β-Cell Generation: Can Rodent Studies Be Translated to Humans?

β-cell replacement by allogeneic islet transplantation is a promising approach for patients with type 1 diabetes, but the shortage of organ donors requires new sources of β cells. Islet regeneration in vivo and generation of β-cells ex vivo followed by transplantation represent attractive therapeutic alternatives to restore the β-cell mass. In this paper, we discuss different postnatal cell types that have been envisaged as potential sources for future β-cell replacement therapy. The ultimate goal being translation to the clinic, a particular attention is given to the discrepancies between findings from studies performed in rodents (both ex vivo on primary cells and in vivo on animal models), when compared with clinical data and studies performed on human cells

Conversion of Mature Human β-Cells Into Glucagon-Producing α-Cells

Conversion of one terminally differentiated cell type into another (or transdifferentiation) usually requires the forced expression of key transcription factors. We examined the plasticity of human insulin-producing β-cells in a model of islet cell aggregate formation. Here, we show that primary human β-cells can undergo a conversion into glucagon-producing α-cells without introduction of any genetic modification. The process occurs within days as revealed by lentivirus-mediated β-cell lineage tracing. Converted cells are indistinguishable from native α-cells based on ultrastructural morphology and maintain their α-cell phenotype after transplantation in vivo. Transition of β-cells into α-cells occurs after β-cell degranulation and is characterized by the presence of β-cell–specific transcription factors Pdx1 and Nkx6.1 in glucagon+ cells. Finally, we show that lentivirus-mediated knockdown of Arx, a determinant of the α-cell lineage, inhibits the conversion. Our findings reveal an unknown plasticity of human adult endocrine cells that can be modulated. This endocrine cell plasticity could have implications for islet development, (patho)physiology, and regeneration

Implication du facteur de transcription Ets-2 dans les phénomènes anti-apoptiques et dans la maturation des cellules T

NICE-BU Sciences (060882101) / SudocSudocFranceF

Bioluminescent reporter assay for monitoring ER stress in human beta cells

During type 1 diabetes development, cells in the islets of Langerhans engage adaptive mechanisms in response to inflammatory signals to cope with stress, to restore cellular homeostasis, and to preserve cell function. Disruption of these mechanisms may induce the formation of a repertoire of stress-induced neoantigens, which are critical in the loss of tolerance to beta cells and the development of autoimmunity. While multiple lines of evidence argue for a critical role of the endoplasmic reticulum in these processes, the lack of tools to specifically monitor beta cell stress hampers the development of therapeutic interventions focusing on maintaining endoplasmic reticulum homeostasis. Here we designed and evaluated a stress-induced reporter in which induction of stress correlates with increased light emission. This Gaussia luciferase-based reporter system employs the unconventional cytoplasmic splicing of XBP1 to report ER stress in cells exposed to known ER-stress inducers. Linking this reporter to a human beta cell-specific promotor allows tracing ER-stress in isolated human beta cells as well as in the EndoC-βH1 cell line. This reporter system represents a valuable tool to assess ER stress in human beta cells and may aid the identification of novel therapeutics that can prevent beta cell stress in human pancreatic islets