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Virus-like infection induces human ? cell dedifferentiation.

ABSTRACT: Type 1 diabetes (T1D) is a chronic disease characterized by an autoimmune-mediated destruction of insulin-producing pancreatic ? cells. Environmental factors such as viruses play an important role in the onset of T1D and interact with predisposing genes. Recent data suggest that viral infection of human islets leads to a decrease in insulin production rather than ? cell death, suggesting loss of ? cell identity. We undertook this study to examine whether viral infection could induce human ? cell dedifferentiation. Using the functional human ? cell line EndoC-?H1, we demonstrate that polyinosinic-polycytidylic acid (PolyI:C), a synthetic double-stranded RNA that mimics a byproduct of viral replication, induces a decrease in ? cell-specific gene expression. In parallel with this loss, the expression of progenitor-like genes such as SOX9 was activated following PolyI:C treatment or enteroviral infection. SOX9 was induced by the NF-?B pathway and also in a paracrine non-cell-autonomous fashion through the secretion of IFN-?. Lastly, we identified SOX9 targets in human ? cells as potentially new markers of dedifferentiation in T1D. These findings reveal that inflammatory signaling has clear implications in human ? cell dedifferentiation.

SUBMITTER: Oshima M

PROVIDER: S-EPMC5821176 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Virus-like infection induces human β cell dedifferentiation.

Oshima Masaya M Knoch Klaus-Peter KP Diedisheim Marc M Petzold Antje A Cattan Pierre P Bugliani Marco M Marchetti Piero P Choudhary Pratik P Huang Guo-Cai GC Bornstein Stefan R SR Solimena Michele M Albagli-Curiel Olivier O Scharfmann Raphael R

JCI insight 20180208 3

Type 1 diabetes (T1D) is a chronic disease characterized by an autoimmune-mediated destruction of insulin-producing pancreatic β cells. Environmental factors such as viruses play an important role in the onset of T1D and interact with predisposing genes. Recent data suggest that viral infection of human islets leads to a decrease in insulin production rather than β cell death, suggesting loss of β cell identity. We undertook this study to examine whether viral infection could induce human β cell ...[more]

PMID: 29415896

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Project description:The Schwann cell (SC) is the major component of the peripheral nervous system (PNS) that provides metabolic and functional support for peripheral axons. The emerging roles of SC mitochondrial function for PNS development and axonal stability indicate the importance of SC metabolism in nerve function and in peripheral neuropathies associated with metabolic disorders. Nicotinamide adenine dinucleotide (NAD+) is a crucial molecule in the regulation of cellular metabolism and redox homeostasis. Here, we investigated the roles of NAD+ metabolism in SC functions in vivo by mutating NAMPT, the rate-limiting enzyme of NAD+ biosynthesis, specifically in SCs. NAMPT SC knock-out male and female mice (NAMPT SCKO mice) had delayed SC maturation in development and developed hypomyelinating peripheral neuropathy without axon degeneration or decreased SC survival. JUN, a master regulator of SC dedifferentiation, is elevated in NAMPT SCKO SCs, suggesting that decreased NAD+ levels cause them to arrest at an immature stage. Nicotinic acid administration rescues the NAD+ decline and reverses the SC maturation defect and the development of peripheral neuropathy, indicating the central role of NAD+ in PNS development. Upon nicotinic acid withdrawal in adulthood, NAMPT SCKO mice showed rapid and severe peripheral neuropathy and activation of ERK/MEK/JUN signaling, which in turn promotes SC dedifferentiation. These data demonstrate the importance of NAD+ metabolism in SC maturation and nerve development and maintenance and suggest that altered SC NAD+ metabolism could underlie neuropathies associated with diabetes and aging.SIGNIFICANCE STATEMENT In this study, we showed that Schwann cell differentiation status is critically dependent on NAD+ homeostasis. Aberrant regulation of NAD+ biosynthesis via NAMPT deletion results in a blockade of Schwann cell maturation during development and severe peripheral neuropathy without significant axon loss. The phenotype can be rescued by supplementation with nicotinic acid; however, withdrawal of nicotinic acid leads to Schwann cell dedifferentiation, myelination defects, and death. These results provide new therapeutic possibilities for peripheral neuropathies associated with NAD+ decline during aging or diabetes.

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Virus-like infection induces human ? cell dedifferentiation.

Publications

Virus-like infection induces human β cell dedifferentiation.

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