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Development of a human embryonic stem cell (hESC)-based therapy for type 1 diabetes will require the translation of proof-of-principle concepts into a scalable, controlled, and regulated cell manufacturing process. We have previously demonstrated that hESC can be directed to differentiate into pancreatic progenitors that mature into functional glucose-responsive, insulin-secreting cells in vivo. In this study we describe hESC expansion and banking methods and a suspension-based differentiation system, which together underpin an integrated scalable manufacturing process for producing pancreatic progenitors. This system has been optimized for the CyT49 cell line. Accordingly, qualified large-scale single-cell master and working cGMP cell banks of CyT49 have been generated to provide a virtually unlimited starting resource for manufacturing. Upon thaw from these banks, we expanded CyT49 for two weeks in an adherent culture format that achieves 50-100 fold expansion per week. Undifferentiated CyT49 were then aggregated into clusters in dynamic rotational suspension culture, followed by differentiation en masse for two weeks with a four-stage protocol. Numerous scaled differentiation runs generated reproducible and defined population compositions highly enriched for pancreatic cell lineages, as shown by examining mRNA expression at each stage of differentiation and flow cytometry of the final population. Islet-like tissue containing glucose-responsive, insulin-secreting cells was generated upon implantation into mice. By four- to five-months post-engraftment, mature neo-pancreatic tissue was sufficient to protect against streptozotocin (STZ)-induced hyperglycemia. In summary, we have developed a tractable manufacturing process for the generation of functional pancreatic progenitors from hESC on a scale amenable to clinical entry.

This paper explores the gas metallicity gradients in a sample of 25 nearby galaxies using new Integral Field Spectroscopy observations from the Metal-THINGS survey. We derive and study the resolved diffuse ionised gas content, Baldwin, Phillips and Terlevich diagrams and gas metallicities for our entire sample, at spatial resolutions of 40-300 pc. Gas metallicity gradients are studied as a function of the galaxy's stellar mass, H I gas fraction, diffuse ionised gas content, and using different parametric length scales for normalisation. The metallicity gradients are analysed using Bayesian statistics based on data from the Metal-THINGS survey. Bayesian MCMC models are developed to explore how metallicity gradients vary with a galaxy's mass and how they correlate with properties such as the stellar mass or the atomic gas fraction. For our sample, we find that the metallicity typically decreases with galactic radius, consistent with inside-out galaxy growth. We find a trend dependent on the stellar mass, with a break at log(M_star/M_sun)=9.5, and another between the metallicity gradients and the atomic gas fraction (f_g,HI) of a galaxy at fg,HI=0.75, indicating relatively shallower gradients for lower gas fractions. We find that normalisation using NUV-band effective radii are preferable for galaxies with a higher atomic gas content and lower stellar masses, while r-band radii are better suited for those with lower atomic gas fractions and more massive ones. Our results highlight a strong connection between gas content, stellar mass, and metallicity gradients. The breaks at log(M_star/M_sun)=9.5 and fg,HI=0.75 mark shifts in chemical enrichment behaviour, with low-mass galaxies showing greater sensitivity to gas processes. Overall, this points to gas accretion and removal as key drivers of chemical evolution in low-mass systems.