S‐Nitrosylation of NOTCH1 Regulates Mesenchymal Stem Cells Differentiation Into Hepatocyte‐Like Cells by Inhibiting Notch Signalling Pathway DOI Creative Commons

Xuesong Wang,

Yan Xu, Yue Wang

et al.

Journal of Cellular and Molecular Medicine, Journal Year: 2024, Volume and Issue: 28(23)

Published: Dec. 1, 2024

The differentiation of mesenchymal stem cells (MSCs) into hepatocyte-like (HLCs) is considered one the most promising strategies for alternative hepatocyte transplantation to treat end-stage liver disease. To advance this method, it crucial gain a deeper understanding mechanisms governing hepatogenic differentiation. study demonstrated that suppression intracellular domain release Notch pathway receptor via γ-secretase inhibitor N-[(3, 5-difluorophenyl)acetyl]-L-alanyl-2-phenylglycine-1, 1-dimethylethyl ester (DAPT) significantly promotes expression hepatocyte-related genes and proteins in HLCs. Increased inducible NO synthase (iNOS) during led elevated endogenous production. Biotin switch assays revealed gradual increase S-nitrosylation (SNO)-NOTCH1 decrease overall NOTCH1 addition exogenous donor S-nitrosoglutathione (GSNO) SNO dithiothreitol (DTT) further SNO-NOTCH1 MSCs mature hepatocytes. Briefly, our results fully modification extracellular by NO, leading formation SNO-NOTCH1, inhibiting signalling pathway. Our highlights critical role regulating offers new insights driving process.

Language: Английский

3D Printing of a Vascularized Mini‐Liver Based on the Size‐Dependent Functional Enhancements of Cell Spheroids for Rescue of Liver Failure DOI Creative Commons
Jiabin Zhang,

Xiaodie Chen,

Yurong Chai

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: 11(17)

Published: Feb. 21, 2024

The emerging stem cell-derived hepatocyte-like cells (HLCs) are the alternative cell sources of hepatocytes for treatment highly lethal acute liver failure (ALF). However, hostile local environment and immature differentiation may compromise their therapeutic efficacy. To this end, human adipose-derived mesenchymal stromal/stem (hASCs) engineered into different-sized multicellular spheroids co-cultured with 3D coaxially hexagonally patterned umbilical vein endothelial (HUVECs) in a lobule-like manner to enhance hepatic efficiency. It is found that small-sized hASC spheroids, diameter ≈50 µm, show superior pro-angiogenic effects compared other counterparts. size-dependent functional enhancements mediated by Wnt signaling pathway. Meanwhile, co-culture hASCs HUVECs, at HUVECs/hASCs seeding density ratio 2:1, distinctly promotes vascularization both vitro vivo, especially when hollow hexagons. After subcutaneous implantation, mini-liver, consisting HLC 3D-printed interconnected vasculatures, can effectively improve regeneration two ALF animal models through amelioration oxidative stress inflammation, reduction necrosis, as well increase proliferation, thereby showing great promise clinical translation.

Language: Английский

Citations

8
Bioactive Decellularized Extracellular Matrix Platform Integrating Multifunctional Nanozymes and Cell-Laden Microgels for Acute Liver Failure Treatment DOI
Gang Xiao, Jiabin Zhang,

Tong Lin

et al.

ACS Nano, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 14, 2025

Mesenchymal stem cell (MSC) therapy has emerged as a promising alternative approach for treating acute liver failure (ALF) while confronting the shortage of low efficiency and poor engraftment within hostile milieu. In this study, we establish bioactive decellularized extracellular matrix (dECM) platform that incorporates dihydrolipoic acid (DHLA)-protected Pt nanoclusters doped with Cu (PtCu-DHLA) nanozymes cell-laden microgels. The PtCu-DHLA nanozymes, selected their versatility, function antioxidant, anti-inflammatory, pro-proliferative, pro-angiogenic agents, enhancing ALF alleviation providing an optimal microenvironment MSC transplantation. Additionally, methacrylic anhydride (MA)-modified porcine liver-derived (PLdECM) hydrogel (PLdECMMA) been developed construction microgels via microfluidic devices. Interferon γ (IFNγ) preconditioned MSCs encapsulated in PLdECMMA exhibit enhanced immunomodulating activity prolonged survival. are codelivered by leveraging PLdECM orthotopic transplanted dECM enables efficient successful rescue CCl4-induced counteracting oxidative stress, suppressing inflammatory storms, promoting cellular regeneration. Overall, study highlights synergistic reinforced strategy combines biomimetic therapy, offering significant potential treatment broader applications regenerative medicine.

Language: Английский

Citations

1
MicroRNA‐Modified DNA Hexahedron‐Induced Hepatocyte‐Like Cells Integrating 3D Printed Scaffold for Acute Liver Failure Therapy DOI
Tiantian Xue, Hongyan Wei,

Fenfang Li

et al.

Advanced Functional Materials, Journal Year: 2024, Volume and Issue: 34(38)

Published: April 18, 2024

Abstract Acute liver failure (ALF) involves extensive necrosis of cells and severe impairment function. Hepatocyte transplantation holds promise for treating ALF by swiftly supporting functions promoting regeneration. However, the scarcity suitable cell sources requires strategies to obtain enough functional hepatocyte‐like (HLCs) optimize their in vivo efficiency. A DNA hexahedral nanostructure (DHN) is developed loaded with microRNA‐122 efficiently induce hepatic differentiation human adipose‐derived mesenchymal stem into HLCs. These HLCs can serve as alternative hepatocyte sources, confirmed expression liver‐specific genes proteins, restoration functions. To enhance survival efficiency HLCs, a versatile scaffold also created 3D printing calcium‐cross‐linked mixture bioink composed sodium alginate, gelatin, silk fibroin excellent ROS scavenging capabilities. The infused chitosan‐DHN hydrogel containing tissue engineering orthotopic CCl 4 ‐induced mice. transplanted composite scaffold‐HLCs successfully repair injury area mice regulate expressions proteins associated inflammation, oxidative stress, Collectively, this study offers novel approach strategy identifying ALF.

