Reprogramming the spleen into a functioning ‘liver’ in vivo

ObjectiveLiver regeneration remains one of the biggest clinical challenges. Here, we aim to transform the spleen into a liver-like organ via directly reprogramming the splenic fibroblasts into hepatocytes in vivo.DesignIn the mouse spleen, the number of fibroblasts was through silica particles (SiO2) stimulation, the expanded fibroblasts were converted to hepatocytes (iHeps) by lentiviral transfection of three key transcriptional factors (Foxa3, Gata4 and Hnf1a), and the iHeps were further expanded with tumour necrosis factor-α (TNF-α) and lentivirus-mediated expression of epidermal growth factor (EGF) and hepatocyte growth factor (HGF).ResultsSiO2 stimulation tripled the number of activated fibroblasts. Foxa3, Gata4 and Hnf1a converted SiO2-remodelled spleen fibroblasts into 2×106 functional iHeps in one spleen. TNF-α protein and lentivirus-mediated expression of EGF and HGF further enabled the total hepatocytes to expand to 8×106 per spleen. iHeps possessed hepatic functions—such as glycogen storage, lipid accumulation and drug metabolism—and performed fundamental liver functions to improve the survival rate of mice with 90% hepatectomy.ConclusionDirect conversion of the spleen into a liver-like organ, without cell or tissue transplantation, establishes fundamental hepatic functions in mice, suggesting its potential value for the treatment of end-stage liver diseases.

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Epidermal growth factor/TNF-α transactivation modulates epithelial cell proliferation and apoptosis in a mouse model of parenteral nutrition

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00142.2011 ◽

2012 ◽

Vol 302 (2) ◽

pp. G236-G249 ◽

Cited By ~ 40

Author(s):

Yongjia Feng ◽

Daniel H. Teitelbaum

Keyword(s):

Growth Factor ◽

Epithelial Cell ◽

Epidermal Growth Factor ◽

Mouse Model ◽

Parenteral Nutrition ◽

Intestinal Epithelial ◽

Tnf Α ◽

Epidermal Growth ◽

Factor Α ◽

Egf Signaling

Epidermal growth factor (EGF) and tumor necrosis factor-α (TNF-α) signaling are critical for effective proliferative and apoptotic actions; however, little is known about the codependency of these signaling pathways in the intestinal epithelium. Because total parenteral nutrition (TPN) is associated with loss of intestinal epithelial cell (IEC) proliferation and increased apoptosis, we utilized a mouse model to explore these transactivation pathways in small bowel epithelium. Mice underwent intravenous cannulation and were given enteral nutrition or TPN for 7 days. Outcomes included IEC proliferation, apoptosis, and survival. To address transactivation or dependence of EGF and TNF on IEC physiology, TNF-α receptor knockout (KO) mice, TNFR1-KO, R2-KO, or R1R2-double KO, were used. Exogenous EGF and pharmacological blockade of ErbB1 were performed in other groups to examine the relevance of the ErB1 pathway. TPN increased IEC TNFR1 and decreased EGF and ErbB1 abundance. Loss of IEC proliferation was prevented by exogenous EGF or blockade of TNFR1. However, EGF action was prevented without effective TNFR2 signaling. Also, blockade of TNFR1 could not prevent loss of IEC proliferation without effective ErbB1 signaling. TPN increased IEC apoptosis and was due to increased TNFR1 signaling. Exogenous EGF or blockade of TNFR1 could prevent increased apoptosis, and both pathways were dependent on effective ErbB1 signaling. Exogenous EGF prevented increased apoptosis in mice lacking TNFR2 signaling. TPN mice had significantly decreased survival vs. controls, and this was associated with the TNFR1 signaling pathway. We concluded that these findings identify critical mechanisms that contribute to TPN-associated mucosal atrophy via altered TNF-α/EGF signaling. It emphasizes the importance of both TNFR1 and TNFR2 pathways, as well as the strong interdependence on an intact EGF/ErbB1 pathway.

