- Macroporous dual compartment hydrogels for minimally invasive transplantation of primary human hepatocytes. [Journal Article]
- TTransplantation 2018 Jun 18
- CONCLUSIONS: Cell transplantation devices that assist the anastomosis of grafts with the host can be potentially used as a minimally invasive ectopic liver accessory to augment liver specific functions as well as potentially treat various pathologies associated with compromised functions of liver such as hemophilia B or alpha-1 antitrypsin deficiency.
- hiPSC hepatocyte model demonstrates the role of unfolded protein response and inflammatory networks in α1-antitrypsin deficiency. [Journal Article]
- JHJ Hepatol 2018 Jun 04
- CONCLUSIONS: Our data identified novel pathways that potentially link the expression of Z A1AT polymers to liver disease. These findings could help pave the way towards identification of new therapeutic targets for treatment of A1ATD.
- Autotaxin exacerbates tumor progression by enhancing MEK1 and overriding the function of miR-489-3p. [Journal Article]
- CLCancer Lett 2018 May 31; 432:84-92
- Upregulated expression of autotaxin, a secreted phospholipase and phosphodiesterase enzyme, appears in malignant disease. The identification of a circulating miRNA signature should distinguish autota...
Upregulated expression of autotaxin, a secreted phospholipase and phosphodiesterase enzyme, appears in malignant disease. The identification of a circulating miRNA signature should distinguish autotaxin-mediated disease and also elucidate unknown molecular mechanisms that rationalize its malignant potential. Using female transgenic 'AT-ATX' mice, whereby human wild-type autotaxin is expressed in liver under the control of the alpha-1 antitrypsin promoter, transgenic animals express augmented autotaxin in circulation and a percentage develop tumors. Serum collected at necropsy had circulating miRNAs analyzed for statistical significance. The ensuing autotaxin-mediated miRNome differentiated between groups: healthy FVB/N mice versus AT-ATX mice with and without tumors. Intriguingly, miR-489-3p was sharply increased in AT-ATX tumor-bearing mice. Tissue analysis showed a correlation between miR-489-3p expression in tumors and surrounding milieu with autotaxin concentration in circulation. Sequence alignment suggested miR-489-3p targets MEK1, which was confirmed through in vitro studies. Exogenously added miR-489-3p, which decreases MEK1 in normal cells, dramatically increased MEK1 expression in cells stably expressing autotaxin. Taken together, this suggests that autotaxin overrides the normal regulatory function of miR-489-3p to inhibit MEK1 via coordinately increased miR-489-3p appearing in serum.
- Human alpha 1-antitrypsin protects neurons and glial cells against oxygen and glucose deprivation through inhibition of interleukins expression. [Journal Article]
- BBBiochim Biophys Acta 2018 May 29
- CONCLUSIONS: Human AAT protects neuronal and glial cells against OGD through interaction with cytokines.Human AAT could be a good therapeutic neuroprotective candidate to treat ischemic stroke.
- Enhancement of Alpha 1-antitrypsin Production in Pichia pastoris by Designing and Optimizing Medium Using Elemental Analysis. [Journal Article]
- IJIran J Biotechnol 2017; 15(4):224-231
- Background: Human alpha 1-antitrypsin (AAT) is a monomeric glycosylated protein; it is the potent inhibitor of a whole range of serine proteases and protects tissues against their destructive effect...
Background: Human alpha 1-antitrypsin (AAT) is a monomeric glycosylated protein; it is the potent inhibitor of a whole range of serine proteases and protects tissues against their destructive effects. The human plasma-derived AAT, which is currently used to augment the AAT level in patients, is limited due to high cost and source limitation. Recombinant production of AAT can be considered as a potential alternative. Objectives: This study aims to develop and optimize a new chemically defi ned medium based on an elemental analysis of the yeast Pichia pastoris for an effi cient culture of the recombinant yeast-producing secretory AAT. Materials and Methods: An elemental analysis of Carbon (C), Hydrogen (H), Nitrogen (N), Sulfur (S); CHNS in its abbreviated form, and metallic elements was performed to determine the exact molecular constituent of the P. pastoris. The medium components were selected according to the obtained formula; they were optimized by the response surface methodology (RSM). The grown yeast cell was measured at the end of 18 h glycerol batch culture. The amounts of AAT production and elastase inhibitory capacity (EIC) were measured at the end of three days' methanol feeding. Results: The optimized medium compositions consist of glycerol (40 g.L-1), KH2PO4 (24.78 g.L-1), NaCl, (0.88 g.L-1), MgSO4 .7H2 O (1.95 g.L-1), (NH4 )2 SO4 (22.76 g.L-1), and trace elements (20 mL.L-1). The presented quadratic models show that KH2 PO4 and (NH4)2 SO4, are the most abundant ones in the P. pastoris biomass and have the greatest effect on the cell growth, EIC, and AAT protein production responses. Conclusions: According to the results of this study, it can be concluded that the characterizing cell composition formula could be considered as an appropriate method to design culture media in order to improve cell growth and productivity. Compared to the common P. pastoris chemically defi ned media, FM22 and BSM, production of AAT protein increased by 1.5 and 1.4 times, respectively, in this new medium.
