The potential therapeutic effect for melatonin and mesenchymal stem cells on hepatocellular carcinoma

Background/aim: Herein, we investigated the potential therapeutic effect of Melatonin (Mel) and/or mesenchymal stem cells (MSCs) on rat model of HCC. Materials and Methods: Female mature rats were divided into 5 groups (n = 10/group): normal (Nor), HCC group intraperitoneally injected with 200 mg/kg DEN, and 3 treated groups; HCC + Mel (Mel) group given Mel intraperitoneally 20 mg/kg, twice a week, HCC + MSCs (MSCs) group intravenously injected by 1 × 106 cells, and HCC + MSCs (Mel +MSCs) group. Results: Rats in HCC group showed most deteriorated effect in form of increased mortality and relative liver weight, elevated serum levels of ALT, AST, ALP, AFP and GGT in addition to increased pre-neoplastic nodules in liver tissues. Liver tissues of HCC group also exhibited lower level of apoptosis as indicated by decreased DNA fragmentation and expression of p53 caspase 9 and caspase 3 genes and increased PCNA immunoreactivity. Moreover, in this group the expression of IL6 and TGFβ1 genes was significantly upregulated. All these deleterious effects induced by DEN were reversed after administration of Mel and/ or MSCs with best improvement for the combined group (MSCs + Mel). Conclusions: These findings reveal a better therapeutic effect for MSCs when given with Mel and we attribute this beneficial effect, at least in part, to triggering apoptosis and targeting inflammation in HCC. Therefore, combined treatment with Mel and MSCs is recommended to enhance the therapeutic potential against HCC.

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Therapeutic potential of mesenchymal stem cells overexpressing human forkhead box A2 gene in the regeneration of damaged liver tissues

Journal of Gastroenterology and Hepatology ◽

10.1111/j.1440-1746.2012.07137.x ◽

2012 ◽

Vol 27 (8) ◽

pp. 1362-1370 ◽

Cited By ~ 24

Author(s):

Jong‐Woo Cho ◽

Chul‐Young Lee ◽

Yong Ko

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Therapeutic Potential ◽

Forkhead Box ◽

Liver Tissues

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AB0119 SERUM LEVELS OF INTERLEUKIN-22 ARE HIGH IN ANKYLOSING SPONDYLITIS, PARTICULARLY IN SMOKERS, BUT DO NOT CORRELATE WITH RADIOGRAPHIC BONE FORMATION NOR WITH DISEASE ACTIVITY

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.2961 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1359.1-1360

Author(s):

M. Sagiv ◽

G. Slobodin ◽

T. Khatib ◽

I. Rosner ◽

M. Rozenbaum ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Ankylosing Spondylitis ◽

Bone Formation ◽

Disease Activity ◽

Radiographic Progression ◽

Elevated Serum ◽

Serum Levels ◽

Interleukin 22 ◽

Activity Indices

Background:Elevated serum levels of interleukin (IL)-22 were reported in patients with ankylosing spondylitis (AS).[1]IL-22 was also reported to drive the osteogenic differentiation of mesenchymal stem cells.[2]Objectives:To confirm the fact that serum levels of IL-22 are elevated in AS patients and to examine the relationship between concentrations of IL-22 and degree of radiographic progression in AS patients.Methods:Seventeen male patients with established AS of more than 4 years duration signed the informed consent and donated 10 ml of peripheral blood. Demographic data was collected from patient’s charts. Disease activity indices were calculated for all patients and radiographic disease progression was calculated as mSASS. A control group included 6 healthy persons and 4 patients with advanced diffuse idiopathic skeletal hyperostosis (DISH). Serum levels of IL-22 were tested using enzyme-linked immunosorbent assay. Intergroup differences were examined using the Mann-Whitney test, while correlations were calculated using Pearson correlation coefficient.Results:Serum IL-22 levels were remarkably elevated in patients with AS, comparing to healthy individuals and patients with DISH (p=0.005). However, increased concentrations of IL-22 did not correlate with the degree of radiographic progression or AS disease activity indices, nor with disease duration or patient’s age. Presence of diarrhea, psoriasis, uveitis, or elevated levels of C-reactive protein did not influence the levels of IL-22 as well. More AS patients with elevated serum IL-22 were smokers (p=0.05).Fig. 1.Serum levels of interleukin 22 (pg/ml)Conclusion:The serum levels of IL-22 are elevated in patients with AS. It seems that smoking can be related to the elevated levels of serum IL-22 in AS. The significance of this data is unclear and further research is needed.References:[1]Zhang L, Li Y gang, Li Y hua, Qi L, Liu X guang, Yuan C zhong, et al. Increased frequencies of th22 cells as well as th17 cells in the peripheral blood of patients with ankylosing spondylitis and rheumatoid arthritis. PLoS One. 2012;7(4).[2]El-Zayadi AA, Jones E, Churchman S, Baboolal T, Cuthbert R, El-Jawhari J, et al. Interleukin-22 drives the proliferation, migration and osteogenic differentiation of mesenchymal stem cells: a novel cytokine that could contribute to new bone formation in spondyloarthropathies. Rheumatology. 2016 Dec 10;56.Disclosure of Interests:None declared

