Tumor Necrosis Factor Directs Allograft-Related Innate Responses and Its Neutralization Improves Hepatocyte Engraftment in Rats

Jaber, Fadi Luc; Sharma, Yogeshwar; Mui, Brandon G.; Kapoor, Sorabh; Gupta, Sanjeev

doi:10.1016/j.ajpath.2020.09.014

Cited by 6 publications

(7 citation statements)

References 46 publications

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“…Jaber et al. (2020) performed syngeneic and allogeneic hepatocyte transplantation in dipeptidyl-peptidase-deficient (DPP) F344 rats, treated with mild lymphocyte immunosuppression (mofetil and tacrolimus) ( 40 ). As expected, syngeneic hepatocytes were successfully engrafted without immunosuppression, whereas allogeneic hepatocytes were rejected.…”

Section: Tnf-α Mediated Inflammatory Diseasesmentioning

confidence: 99%

Leveraging the tolerogenic potential of TNF-α and regulatory B cells in organ transplantation

Poznansky

Deng

et al. 2023

Front. Immunol.

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A subset of B-cells with tolerogenic functions, termed B-regulatory cells or Bregs, is characterized by the expression of anti-inflammatory/tolerogenic cytokines, namely IL-10, TGF-β, and IL-35, that contribute to their regulatory functions. Breg regulation favors graft acceptance within a tolerogenic milieu. As organ transplantation invariably triggers inflammation, new insights into the crosstalk between cytokines with dual properties and the inflamed milieu are needed to tailor their function toward tolerance. Using TNF-α as a proxy of dual-function cytokines involved in immune-related diseases and transplantation settings, the current review highlights the multifaceted role of TNF-α. It focuses on therapeutic approaches that have revealed the complexity of TNF-α properties tested in clinical settings where total TNF-α inhibition has proven ineffective and often detrimental to clinical outcomes. To improve the efficacy of current TNF-α inhibiting therapeutics, we propose a three-prong strategy to upregulate the tolerogenic pathway engaging the TNFR2 receptor while simultaneously inhibiting the inflammatory mechanisms associated with TNFR1 engagement. When combined with additional administrations of Bregs-TLR that activate Tregs, this approach may become a potential therapeutic in overcoming transplant rejection and promoting graft tolerance.

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Section: Tnf-α Mediated Inflammatory Diseasesmentioning

confidence: 99%

Leveraging the tolerogenic potential of TNF-α and regulatory B cells in organ transplantation

Poznansky

Deng

et al. 2023

Front. Immunol.

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“…While orthotopic liver transplantation can sometimes provide rescue in ALF, widespread donor organ shortages, the irreversibility of this procedure, need for life-long immunosuppression with attendant complications, and other issues pose extensive difficulties. 1 Thus, regenerating the native liver itself with alternative approaches holds much interest, for example, transplanting cells and applying highly effective molecular therapy targets. 2 In ALF, the major goals for alternative therapies are to offer life-sustaining metabolic functions during overwhelming hepatic injury and to engage drivers of liver regeneration (LR).…”

Section: Introductionmentioning

confidence: 99%

“…Since acetaminophen (APAP), is the leading cause of ALF in people, 21 we applied established drug toxicity models in cells, 22‐24 and C57BL/6 mouse 25 . Dipeptidylpeptidase (DPP)‐IV+ donor cells were transplanted into DPPIV knockout mice in C57BL/6 background to avoid confounding from cell rejection 1,26 . The focus concerned major APAP injury mechanisms, that is, oxidative stress, mitochondrial dysfunction, inflammation, DNA damage response (DDR), and cell growth‐arrest related to ataxia telangiectasia mutated (ATM) gene 23,25 .…”

Section: Introductionmentioning

confidence: 99%

“…25 Dipeptidylpeptidase (DPP)-IV+ donor cells were transplanted into DPPIV knockout mice in C57BL/6 background to avoid confounding from cell rejection. 1,26 The focus concerned major APAP injury mechanisms, that is, oxidative stress, mitochondrial dysfunction, inflammation, DNA damage response (DDR), and cell growth-arrest related to ataxia telangiectasia mutated (ATM) gene. 23,25 We interrogated JAK/STAT3 signaling in selected growth factors (GFs) because this intersects with ATM pathways to restore DDR in APAP toxicity.…”

