Severely fibrotic pancreases from young patients with chronic pancreatitis: evidence for a ductal origin of islet neogenesis

Abstract

While it is known that islet cell mass increases considerably after birth, general uncertainty surrounds the source of new beta cells in humans. Chronic pancreatitis (CP) presents a natural injury model for studying postnatal beta-cell regeneration in the human pancreas. In this report, we present histological evidence from human CP pancreases to support the theory that islet neogenesis can occur from ductal precursor cells after birth. Three young patients (ages 16, 12, and 28 years) underwent total pancreatectomy for the management of CP followed by islet isolation and autologous transplantation to prevent or minimize post-surgical diabetes. In all cases, the pancreases had extensive fibrosis, a rock-like consistency, and calcifications in the ducts. During islet isolations, we observed the unusual release of islets with many ductal fragments. In histopathological evaluation of these pancreases, solid cords of cells sometimes formed islet like structures intraductally or extending from ductal structures. Immunofluorescence staining for chromogranin, insulin, proinsulin, PDX1, glucagon and cytokeratins confirmed these structures to be composed of chromogranin-positive endocrine cells which included both β-cells and α-cells. Labeling for Ki67 to demonstrate mitotic activity showed frequent labeling of duct epithelial cells and of some periductal cells. Using insulin and wide-spectrum cytokeratin double-immunofluorescent labeling, we found insulin positive cells to be present within the ductal lumens, among the cytokeratin positive ductal epithelium, and extending from the ductal epithelium into surrounding connective tissues, providing evidence for a ductal origin of islet neogenesis.

Five-year follow-up of patients with type 1 diabetes transplanted with allogeneic islets: the UIC experience

“…Donor selection and the procedures of islet isolation and transplantation have been previously described [17–20]. Subjects were eligible for further transplant if by the end of the fourth week after the first islet infusion or by the end of the fourth week after the second islet infusion they do not meet insulin-independence criteria [21], or HbA1c increased over 6.5% (47.5 mmol/mol) [22] (three patients required a supplemental islet infusion after the initial study period).…”

Islet autotransplantation: past, present and future. Chapter II: the role of islet autotransplantation for the treatment of chronic pancreatitis

“…Furthermore, as demonstrated in the autopsy studies of the young nondiabetic children, younger patients have higher b-cell replication capacity compared with adult patients [74]. As demonstrated by the histological examination of severely fibrotic Review Linetsky, Sayki Arslan, Alejandro & Camillo future science group pancreatic tissue from three young CP patients, insulin-positive cells were observed within the ductal lumen, thereby providing evidence of islet neogenesis [75]. However, b-cell replication or neo genesis as a result of the co-infusion of ductal tissue with islet cells as part of the IAT has never been demonstrated.…”

Total Pancreatectomy and Islet Autotransplantation in Children for Chronic Pancreatitis

“…36 We have also demonstrated previously a capacity for neogenesis of islet like structures from ductal cells in the young patients with severe pancreatitis suggesting that ductal precursors transplanted in the “impure” fractions of the islet preparation could also theoretically provide a precursor for islet mass in these younger patients. 37 …”