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Human umbilical cord-derived mesenchymal stem cells improve the function of liver in rats with acute-on-chronic liver failure via downregulating Notch and Stat1/Stat3 signaling

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02468-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yulin He ◽

Xingrong Guo ◽

Tingyu Lan ◽

Jianbo Xia ◽

Jinsong Wang ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Sodium Chloride ◽

Inflammatory Cell ◽

Serum Levels ◽

Chronic Liver ◽

Human Umbilical Cord ◽

Chronic Liver Failure ◽

Stat3 Signaling ◽

Liver Tissues

Abstract Background Effective treatments for acute-on-chronic liver failure (ACLF) are lacking. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been applied in tissue regeneration and repair, acting through paracrine effects, cell fusion, and actual transdifferentiation. The present study was designed to investigate the therapeutic potential of hUC-MSCs in acute-on-chronic liver injury (ACLI) and ACLF rat models. Methods Wistar rats aged 6 weeks were intraperitoneally administered porcine serum (PS) at a dose of 0.5 mL twice per week for 11 weeks to generate an immune liver fibrosis model. After 11 weeks, rats with immune liver fibrosis were injected intravenously with lipopolysaccharide (LPS) to induce an ACLI model or combined LPS and D-galactosamine (D-GalN) to induce an ACLF model. The rats with ACLI or ACLF were injected intravenously with 2×106 hUC-MSCs, 4×106 hUC-MSCs, or 0.9% sodium chloride as a control. The rats were sacrificed at 1, 2, 4, and 6 weeks (ACLI rats) or 4, 12, and 24 h (ACLF rats). The blood and liver tissues were collected for biochemical and histological investigation. Results The application of hUC-MSCs in rats with ACLI and ACLF led to a significant decrease in the serum levels of ALT, AST, TBil, DBil, ALP, ammonia, and PT, with ALB gradually returned to normal levels. Inflammatory cell infiltration and collagen fiber deposition in liver tissues were significantly attenuated in ACLI rats that received hUC-MSCs. Inflammatory cell infiltration and apoptosis in liver tissues of ACLF rats that received hUC-MSCs were significantly attenuated. Compared with those in the rats that received 0.9% sodium chloride, a significant reduction in proinflammatory cytokine levels and elevated serum levels of hepatocyte growth factor (HGF) were found in ACLF rats that received hUC-MSCs. Furthermore, Notch, IFN-γ/Stat1, and IL-6/Stat3 signaling were inhibited in ACLI/ACLF rats that received hUC-MSCs. Conclusions hUC-MSC transplantation can improve liver function, the degree of fibrosis, and liver damage and promote liver repair in rats with ACLI or ACLF, mediated most likely by inhibiting Notch signaling and reversing the imbalance of the Stat1/Stat3 pathway.