Section: Introductionmentioning

confidence: 99%

“…The sudden onset of acute liver failure (ALF) in previously healthy individuals has high mortalities of 40%‐60% and this condition constitutes a true medical emergency. While orthotopic liver transplantation can sometimes provide rescue in ALF, widespread donor organ shortages, the irreversibility of this procedure, need for life‐long immunosuppression with attendant complications, and other issues pose extensive difficulties 1 . Thus, regenerating the native liver itself with alternative approaches holds much interest, for example, transplanting cells and applying highly effective molecular therapy targets 2 …”

Section: Introductionmentioning

confidence: 99%

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Transplanted hepatocytes rescue mice in acetaminophen‐induced acute liver failure through paracrine signals for hepatic ATM and STAT3 pathways

et al. 2021

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Acute liver failure constitutes a devastating condition that needs novel cell and molecular therapies. To elicit synergisms in cell types of therapeutic interest, we studied hepatocytes and liver sinusoidal endothelial in mice with acetaminophen-induced acute liver failure. The context of regenerative signals was examined by transplants in peritoneal cavity because it possesses considerable capacity and allows soluble signals to enter the systemic circulation. Whereas transplanted hepatocytes and liver sinusoidal endothelial cells engrafted in peritoneal cavity, only the former could rescue mice in liver failure by improving injury outcomes, activating hepatic DNA damage repair, and inducing liver regeneration. The cytokines secreted by donor hepatocytes or liver sinusoidal endothelial cells differed and in hepatocytes from mice undergoing acetaminophen toxicity major cytokines were even rendered deficient (eg, G-CSF, VEGF, and others). Significantly, recapitulating hepatotoxicity-related DNA damage response in cultured cells identified impairments in ATM and JAK/STAT3 intersections since replacing cytokines produced less from injured hepatocytes restored these pathways to avoid acetaminophen hepatotoxicity. Similarly, hepatocyte transplantation in acute liver failure restored ATM and JAK/STAT3 pathways to advance DNA damage/repair and liver regeneration. The unexpected identification of novel hepatic G-CSF receptor expression following injury allowed paradigmatic studies of G-CSF supplementation to confirm the centrality of this paracrine ATM and STAT3 intersection. Remarkably, DNA damage/repair and hepatic regeneration directed by G-CSF concerned rebalancing of regulatory gene networks overseeing inflammation, metabolism, and cell viability. We conclude that healthy donor hepatocytes offer 2 of 16 | VISWANATHAN eT Al.

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Temporary Nanoencapsulation of Human Intestinal Organoids Using Silk Ionomers

Wang,

Hasturk,

Kumarasinghe

et al. 2024

Adv Healthcare Materials

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Human intestinal organoids (HIOs) are vital for modeling intestinal development, disease, and therapeutic tissue regeneration. However, their susceptibility to stress, immunological attack, and environmental fluctuations limits their utility in research and therapeutic applications. This study evaluated the effectiveness of temporary silk protein‐based layer‐by‐layer (LbL) nanoencapsulation technique to enhance the viability and functions of HIOs against common biomedical stressors, without compromising their native functions. Cell viability and differentiation capacity are assessed, finding that nanoencapsulation significantly improved HIO survival under the various environmental perturbations studied without compromising cellular functionality. Post‐stress exposures, the encapsulated HIOs still successfully differentiated into essential intestinal cell types such as enterocytes, goblet cells, enteroendocrine cells, and Paneth cells. Moreover, the silk nanocoatings effectively protected against environmental stressors such as ultraviolet (UV) light exposure, protease degradation, antibody binding, and cytokine‐induced inflammation. This nanoencapsulation technique shows promise for advancing HIO applications in disease modeling, drug testing, and potential transplantation therapies.

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Tumor Necrosis Factor Directs Allograft-Related Innate Responses and Its Neutralization Improves Hepatocyte Engraftment in Rats

Cited by 6 publications

References 46 publications

Leveraging the tolerogenic potential of TNF-α and regulatory B cells in organ transplantation

Leveraging the tolerogenic potential of TNF-α and regulatory B cells in organ transplantation

Transplanted hepatocytes rescue mice in acetaminophen‐induced acute liver failure through paracrine signals for hepatic ATM and STAT3 pathways

Temporary Nanoencapsulation of Human Intestinal Organoids Using Silk Ionomers

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