Abstract
Aldh1 expression is known to mark candidate progenitor populations in adult and embryonic mouse pancreas, and Aldh1 enzymatic activity has been identified as a potent regulator of pancreatic endocrine differentiation in zebrafish. However, the location and identity of Aldh1-expressing cells in zebrafish pancreas remain unknown. In this study we demonstrate that Aldh1-expressing cells are located immediately adjacent to 2F11-positive pancreatic ductal epithelial cells, and that their abundance dramatically increases during zebrafish secondary islet formation. These cells also express neurod, a marker of endocrine progenitor cells, but do not express markers of more mature endocrine cells such as pax6b or insulin. Using formal cre/lox-based lineage tracing, we further show that Aldh1-expressing pancreatic epithelial cells are the direct progeny of pancreatic notch-responsive progenitor cells, identifying them as a critical intermediate between multi-lineage progenitors and mature endocrine cells. Pharmacologic manipulation of Aldh1 enzymatic activity accelerates cell entry into the Aldh1-expressing endocrine progenitor pool, and also leads to the premature maturation of these cells, as evidenced by accelerated pax6b expression. Together, these findings suggest that Aldh1-expressing cells act as both participants and regulators of endocrine differentiation during zebrafish secondary islet formation.
Highlights
In mammals, pancreatic endocrine differentiation occurs through a defined sequence of progenitor cell types, which undergo progressive lineage restriction [1,2,3]
Between 5-15 dpf, pancreatic Aldh1 immunoreactivity was confined to the principle islet, where Aldh1-positive cells were often observed in proximity to Insulinpositive β-cells (Figure 1A-C)
These cells increase in abundance in association with secondary islet formation and are frequently located within the pancreatic ductal epithelial tree adjacent to insulin expressing cells, consistent with possible endocrine progenitor function
Summary
Pancreatic endocrine differentiation occurs through a defined sequence of progenitor cell types, which undergo progressive lineage restriction [1,2,3] Detailed elaboration of this step-wise differentiation program has allowed progress towards the guided programming of human stem cells towards a β-cell fate [4], potentially providing a source of insulin-producing cells suitable for cell replacement therapy in diabetes. Complementing these mammalian studies, the zebrafish (Danio rerio) has emerged as a highly productive model organism in which to study mechanisms of pancreas development and β-cell differentiation, with multiple studies demonstrating that fish and mammals rely on shared transcriptional and signaling networks during pancreas development. Among these differences is the presence of an early appearing principle islet in zebrafish, which arises from a ptf1aindependent lineage that is both temporally and spatially segregated from progenitor cells destined to give rise to the exocrine pancreas [13,14,19]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
