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

Abstract

■ AbstractType 1 diabetes (T1D) is a devastating disease precipitated by an autoimmune response directed at the insulinproducing beta-cells of the pancreas for which no cure exists. Stem cell-derived beta-cells show great promise for a cure as they have the potential to supply unlimited numbers of cells that could be derived from a patient's own cells, thus eliminating the need for immunosuppression. Current in vitro protocols for the differentiation of stem cell-derived beta-cells can successfully generate pancreatic endoderm cells. In diabetic rodents, such cells can differentiate further along the beta-cell lineage until they are eventually capable of restoring normoglycemia. While these observations demonstrate that stem cell-derived pancreatic endoderm has the potential to differentiate into mature, glucose-responsive beta-cells, the signals that direct differentiation and maturation from pancreatic endoderm onwards remain poorly understood. In this review, we analyze the sequence of events that culminates in the formation of beta-cells during embryonic development, and we summarize how current protocols to generate beta-cells have sought to capitalize on this ontogenic template. We place particular emphasis on the current challenges and opportunities which occur in the later stages of beta-cell differentiation and maturation of transplantable stem cell-derived beta-cells. Another focus is on the question how the use of recently identified maturation markers such as urocortin 3 can be instrumental in guiding these efforts.

Evidence for a Neogenic Niche at the Periphery of Pancreatic Islets

“…It is first detectable in a few beta cells by embryonic day 16.5, but it takes until 2–3 weeks postnatally for most beta cells to acquire expression . This onset of UCN3 expression is later than that of a series of other beta cell markers, including MAFA, Connexin 36, Zinc transporter 8, and several prohormone convertases . The late onset of UCN3 expression during beta cell maturation combined with the fact that excellent tools exist to detect it, make UCN3 an appealing and convenient marker to study beta cell maturation.…”

“…[52,53] This onset of UCN3 expression is later than that of a series of other beta cell markers, including MAFA, Connexin 36, Zinc transporter 8, and several prohormone convertases. [54] The late onset of UCN3 expression during beta cell maturation combined with the fact that excellent tools exist to detect it, make UCN3 an appealing and convenient marker to study beta cell maturation. To our initial surprise, in staining islets from adult mice for UCN3 and insulin, we observed insulin-positive beta cells with no detectable UCN3 expression.…”

Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets

“…This is evident from the presence of a distinct population of immature beta cells at the islet periphery that does not yet express the late maturation marker Urocortin3 (Ucn3) (Blum et al, 2012;van der Meulen and Huising, 2014;van der Meulen et al, 2012). Similar Ucn3-negative beta cells are readily identifiable in human pancreas of different ages and in donors with T1D.…”

Identification of CD90 as Putative Cancer Stem Cell Marker and Therapeutic Target in Insulinomas

“…Regarding the first theory, the presence and origin of stem cells in the adult pancreas remains unverified and strongly debated. The early endocrine progenitor cell in the embryonic islet lineage developmental pathway has been extensively characterized, and is known for its expression of transcription factors NGN3, NKX6.1, PDX1, and NKX2.2 [7]. However, no consensus has been obtained on the location of adult pancreatic stem cells that give rise to b-cells, as conflicting in vivo data suggest that they are either present in the ductal, acinar, or islet compartment of the pancreas [8].…”