<i>Hemgn</i> Protects Hematopoietic Stem and Progenitor Cells Against Transplantation Stress Through Negatively Regulating IFN‐<i>γ</i> Signaling

Zhao, Ke; Liu, Jin‐Fang; Zhu, Yaxin; Dong, Xian-Zi; Yin, Rong‐Hua; Liu, Xian; Gao, Huiying; Xiao, Fengjun; Gao, Rui; Wang, Qi; Yao, Zhan; Yu, Miao; Chen, Hui; Ning, Hongmei; Zhang, Cai‐Bo; Yang, Xiaoming; Li, Chang‐Yan

doi:10.1002/advs.202103838

Cited by 3 publications

(1 citation statement)

References 54 publications

(77 reference statements)

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“…We next extended our investigation to NOD mice (Figure 7). In this model, TYK2i treatment resulted in the downregulation of genes associated with innate immune cell proliferation (Hemgn, Mcemp1, and En2) (50)(51)(52)(53)(54). In addition, there was increased expression of genes associated with the negative regulation of the Rho signaling pathway (Arhgap4 and Arhgap45) (55,56), which has been shown to modulate immune cell viability, glucose uptake, and lactate release (Figure 7D).…”

Section: Figure 7c)mentioning

confidence: 89%

Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice

Syed,

Ballew,

Lee

et al. 2024

Preprint

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SUMMARYTyrosine protein-kinase 2 (TYK2), a member of the Janus kinase family, mediates inflammatory signaling through multiple cytokines, including interferon-α (IFNα), interleukin (IL)-12, and IL-23. Missense mutations in TYK2 are associated with protection against type 1 diabetes (T1D), and inhibition of TYK2 shows promise in the management of other autoimmune conditions. Here, we evaluated the effects of specific TYK2 inhibitors (TYK2is) in pre-clinical models of T1D. First, human β cells, cadaveric donor islets, and iPSC-derived islets were treatedin vitrowith IFNα in combination with a small molecule TYK2i (BMS-986165 or a related molecule BMS-986202). TYK2 inhibition prevented IFNα-induced β cell HLA class I up-regulation, endoplasmic reticulum stress, and chemokine production. In co-culture studies, pre-treatment of β cells with a TYK2i prevented IFNα-induced activation of T cells targeting an epitope of insulin.In vivoadministration of BMS-986202 in two mouse models of T1D (RIP-LCMV-GPmice and NOD mice) reduced systemic and tissue-localized inflammation, prevented β cell death, and delayed T1D onset. Transcriptional phenotyping of pancreatic islets, pancreatic lymph nodes (PLN), and spleen during early disease pathogenesis highlighted a role for TYK2 inhibition in modulating signaling pathways associated with inflammation, translational control, stress signaling, secretory function, immunity, and diabetes. Additionally, TYK2i treatment changed the composition of innate and adaptive immune cell populations in the blood and disease target tissues, resulting in an immune phenotype with a diminished capacity for β cell destruction. Overall, these findings indicate that TYK2i has beneficial effects in both the immune and endocrine compartments in models of T1D, thus supporting a path forward for testing TYK2 inhibitors in human T1D.

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Section: Figure 7c)mentioning

confidence: 89%

Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice

Syed,

Ballew,

Lee

et al. 2024

Preprint

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Hemgn Protects Hematopoietic Stem and Progenitor Cells Against Transplantation Stress Through Negatively Regulating IFN‐γ Signaling

et al. 2021

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Hematopoietic stem and progenitor cells (HSPCs) possess the remarkable ability to regenerate the whole blood system in response to ablated stress demands. Delineating the mechanisms that maintain HSPCs during regenerative stresses is increasingly important. Here, it is shown that Hemgn is significantly induced by hematopoietic stresses including irradiation and bone marrow transplantation (BMT). Hemgn deficiency does not disturb steady-state hematopoiesis in young mice. Hemgn −/-HSPCs display defective engraftment activity during BMT with reduced homing and survival and increased apoptosis. Transcriptome profiling analysis reveals that upregulated genes in transplanted Hemgn −/− HSPCs are enriched for gene sets related to interferon gamma (IFN-𝜸) signaling. Hemgn −/− HSPCs show enhanced responses to IFN-𝜸 treatment and increased aging over time. Blocking IFN-𝜸 signaling in irradiated recipients either pharmacologically or genetically rescues Hemgn −/-HSPCs engraftment defect. Mechanistical studies reveal that Hemgn deficiency sustain nuclear Stat1 tyrosine phosphorylation via suppressing T-cell protein tyrosine phosphatase TC45 activity. Spermidine, a selective activator of TC45, rescues exacerbated phenotype of HSPCs in IFN-𝜸-treated Hemgn −/− mice. Collectively, these results identify that Hemgn is a critical regulator for successful engraftment and reconstitution of HSPCs in mice through negatively regulating IFN-𝜸 signaling. Targeted Hemgn may be used to improve conditioning regimens and engraftment during HSPCs transplantation.

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Lysine 117 Residue Is Essential for the Function of the Hepatocyte Nuclear Factor 1α

et al. 2023

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Hepatocyte nuclear factor 1α (HNF1α) plays essential roles in controlling development and metabolism, its mutations are clearly linked to the occurrence of maturity-onset diabetes of the young (MODY3) in humans. Lysine 117 (K117) to glutamic acid (E117) mutation in the HNF1α gene has been clinically associated with MODY3, but no functional data on this variant is available. Here, we addressed the role of lysine 117 in HNF1α function using a knock-in animal model and site-directed mutagenesis. HNF1α K117E homozygous mice exhibited dwarfism, hepatic dysfunction, renal Fanconi syndrome and progressive wasting syndrome. These phenotypes were very similar to those of mice with complete HNF1α deficiency, suggesting that K117 is critical to HNF1α functions. K117E homozygotes developed diabetes in the early postnatal period. The relative deficiency of serum insulin levels and the normal response to insulin treatment in homozygous mice were markedly similar to those in the MODY3 disorder in humans. Moreover, K117E heterozygous mutant causes age-dependent glucose intolerance which is similar with the pathogenesis of MODY3 as well. K117 mutants significantly reduced the overall transactivation and DNA binding capacity of HNF1α by disrupting dimerization. Collectively. our findings reveal a previously unappreciated role of POU domain of HNF1α in homodimerization, and also provide important clues for identifying the molecular basis of HNF1α related diseases such as MODY3.

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Hemgn Protects Hematopoietic Stem and Progenitor Cells Against Transplantation Stress Through Negatively Regulating IFN‐γ Signaling

Cited by 3 publications

References 54 publications

Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice

Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice

Hemgn Protects Hematopoietic Stem and Progenitor Cells Against Transplantation Stress Through Negatively Regulating IFN‐γ Signaling

Lysine 117 Residue Is Essential for the Function of the Hepatocyte Nuclear Factor 1α

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