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Faculty Opinions recommendation of Therapeutic effect of human umbilical cord mesenchymal stem cells modified by angiotensin-converting enzyme 2 gene on bleomycin-induced lung fibrosis injury.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725786283.793519987 ◽

2016 ◽

Author(s):

John Laffey

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Angiotensin Converting Enzyme ◽

Therapeutic Effect ◽

Umbilical Cord ◽

Lung Fibrosis ◽

Human Umbilical Cord ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2

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Therapeutic Potential of Amniotic Fluid Derived Mesenchymal Stem Cells Based on their Differentiation Capacity and Immunomodulatory Properties

Current Stem Cell Research & Therapy ◽

10.2174/1574888x14666190222201749 ◽

2019 ◽

Vol 14 (4) ◽

pp. 327-336 ◽

Cited By ~ 9

Author(s):

Carl R. Harrell ◽

Marina Gazdic ◽

Crissy Fellabaum ◽

Nemanja Jovicic ◽

Valentin Djonov ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Animal Models ◽

Amniotic Fluid ◽

Therapeutic Potential ◽

Inflammatory Diseases ◽

Therapeutic Effects ◽

Differentiation Potential ◽

Differentiation Capacity ◽

Cell Based Therapy

Background: Amniotic Fluid Derived Mesenchymal Stem Cells (AF-MSCs) are adult, fibroblast- like, self-renewable, multipotent stem cells. During the last decade, the therapeutic potential of AF-MSCs, based on their huge differentiation capacity and immunomodulatory characteristics, has been extensively explored in animal models of degenerative and inflammatory diseases. Objective: In order to describe molecular mechanisms responsible for the therapeutic effects of AFMSCs, we summarized current knowledge about phenotype, differentiation potential and immunosuppressive properties of AF-MSCs. Methods: An extensive literature review was carried out in March 2018 across several databases (MEDLINE, EMBASE, Google Scholar), from 1990 to present. Keywords used in the selection were: “amniotic fluid derived mesenchymal stem cells”, “cell-therapy”, “degenerative diseases”, “inflammatory diseases”, “regeneration”, “immunosuppression”. Studies that emphasized molecular and cellular mechanisms responsible for AF-MSC-based therapy were analyzed in this review. Results: AF-MSCs have huge differentiation and immunosuppressive potential. AF-MSCs are capable of generating cells of mesodermal origin (chondrocytes, osteocytes and adipocytes), neural cells, hepatocytes, alveolar epithelial cells, insulin-producing cells, cardiomyocytes and germ cells. AF-MSCs, in juxtacrine or paracrine manner, regulate proliferation, activation and effector function of immune cells. Due to their huge differentiation capacity and immunosuppressive characteristic, transplantation of AFMSCs showed beneficent effects in animal models of degenerative and inflammatory diseases of nervous, respiratory, urogenital, cardiovascular and gastrointestinal system. Conclusion: Considering the fact that amniotic fluid is obtained through routine prenatal diagnosis, with minimal invasive procedure and without ethical concerns, AF-MSCs represents a valuable source for cell-based therapy of organ-specific or systemic degenerative and inflammatory diseases.

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Mesenchymal Stem Cells Differentiation: Mitochondria Matter in Osteogenesis or Adipogenesis Direction

Current Stem Cell Research & Therapy ◽

10.2174/1574888x15666200324165655 ◽

2020 ◽

Vol 15 (7) ◽

pp. 602-606

Author(s):

Kun Ji ◽

Ling Ding ◽

Xi Chen ◽

Yun Dai ◽

Fangfang Sun ◽

...

Keyword(s):

Tissue Engineering ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Therapeutic Potential ◽

Mesodermal Cell ◽

Cell Lineages ◽

Current Review ◽

Differentiation Factors ◽

The Relationship ◽

Msc Differentiation

Mesenchymal Stem Cells (MSCs) exhibit enormous therapeutic potential because of their indispensable regenerative, reparative, angiogenic, anti-apoptotic, and immunosuppressive properties. MSCs can best differentiate into mesodermal cell lineages, including osteoblasts, adipocytes, muscle cells, endothelial cells and chondrocytes. Specific differentiation of MSCs could be induced through limited conditions. In addition to the relevant differentiation factors, drastic changes also occur in the microenvironment to conduct it in an optimal manner for particular differentiation. Recent evidence suggests that the mitochondria participate in the regulating of direction and process of MSCs differentiation. Therefore, our current review focuses on how mitochondria participate in both osteogenesis and adipogenesis of MSC differentiation. Besides that, in our current review, we try to provide a further understanding of the relationship between the behavior of mitochondria and the direction of MSC differentiation, which could optimize current cellular culturing protocols for further facilitating tissue engineering by adjusting specific conditions of stem cells.