- Serum α1-Antitrypsin Concentration in the Diagnosis of α1-Antitrypsin Deficiency. [Case Reports]
- JAMAJAMA 2018 May 15; 319(19):2034-2035
- Preservation with α1-antitrypsin improves primary graft function of murine lung transplants. [Journal Article]
- JHJ Heart Lung Transplant 2018 Mar 30
- CONCLUSIONS: PR3 and NE, the principal targets of AAT, are major triggers of post-ischemic reperfusion damage. Their effective inhibition in the graft and recipient is a promising strategy for organ usage after storage for >6 hours.
- Human iPS Cell-based Liver-like Tissue Engineering at Extrahepatic Sites in Mice as a New Cell Therapy for Hemophilia B. [Journal Article]
- CTCell Transplant 2018; 27(2):299-309
- Instead of liver transplantation or liver-directed gene therapy, genetic liver diseases are expected to be treated effectively using liver tissue engineering technology. Hepatocyte-like cells (HLCs) ...
Instead of liver transplantation or liver-directed gene therapy, genetic liver diseases are expected to be treated effectively using liver tissue engineering technology. Hepatocyte-like cells (HLCs) generated from human-induced pluripotent stem (iPS) cells are an attractive unlimited cell source for liver-like tissue engineering. In this study, we attempted to show the effectiveness of human iPS cell-based liver-like tissue engineering at an extrahepatic site for treatment of hemophilia B, also called factor IX (FIX) deficiency. HLCs were transplanted under the kidney capsule where the transplanted cells could be efficiently engrafted. Ten weeks after the transplantation, human albumin (253 μg/mL) and α-1 antitrypsin (1.2 μg/mL) could be detected in the serum of transplanted mice. HLCs were transplanted under the kidney capsule of FIX-deficient mice. The clotting activities in the transplanted mice were approximately 5% of those in wild-type mice. The bleeding time in transplanted mice was shorter than that in the nontransplanted mice. Taken together, these results indicate the success in generating functional liver-like tissues under the kidney capsule by using human iPS cell-derived HLCs. We also demonstrated that the human iPS cell-based liver-like tissue engineering technology would be an effective treatment of genetic liver disease including hemophilia B.
- Differentiation of hepatocyte-like cells from human pluripotent stem cells using small molecules. [Journal Article]
- DDifferentiation 2018 May - Jun; 101:16-24
- A variety of approaches have been developed for the derivation of hepatocyte-like cells from pluripotent stem cells. Currently, most of these strategies employ step-wise differentiation approaches wi...
A variety of approaches have been developed for the derivation of hepatocyte-like cells from pluripotent stem cells. Currently, most of these strategies employ step-wise differentiation approaches with recombinant growth-factors or small-molecule analogs to recapitulate developmental signaling pathways. Here, we tested the efficacy of a small-molecule based differentiation protocol for the generation of hepatocyte-like cells from human pluripotent stem cells. Quantitative gene-expression, immunohistochemical, and western blot analyses for SOX17, FOXA2, CXCR4, HNF4A, AFP, indicated the stage-specific differentiation into definitive endoderm, hepatoblast and hepatocyte-like derivatives. Furthermore, hepatocyte-like cells displayed morphological and functional features characteristic of primary hepatocytes, as indicated by the production of ALB (albumin) and α-1-antitrypsin (A1AT), as well as glycogen storage capacity by periodic acid-Schiff staining. Together, these data support that the small-molecule based hepatic differentiation protocol is a simple, reproducible, and inexpensive method to efficiently drive the differentiation of human pluripotent stem cells towards a hepatocyte-like phenotype, for downstream pharmacogenomic and regenerative medicine applications.
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- Alpha-1-antitrypsin in cell and organ transplantation. [Review]
- AJAm J Transplant 2018 Apr 01
- Limited availability of donor organs and risk of ischemia-reperfusion injury (IRI) seriously restrict organ transplantation. Therapeutics that can prevent or reduce IRI could potentially increase the...
Limited availability of donor organs and risk of ischemia-reperfusion injury (IRI) seriously restrict organ transplantation. Therapeutics that can prevent or reduce IRI could potentially increase the number of transplants by increasing use of borderline organs and decreasing discards. Alpha-1 antitrypsin (AAT) is an acute phase reactant and serine protease inhibitor that limits inflammatory tissue damage. Purified plasma-derived AAT has been well tolerated in more than 30 years of use to prevent emphysema in AAT-deficient individuals. Accumulating evidence suggests that AAT has additional anti-inflammatory and tissue-protective effects including improving mitochondrial membrane stability, inhibiting apoptosis, inhibiting nuclear factor kappa B activation, modulating pro- vs anti-inflammatory cytokine balance, and promoting immunologic tolerance. Cell culture and animal studies have shown that AAT limits tissue injury and promotes cell and tissue survival. AAT can promote tolerance in animal models by downregulating early inflammation and favoring induction and stabilization of regulatory T cells. The diverse intracellular and immune-modulatory effects of AAT and its well-established tolerability in patients suggest that it might be useful in transplantation. Clinical trials, planned and/or in progress, should help determine whether the promise of the animal and cellular studies will be fulfilled by improving outcomes in human organ transplantation.