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Measurement of Hepatocyte Growth Factor, Interleukin 6 and Tumor necrosis factor α in Acute Myocardial Infarction

Nepalese Heart Journal ◽

10.3126/njh.v16i1.23896 ◽

2019 ◽

Vol 16 (1) ◽

pp. 33-37

Author(s):

Asadallah Keshmiri ◽

Ali Reza Derakhshan ◽

Afsoon Fazlinejad ◽

Reza Farid-Hosseini

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Growth Factor ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Tnf Α ◽

Factor Α ◽

Hepatocyte Growth ◽

Necrosis Factor

Background: Early mortality rate due to acute myocardial infarction (AMI) is approximately 30%, and half of these deaths occur before reaching a hospital. The prevention and early detection play a key role in reducing mortality in AMI. Hepatocyte Growth Factor (HGF), Interleukin 6 (IL-6), and Tumor Necrosis Factor α (TNF-α) are most recent prognostic biomarkers for AMI. The present study was aimed to evaluate the level of these cytokines in AMI. Methods: In this case control study, 39 patients with AMI were compared with 30 healthy subjects. Age, sex and other possible confounding factors were matched. AMI diagnosis was confirmed by typical symptoms, electrocardiogram changes and serum concentration of troponin I and creatine kinase-MB. The levels of TNF-α, IL-6 an HGF at baseline and 3 and 7 days later were measured using ELISA method. Results: Levels of IL-6, TNF-α and HGF increased over time after AMI with ST-segment elevation in study group. The baseline IL-6 levels in AMI group were significantly higher than control group (P<0.05). Conclusions: The results of this study suggest that baseline levels of IL-6 as well as serial changes of serum IL-6, TNF-α and HGF concentrations can be used as potential diagnostic biomarkers in AMI.

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MEK, p38, and PI-3K mediate cross talk between EGFR and TNFR in enhancing hepatocyte growth factor production from human mesenchymal stem cells

AJP Cell Physiology ◽

10.1152/ajpcell.00183.2009 ◽

2009 ◽

Vol 297 (5) ◽

pp. C1284-C1293 ◽

Cited By ~ 28

Author(s):

Yue Wang ◽

Brent R. Weil ◽

Jeremy L. Herrmann ◽

Aaron M. Abarbanell ◽

Jiangning Tan ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Growth Factor ◽

Cross Talk ◽

Tumor Necrosis ◽

Tnf Receptor ◽

Tnf Α ◽

Factor Α ◽

Hepatocyte Growth ◽

Necrosis Factor

Human bone marrow mesenchymal stem cells (MSCs) are a potent source of growth factors, which are partly responsible for their beneficial paracrine effects. We reported previously that transforming growth factor-α (TGF-α), a putative mediator of wound healing and the injury response, increases the release of vascular endothelial growth factor (VEGF), augments tumor necrosis factor-α (TNF-α)-stimulated VEGF production, and activates mitogen-activated protein kinases and phosphatidylinositol 3-kinase (PI-3K) pathway in human MSCs. The experiments described in this report indicate that TGF-α increases MSC-derived hepatocyte growth factor (HGF) production. TGF-α-stimulated HGF production was abolished by inhibition of MEK, p38, PI-3K, or by small interfering RNA (siRNA) targeting TNF receptor 2 (TNFR2), but was not attenuated by siRNA targeting TNF receptor 1 (TNFR1). Ablation of TNFR1 significantly increased basal and stimulated HGF. A potent synergy between TGF-α and TNF-α was noted in MSC HGF production. This synergistic effect was abolished by MEK, P38, PI-3K inhibition, or by ablation of both TNF receptors using siRNA. We conclude that 1) novel cross talk occurs between tumor necrosis factor receptor and TGF-α/epidermal growth factor receptor in stimulating MSC HGF production; 2) this cross talk is mediated, at least partially, via activation of MEK, p38, and PI-3K; 3) TGF-α stimulates MSCs to produce HGF by MEK, p38, PI-3K, and TNFR2-dependent mechanisms; and 4) TNFR1 acts to decrease basal TGF-α and TNF-α-stimulated HGF.

