Islet Neogenesis: A Possible Pathway for Beta-Cell Replenishment

Abstract

■ AbstractDiabetes, particularly type 1 diabetes, results from the lack of pancreatic β-cells. β-cell replenishment can functionally reverse diabetes, but two critical challenges face the field: 1. protection of the new β-cells from autoimmunity and allorejection, and 2. development of β-cells that are readily available and reliably functional. This chapter will examine the potential of endogenous replenishment of pancreatic β-cells as a possible therapeutic tool if autoimmunity could be blunted. Two pathways for endogenous replenishment exist in the pancreas: replication and neogenesis, defined as the formation of new islet cells from pancreatic progenitor/stem cells. These pathways of β-cell expansion are not mutually exclusive and both occur in embryonic development, in postnatal growth, and in response to some injuries. Since the β-cell population is dramatically reduced in the pancreas of type 1 diabetes patients, with only a small fraction of the β-cells surviving years after onset, replication of preexisting β-cells would not be a reasonable start for replenishment. However, induction of neogenesis could provide a starting population that could be further expanded by replication. It is widely accepted that neogenesis occurs in the initial embryonic formation of the endocrine pancreas, but its occurrence anytime after birth has become controversial because of discordant data from lineage tracing experiments. However, the concept was built upon many observations from different models and species over many years. Herein, we discuss the role of neogenesis in normal growth and regeneration, as learned from rodent models, followed by an analysis of what has been found in humans.

Maturation of Stem Cell-Derived Beta-cells Guided by the Expression of Urocortin 3

“…Several non-beta-cell types within the pancreas (duct, acinar, and alpha cells) and outside the pancreas (hepatocytes) have been demonstrated to possess the capacity to differentiate into beta-cells under different experimental conditions and/or following genetic manipulations in mice [9]. While these strategies hold promise, the translation of neogenesis into the clinic has not been made [10,11]. With respect to transplantation, a clinical trial by Living Cell Technologies TM using encapsulated porcine islets in human subjects is underway [12].…”

La thérapie cellulaire du diabète

“…Le rôle et l'identité de ces progéniteurs restent imprécis et controversés [52]. Les cellules ductales ne représentent pas un modèle idéal pour des stratégies d'expansion ou de transdifférenciation in vivo, étant impliquées dans le cancer pancréatique [53].…”

In Vitro Differentiation and Expansion of Human Pluripotent Stem Cell-Derived Pancreatic Progenitors

“…Currently, cadaveric islets are transplanted into the portal vein of the recipient patient, which is chosen because of its proximity to the liver and the advantage of minimal invasion. However, about half of the islets introduced into the liver die during or shortly after transplantation [91][92][93]. Transplantation studies with mice showed that the kidney capsule, peritoneum or omental pouch provide a permissive environment for pancreatic population maturation and function.…”