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Extracellular vesicles from three dimensional culture of human placental mesenchymal stem cells ameliorated renal ischemia/reperfusion injury

The International Journal of Artificial Organs ◽

10.1177/0391398820986809 ◽

2021 ◽

pp. 039139882098680

Author(s):

Xuefeng Zhang ◽

Nan Wang ◽

Yuhua Huang ◽

Yan Li ◽

Gang Li ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Extracellular Vesicles ◽

Therapeutic Potential ◽

Expression Profiles ◽

Ischemia Reperfusion ◽

Three Dimensional ◽

3D Culture ◽

Placental Mesenchymal Stem Cells ◽

2D And 3D

Background: Three-dimensional (3D) culture has been reported to increase the therapeutic potential of mesenchymal stem cells (MSCs). The present study assessed the therapeutic efficacy of extracellular vesicles (EVs) from 3D cultures of human placental MSCs (hPMSCs) for acute kidney injury (AKI). Methods: The supernatants from monolayer culture (2D) and 3D culture of hPMSCs were ultra-centrifuged for EVs isolation. C57BL/6 male mice were submitted to 45 min bilateral ischemia of kidney, followed by renal intra-capsular administration of EVs within a 72 h reperfusion period. Histological, immunohistochemical, and ELISA analyses of kidney samples were performed to evaluate cell death and inflammation. Kidney function was evaluated by measuring serum creatinine and urea nitrogen. The miRNA expression profiles of EVs from 2D and 3D culture of hPMSCs were evaluated using miRNA microarray analysis. Results: The 3D culture of hPMSCs formed spheroids with different diameters depending on the cell density seeded. The hPMSCs produced significantly more EVs in 3D culture than in 2D culture. More importantly, injection of EVs from 3D culture of hPMSCs into mouse kidney with ischemia-reperfusion (I/R)-AKI was more beneficial in protecting from progression of I/R than those from 2D culture. The EVs from 3D culture of hPMSCs were more efficient against apoptosis and inflammation than those from 2D culture, which resulted in a reduction in tissue damage and amelioration of renal function. MicroRNA profiling analysis revealed that a set of microRNAs were significantly changed in EVs from 3D culture of hPMSCs, especially miR-93-5p. Conclusion: The EVs from 3D culture of hPMSCs have therapeutic potential for I/R-AKI.

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Adropin-based dual treatment enhances the therapeutic potential of mesenchymal stem cells in rat myocardial infarction

Cell Death and Disease ◽

10.1038/s41419-021-03610-1 ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

HuiYa Li ◽

DanQing Hu ◽

Guilin Chen ◽

DeDong Zheng ◽

ShuMei Li ◽

...

Keyword(s):

Myocardial Infarction ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Therapeutic Potential ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Paracrine Factors ◽

Dual Treatment

AbstractBoth weak survival ability of stem cells and hostile microenvironment are dual dilemma for cell therapy. Adropin, a bioactive substance, has been demonstrated to be cytoprotective. We therefore hypothesized that adropin may produce dual protective effects on the therapeutic potential of stem cells in myocardial infarction by employing an adropin-based dual treatment of promoting stem cell survival in vitro and modifying microenvironment in vivo. In the current study, adropin (25 ng/ml) in vitro reduced hydrogen peroxide-induced apoptosis in rat bone marrow mesenchymal stem cells (MSCs) and improved MSCs survival with increased phosphorylation of Akt and extracellular regulated protein kinases (ERK) l/2. Adropin-induced cytoprotection was blocked by the inhibitors of Akt and ERK1/2. The left main coronary artery of rats was ligated for 3 or 28 days to induce myocardial infarction. Bromodeoxyuridine (BrdU)-labeled MSCs, which were in vitro pretreated with adropin, were in vivo intramyocardially injected after ischemia, following an intravenous injection of 0.2 mg/kg adropin (dual treatment). Compared with MSCs transplantation alone, the dual treatment with adropin reported a higher level of interleukin-10, a lower level of tumor necrosis factor-α and interleukin-1β in plasma at day 3, and higher left ventricular ejection fraction and expression of paracrine factors at day 28, with less myocardial fibrosis and higher capillary density, and produced more surviving BrdU-positive cells at day 3 and 28. In conclusion, our data evidence that adropin-based dual treatment may enhance the therapeutic potential of MSCs to repair myocardium through paracrine mechanism via the pro-survival pathways.

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