Deconstructive somatic cell nuclear transfer reveals novel regulatory T-cell subsets

Ku, Manching; Ke, Eugene; Sabouri-Ghomi, Mohsen; Abadejos, Justin R.; Freeman, Brent; Nham, Amy; Phillips, Nathaniel; Yang, Kevin Yi; Lui, Kathy O.; Kirak, Oktay

doi:10.1016/j.jaci.2018.04.038

Cited by 5 publications

(8 citation statements)

References 13 publications

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“…In order to understand how Treg regulate neonatal heart regeneration, we performed genome-wide single-cell transcriptomic profiling (scRNA-seq) as recently described 21,22 with CD3 + T-cells purified at day 7 following injury of ICR mice that underwent CI at P3. In this study, the spleen served as a source of naive T-cells (control) while the heart served as a source of neoantigen-activated T-cells.…”

Section: Resultsmentioning

confidence: 99%

Regulatory T-cells are required for neonatal heart regeneration

et al. 2018

Preprint

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Previous work has elegantly demonstrated that, unlike adult mammalian heart, the neonatal heart is able to regenerate after injury from postnatal day (P) 1 to 7. Recently, macrophages are found to be required in the repair process as depletion of which abolishes endogenous regenerative capability of the neonatal heart. Nevertheless, whether innate immunity alone is sufficient for neonatal heart regeneration is obscure. source of chemokines and cytokines that attract monocytes and macrophages previously known to drive neonatal heart regeneration. Furthermore, Treg directly promote proliferation of both mouse and human cardiomyocytes in a paracrine manner. Our findings uncover an unappreciated mechanism in neonatal heart regeneration; and offer new avenues for developing novel therapeutics targeting Treg-mediated heart regeneration.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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Section: Resultsmentioning

confidence: 99%

Regulatory T-cells are required for neonatal heart regeneration

et al. 2018

Preprint

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“…We had previously generated two novel SCNT-derived thymic T reg model using donor cells from pure NOD background (27,28). For an unbiased approach, we utilized NOD-Rag1 +/− mice in which the BCR IgH and IgL-locus were initially in wildtype configuration.…”

Section: Generation Of a Novel Scnt-derived B Cell Modelmentioning

confidence: 99%

“…We had successfully created novel T reg mouse models on pure NOD background by epigenetic reprogramming through somatic cell nuclear transfer (SCNT) (27,28). Strikingly, these T reg models provided new insights into the existence of distinct thymic T reg subsets.…”

Section: Introductionmentioning

confidence: 99%

Prediabetes Induced by a Single Autoimmune B Cell Clone

Phillips

Nham

et al. 2020

Front. Immunol.

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While B cells play a significant role in the onset of type-1 diabetes (T1D), little is know about their role in those early stages. Thus, to gain new insights into the role of B cells in T1D, we converted a physiological early pancreas-infiltrating B cell into a novel BCR mouse model using Somatic Cell Nuclear Transfer (SCNT). Strikingly, SCNT-derived B1411 model displayed neither developmental block nor anergy. Instead, B1411 underwent spontaneous germinal center reactions. Without T cell help, B1411-Rag1 −/− was capable of forming peri-/intra-pancreatic lymph nodes, and undergoing class-switching. RNA-Seq analysis identified 93 differentially expressed genes in B1411 compared to WT B cells, including Irf7, Usp18, and Mda5 that had been linked to a potential viral etiology of T1D. We also found various members of the oligoadenylate synthase (OAS) family to be enriched in B1411, such as Oas1, which had recently also been linked to T1D. Strikingly, when challenged with glucose B1411-Rag1 −/− mice displayed impaired glucose tolerance.

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“…Two compounds, a MEK inhibitor and a GSK3 inhibitor, have been identified that facilitate derivation of ES cells from un-manipulated as well as cloned (a.k.a. somatic cell nuclear transfer) NOD blastocysts [16,[23][24][25]. The culture conditions are referred to as 2i.…”

Section: Derivation Of Es Cells From the Inbred Strains Nod And B6mentioning

confidence: 99%

“…All animal experiments were approved by the Scripps Research Institute Institutional Animal Care and Use Committee. Embryonic stem cells were derived from blastocysts isolated from C57BL/6, NOD and NZB mice and cultured in the presence of 2i inhibitors for MEK and GSK3 (PD032590 and CHIR99021), as described previously [16,23,24]. For germline transmission test, B6 ES cells were injected into albino blastocysts.…”

Section: Mice Preimplantation Embryos and Es Cell Derivationmentioning

confidence: 99%

Premature Activation of Immune Transcription Programs in Autoimmune-Predisposed Mouse Embryonic Stem Cells and Blastocysts

Kirak

Yang

et al. 2020

IJMS

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Autoimmune diabetes is a complex multifactorial disease with genetic and environmental factors playing pivotal roles. While many genes associated with the risk of diabetes have been identified to date, the mechanisms by which external triggers contribute to the genetic predisposition remain unclear. Here, we derived embryonic stem (ES) cell lines from diabetes-prone non-obese diabetic (NOD) and healthy C57BL/6 (B6) mice. While overall pluripotency markers were indistinguishable between newly derived NOD and B6 ES cells, we discovered several differentially expressed genes that normally are not expressed in ES cells. Several genes that reside in previously identified insulin-dependent diabetics (Idd) genomic regions were up-regulated in NOD ES cells. Gene set enrichment analysis showed that different groups of genes associated with immune functions are differentially expressed in NOD. Transcriptomic analysis of NOD blastocysts validated several differentially overexpressed Idd genes compared to B6. Genome-wide mapping of active histone modifications using ChIP-Seq supports active expression as the promoters and enhancers of activated genes are also marked by active histone modifications. We have also found that NOD ES cells secrete more inflammatory cytokines. Our data suggest that the known genetic predisposition of NOD to autoimmune diabetes leads to epigenetic instability of several Idd regions.

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Deconstructive somatic cell nuclear transfer reveals novel regulatory T-cell subsets

Cited by 5 publications

References 13 publications

Regulatory T-cells are required for neonatal heart regeneration

Regulatory T-cells are required for neonatal heart regeneration

Prediabetes Induced by a Single Autoimmune B Cell Clone

Premature Activation of Immune Transcription Programs in Autoimmune-Predisposed Mouse Embryonic Stem Cells and Blastocysts

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