates.

Development of the endocrine pancreas includes a series of early events wherein precursor cells cluster, that is migrate to form cell aggregates, which subsequently differentiate into islets of Langerhans. We show that PANC-1 cells, a human pancreatic cell line, differentiates into hormone-producing islet-like cell aggregates after exposure to a defined serum-free medium. These cells were used to provide the following evidence that fibroblast growth factor (FGF)2 is a paracrine chemoattractant during PANC-1 cell clustering: (i) FGF2 is secreted and remains bound to the extracellular matrix from where it may diffuse to form chemoattractive gradients; (ii) a subset of cells expresses FGF receptors (FGFRs) -1, -2, -3, and -4; (iii) inhibition of FGFR tyrosine kinase inhibits cell clustering; and (iv) FGF2 neutralizing antibody inhibits clustering. In addition, adult human islet-derived precursor cells, which cluster and differentiate in a manner similar to PANC-1 cells, also secrete FGF2 and express FGFRs. We conclude that FGF2, acting as a paracrine chemoattractant, stimulates clustering of precursor cells, an early step leading to islet-like cell aggregate formation. Similar processes may occur during development of the islet of Langerhans in humans.

Cell Aggregation↗
PubMed2002

Functional maturation of fetal porcine beta-cells by glucagon-like peptide 1 and cholecystokinin.

Fetal beta-cells are immature in their responsiveness to glucose, and maturation occurs after oral feeding commences at birth. The incretin hormones glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK) are known to be released from the gut in response to oral feeding and enhance insulin secretion from pancreatic beta-cells. We hypothesized that these fetal beta-cells would mature in their glucose responsiveness if they were previously exposed to incretins. We exposed fetal pig islet-like cell clusters (ICCs) to 100 nM GLP-1, 5 micro M CCK, or 10 mM nicotinamide (NIC; a positive control) for 6 h and demonstrated 3- and 1.7-fold increases in glucose-induced insulin secretion for GLP-1 and CCK, respectively. This effect did not reach statistical significance if the ICCs were exposed to the incretins for 3 d. However, exposure for 4 d enhanced formation of beta-cells from undifferentiated cells, from 8 +/- 1% (controls) to 17 +/- 3% for GLP-1, 20 +/- 4% for CCK, and 15 +/- 1 for NIC (P < 0.001). ICCs exposed to GLP-1 for 3 d also showed a 1.9-fold increase in the intensity of PDX-1(+) cells, as assessed by semiquantitative fluorescent immunocytochemistry. Exposure of ICCs to incretins for 3 d did not show any increase in size of the islet clusters. ICCs exposed to either incretin as well as controls were transplanted into severe combined immunodeficient mice and examined at 1 and 2 months. We found a significant increase in the number of beta-cells in the GLP-1- and NIC-treated groups compared with the untreated controls or CCK. Perfusion of these grafts at 2 months showed that ICCs previously exposed to GLP-1, CCK, and NIC (but not controls), were functional and mature. In conclusion, GLP-1 and CCK have a dual effect on fetal pig ICCs, causing maturation of glucose-induced insulin secretion from beta-cells as well as enhancement of differentiation from undifferentiated precursors.

Animals↗