The supply chain of human pancreatic β cell lines
Raphael Scharfmann, … , Willem Staels, Olivier Albagli
Raphael Scharfmann, … , Willem Staels, Olivier Albagli
Published September 3, 2019
Citation Information: J Clin Invest. 2019;129(9):3511-3520. https://doi.org/10.1172/JCI129484.
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Review

The supply chain of human pancreatic β cell lines

Abstract

Patients with type 1 or type 2 diabetes have an insufficiency in their functional β cell mass. To advance diabetes treatment and to work toward a cure, a better understanding of how to protect the pancreatic β cells against autoimmune or metabolic assaults (e.g., obesity, gestation) will be required. Over the past decades, β cell protection has been extensively investigated in rodents both in vivo and in vitro using isolated islets or rodent β cell lines. Transferring these rodent data to humans has long been challenging, at least partly for technical reasons: primary human islet preparations were scarce and functional human β cell lines were lacking. In 2011, we described a robust protocol of targeted oncogenesis in human fetal pancreas and produced the first functional human β cell line, and in subsequent years additional lines with specific traits. These cell lines are currently used by more than 150 academic and industrial laboratories worldwide. In this Review, we first explain how we developed the human β cell lines and why we think we succeeded where others, despite major efforts, did not. Next, we discuss the use of such functional human β cell lines and share some perspectives on their use to advance diabetes research.

Authors

Raphael Scharfmann, Willem Staels, Olivier Albagli

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Figure 2

Potential mechanisms underlying the stability of EndoC-βH cell lines and the reversion of their immortalization.

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Potential mechanisms underlying the stability of EndoC-βH cell lines and...
Positive or negative variation in RIP activity is counteracted by its effects on SV40LT expression levels at both an individual and a population level. At the individual cell level, an increase (or decrease) in SV40LT expression decreases (or increases) RIP activity by a mechanism involving the Rb pathway. At the cell population level, decrease in SV40LT expression level in a given cell impairs its viability or proliferation compared with the other cells. The result of these mechanistic and selective forces (red and blue arrows) is to keep RIP activity constant in most cells (narrow bell curve). This maintains stable activity within a putative RIP-regulating module, which in turn ensures long-term phenotypic stability. Persistent subthreshold SV40LT expression, as in experiments aimed to reverse immortalization, triggers cell cycle exit and terminal differentiation. For more details, see main text. Rb, activity of the retinoblastoma protein family; RIP, rat insulin promoter; SV40LT, simian virus 40 large T antigen expression.