Language: Английский

Citations

5
Advanced 3D bioprinted liver models with human-induced hepatocytes for personalized toxicity screening DOI Creative Commons
Yue Ma,

Runbang He,

Bo Deng

et al.

Journal of Tissue Engineering, Journal Year: 2025, Volume and Issue: 16

Published: Jan. 1, 2025

The development of advanced in vitro models for assessing liver toxicity and drug responses is crucial personalized medicine preclinical development. 3D bioprinting technology provides opportunities to create human that are suitable conducting high-throughput screening toxicity. In this study, we fabricated a humanized model using human-induced hepatocytes (hiHeps) derived from fibroblasts via rapid efficient reprogramming process. These hiHeps were then employed bioprinted with bioink materials closely mimic the natural extracellular matrix. constructed livers (h3DPLs) exhibited mature hepatocyte functions, including albumin expression, glycogen storage, uptake/release indocyanine green acetylated low-density lipoprotein. Notably, h3DPLs demonstrated increased sensitivity hepatotoxic agents such as acetaminophen (APAP), making them promising platform studying drug-induced injury. Furthermore, our accurately reflected impact rifampin, cytochrome P450 inducer, on CYP2E1 levels APAP hepatotoxicity. results highlight potential hiHep-based cost-effective high-performance alternative testing, paving way improved strategies therapeutic interventions.

Language: Английский

Citations

0
Outermost Cationic Surface Charge of Layer‐by‐Layer Films Prevents Endothelial Cells Migration for Cell Compartmentalization in Three‐Dimensional Tissues DOI Creative Commons
Jinfeng Zeng,

Sven Heilig,

Matthias Ryma

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 22, 2025

Abstract Tissues and organs possess an organized cellular arrangement that enables their unique functions. However, conventional three‐dimensional (3D) encapsulation techniques fail to recapitulate this complexity due the cell migration during culture. In biological tissues, basement membranes (BMs) are essential mechanically support organization. This study finds a positively charged outermost surface of multilayered nanofilms, fabricated through layer‐by‐layer assembly poly‐ l ‐lysine (PLL) dextran (Dex) via hydrogen bonds, stimulates barrier functions BMs. type artificial BM (A‐BM) demonstrates enhanced properties in comparison other types A‐BMs composed components such as collagen IV laminin. Such enhancement is potentially associated with cationic layer, which inhibits sprouting endothelial cells (ECs) effectively prevents EC over 14‐d period, aligning formation timeline natural BMs 3D tissues. Finally, vascular channels successfully engineered shape‐adaptable PLL/Dex nanofilms. approach offers guideline for engineering tissue models by regulating migration, can provide reliable platforms vitro permeability assay new drugs or drug delivery carriers.

Language: Английский

Citations

0
Mesenchymal stromal/stem cell spheroid-derived extracellular vesicles advance the therapeutic efficacy of 3D-printed vascularized artificial liver lobules in liver failure treatment DOI
Jiabin Zhang,

Xiaodie Chen,

Yurong Chai

et al.

Bioactive Materials, Journal Year: 2025, Volume and Issue: 49, P. 121 - 139

Published: March 6, 2025

Language: Английский

Citations

0
Boosting the angiogenesis potential of self-assembled mesenchymal stem cell spheroids by size mediated physiological hypoxia for vascularized pulp regeneration DOI
Xiaojing Yuan, Shuyi Wang, Zuoying Yuan

et al.

Acta Biomaterialia, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

Citations

0
S‐Nitrosylation of NOTCH1 Regulates Mesenchymal Stem Cells Differentiation Into Hepatocyte‐Like Cells by Inhibiting Notch Signalling Pathway DOI Creative Commons

Xuesong Wang,

Yan Xu, Yue Wang

et al.

Journal of Cellular and Molecular Medicine, Journal Year: 2024, Volume and Issue: 28(23)

Published: Dec. 1, 2024

The differentiation of mesenchymal stem cells (MSCs) into hepatocyte-like (HLCs) is considered one the most promising strategies for alternative hepatocyte transplantation to treat end-stage liver disease. To advance this method, it crucial gain a deeper understanding mechanisms governing hepatogenic differentiation. study demonstrated that suppression intracellular domain release Notch pathway receptor via γ-secretase inhibitor N-[(3, 5-difluorophenyl)acetyl]-L-alanyl-2-phenylglycine-1, 1-dimethylethyl ester (DAPT) significantly promotes expression hepatocyte-related genes and proteins in HLCs. Increased inducible NO synthase (iNOS) during led elevated endogenous production. Biotin switch assays revealed gradual increase S-nitrosylation (SNO)-NOTCH1 decrease overall NOTCH1 addition exogenous donor S-nitrosoglutathione (GSNO) SNO dithiothreitol (DTT) further SNO-NOTCH1 MSCs mature hepatocytes. Briefly, our results fully modification extracellular by NO, leading formation SNO-NOTCH1, inhibiting signalling pathway. Our highlights critical role regulating offers new insights driving process.

Language: Английский

Citations

0