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Development of stabilized dual growth factor-loaded hyaluronate collagen dressing matrix

Journal of Tissue Engineering ◽

10.1177/2041731421999750 ◽

2021 ◽

Vol 12 ◽

pp. 204173142199975

Author(s):

Jihyun Kim ◽

Kyoung-Mi Lee ◽

Seung Hwan Han ◽

Eun Ae Ko ◽

Dong Suk Yoon ◽

...

Keyword(s):

Wound Healing ◽

Growth Factor ◽

Type I ◽

Diabetic Mice ◽

Patients With Diabetes ◽

Diabetic Wound Healing ◽

Epidermal Growth ◽

Wound Healing Effect ◽

Growth Factor Production

Patients with diabetes experience impaired growth factor production such as epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF), and they are reportedly involved in wound healing processes. Here, we report dual growth factor-loaded hyaluronate collagen dressing (Dual-HCD) matrix, using different ratios of the concentration of stabilized growth factors—stabilized-EGF (S-EGF) and stabilized-bFGF (S-bFGF). At first, the optimal concentration ratio of S-EGF to S-bFGF in the Dual-HCD matrix is determined to be 1:2 in type I diabetic mice. This Dual-HCD matrix does not cause cytotoxicity and can be used in vivo. The wound-healing effect of this matrix is confirmed in type II diabetic mice. Dual HCD enhances angiogenesis which promotes wound healing and thus, it shows a significantly greater synergistic effect than the HCD matrix loaded with a single growth factor. Overall, we conclude that the Dual-HCD matrix represents an effective therapeutic agent for impaired diabetic wound healing.

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The Effects of Rice Husk Liquid Smoke in Porphyromonas gingivalis-Induced Periodontitis

European Journal of Dentistry ◽

10.1055/s-0041-1727554 ◽

2021 ◽

Author(s):

Theresia Indah Budhy ◽

Ira Arundina ◽

Meircurius Dwi Condro Surboyo ◽

Anisa Nur Halimah

Keyword(s):

Growth Factor ◽

Porphyromonas Gingivalis ◽

Rice Husk ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Control Group ◽

Proliferation Markers ◽

Liquid Smoke ◽

Tnf Α ◽

Factor Α

Abstract Objectives The purpose of this study is to analyze the effects of rice husk liquid smoke in Porphyromonas gingivalis-induced periodontitis in the inflammatory and proliferation marker such as nuclear factor kappa β (NF-kB), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), transforming growth factor-β (TGF-β), fibroblast growth factor 2 (FGF2), collagen type 1 (COL-1) expression, and the number of macrophages, lymphocytes, and fibroblasts. Materials and Methods Rice husk liquid smoke is obtained by the pyrolysis process. Porphyromonas gingivalis-induced periodontitis in 20 μL phosphate-buffered saline containing 1 × 109 CFU was injected into the lower anterior gingival sulcus of Wistar rats. The periodontitis was then treated with 20 μL/20 g body weight of rice husk liquid smoke once a day for 2 and 7 days, respectively. After treatment, the bone and lower anterior gingival sulcus were analyzed with immunohistochemistry and hematoxylin–eosin staining. Results The treatment of periodontitis with rice husk liquid smoke showed a lower NF-kB, TNF-α, and IL-6 expression and a higher TGF-β, FGF2, and COL-1 expression than the control after treatment for 2 and 7 days (p < 0.05), respectively. The number of macrophages and fibroblasts was also higher when compared with the control group (p < 0.05), but the number of lymphocytes was lower than the control (p < 0.05). Conclusion Rice husk liquid smoke showed its effects on Porphyromonas gingivalis-induced periodontitis with a decrease in inflammatory markers and an increase in proliferation markers. The development of a rice husk liquid smoke periodontitis treatment is promising.

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