Beta Cell Dedifferentiation Induced by IRE1α Deletion Prevents Type 1 Diabetes

Lee, Hugo; Lee, Yong-Syu; Harenda, Quincy Eckert; Pietrzak, Stefan; Oktay, Hülya Zeynep; Schreiber, Sierra; Liao, Yi-An; Sonthalia, Shreyash; Ciecko, Ashley E.; Chen, Yi-Guang; Keleş, Sündüz; Sridharan, Rupa; Engin, Feyza

doi:10.1016/j.cmet.2020.03.002

Cited by 108 publications

(95 citation statements)

References 93 publications

(76 reference statements)

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“…7 ). Meanwhile, β cells from KO recipients expressed genes associated with immune suppression (GABA receptor A (Gabrg3) 27 , Gad2, CD14 28 and H2-Q7 (Qa-2) 12 13 ( Fig. 6 a, b).…”

Section: Resultsmentioning

confidence: 99%

“…Thompson et al described a subpopulation of β cells that become senescent and actively promotes the immune-mediated destruction process 11 . Recently Lee et al reported that modulating the unfolded protein response (UPR) in NOD β cells by deleting the UPR sensor IRE1α prior to insulitis induced a transient dedifferentiation of β cells, resulting in substantially reduced islet immune cell infiltration and β cell apoptosis and protection from diabetes 12 . When we analyzed β cells during the progression of diabetes, we identified a subset of β cells with dedifferentiated features such as reduced expression of Pdx1, Nkx6.1, MafA , and Ins1, Ins2 as well as β cell autoantigens and those cells were resistant to immune mediated killing 13 .…”

Section: Introductionmentioning

confidence: 99%

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Tet2 Controls β cells Responses to Inflammation in Type 1 Diabetes

Rui¹,

Deng²,

Ponath

et al. 2020

Preprint

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Abstractβ cells may participate and contribute to their own demise during Type 1 diabetes (T1D). We identified a novel role of Tet2 in regulating immune killing of β cells. Tet2 is induced in murine and human β cells with inflammation but its expression is reduced in surviving β cells. Tet2-KO mice that receive WT bone marrow transplants develop insulitis but not diabetes and islet infiltrates do not eliminate β cells even though immune cells from the mice can transfer diabetes to NOD/scid recipients. Tet2-KO β cells show reduced expression of inflammatory genes, associated with closed transcription factor binding sites. Tet2-KO recipients are protected from transfer of disease by diabetogenic immune cells. We conclude that Tet2 regulates pathologic interactions between β cells and immune cells and controls intrinsic protective pathways. Modulating TET2 may enable survival of β cells or their replacements in the setting of pathologic immune cells.

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“…7 ). Meanwhile, β cells from KO recipients expressed genes associated with immune suppression (GABA receptor A (Gabrg3) 27 , Gad2, CD14 28 and H2-Q7 (Qa-2) 12 13 ( Fig. 6 a, b).…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tet2 Controls β cells Responses to Inflammation in Type 1 Diabetes

Rui¹,

Deng²,

Ponath

et al. 2020

Preprint

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show abstract

“…In such cases the beta-cells maintain the expression of marker genes, like Pdx1 and MafA, but adopt a dedifferentiated fate and do not release insulin. Recent work by Lee et al confirms that dedifferentiated beta-cells exhibit reduced levels of beta-cell autoantigens and increased expression of immune inhibitory markers (Lee et al, 2020). Evidently, the preservation of beta-cell function and their mature populations should be a priority.…”

Section: Methods For Beta-cell Preservationmentioning

confidence: 99%

Advances and complications of regenerative medicine in diabetes therapy

Brovkina

Дашинимаев

2020

PeerJ

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The rapid development of technologies in regenerative medicine indicates clearly that their common application is not a matter of if, but of when. However, the regeneration of beta-cells for diabetes patients remains a complex challenge due to the plurality of related problems. Indeed, the generation of beta-cells masses expressing marker genes is only a first step, with maintaining permanent insulin secretion, their protection from the immune system and avoiding pathological modifications in the genome being the necessary next developments. The prospects of regenerative medicine in diabetes therapy were promoted by the emergence of promising results with embryonic stem cells (ESCs). Their pluripotency and proliferation in an undifferentiated state during culture have ensured the success of ESCs in regenerative medicine. The discovery of induced pluripotent stem cells (iPSCs) derived from the patients’ own mesenchymal cells has provided further hope for diabetes treatment. Nonetheless, the use of stem cells has significant limitations related to the pluripotent stage, such as the risk of development of teratomas. Thus, the direct conversion of mature cells into beta-cells could address this issue. Recent studies have shown the possibility of such transdifferentiation and have set trends for regeneration medicine, directed at minimizing genome modifications and invasive procedures. In this review, we will discuss the published results of beta-cell regeneration and the advantages and disadvantages illustrated by these experiments.

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“…As a matter of fact, it has been shown that in the NOD mouse, the specific deletion of the unfolded protein response (UPR) sensor IRE1-α prior to insulitis establishment led to the loss of β cell phenotype and was associated to a reduction of islet inflammation alongside with a relief of immune cells infiltration. Of importance, Ire1-α -deficient β cells were characterized by ( i ) reduced levels of typical β cell autoantigens; ( ii ) lower expression of MHC class I components; ( iii ) higher levels of immune inhibitory markers [ 30 ]. Collectively, these data indicate that β cell dedifferentiation may represent an escaping mechanism from the inflammatory insults during T1D progression.…”

Section: β Cell Identity and Function In Health And Diseasementioning

confidence: 99%

“…Importantly, downregulation of Ire1α secondary to the overexpression of miR-24 was able to protect β cells from both palmitate- and thapsigargin- induced apoptosis [ 74 ]. Accordingly, it was demonstrated that Ire1α deletion restricted to β cells was able to inhibit β cell apoptosis, thus preventing disease onset in NOD mice [ 30 ]. Therefore, it is conceivable that the regulation of Ire1α -XBP1 by miR-24 is part of the molecular mechanisms involved in β cell protection from inflammatory-stress induced apoptosis.…”

Section: Can We Protect or Restore β Cell Function By Mimicking Ormentioning

confidence: 99%

The Landscape of microRNAs in βCell: Between Phenotype Maintenance and Protection

Grieco

Brusco

Licata

et al. 2021

IJMS

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Diabetes mellitus is a group of heterogeneous metabolic disorders characterized by chronic hyperglycaemia mainly due to pancreatic β cell death and/or dysfunction, caused by several types of stress such as glucotoxicity, lipotoxicity and inflammation. Different patho-physiological mechanisms driving β cell response to these stresses are tightly regulated by microRNAs (miRNAs), a class of negative regulators of gene expression, involved in pathogenic mechanisms occurring in diabetes and in its complications. In this review, we aim to shed light on the most important miRNAs regulating the maintenance and the robustness of β cell identity, as well as on those miRNAs involved in the pathogenesis of the two main forms of diabetes mellitus, i.e., type 1 and type 2 diabetes. Additionally, we acknowledge that the understanding of miRNAs-regulated molecular mechanisms is fundamental in order to develop specific and effective strategies based on miRNAs as therapeutic targets, employing innovative molecules.

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Beta Cell Dedifferentiation Induced by IRE1α Deletion Prevents Type 1 Diabetes

Cited by 108 publications

References 93 publications

Tet2 Controls β cells Responses to Inflammation in Type 1 Diabetes

Tet2 Controls β cells Responses to Inflammation in Type 1 Diabetes

Advances and complications of regenerative medicine in diabetes therapy

The Landscape of microRNAs in βCell: Between Phenotype Maintenance and Protection

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