Interleukin‐4 Gene Transfection and Spheroid Formation Potentiate Therapeutic Efficacy of Mesenchymal Stem Cells for Osteoarthritis

Abstract Background The therapeutic efficacy of mesenchymal stem cells (MSCs) of different tissue origins on metabolic disorders can be varied in many ways but remains poorly defined. Here we report a comprehensive comparison of human MSCs derived from umbilical cord Wharton’s jelly (UC-MSCs), dental pulp (PU-MSCs), and adipose tissue (AD-MSCs) on the treatment of glucose and lipid metabolic disorders in type II diabetic mice. Methods Fourteen-to-fifteen-week-old male C57BL/6 db/db mice were intravenously administered with human UC-MSCs, PU-MSCs, and AD-MSCs at various doses or vehicle control once every 2 weeks for 6 weeks. Metformin (MET) was given orally to animals in a separate group once a day at weeks 4 to 6 as a positive control. Body weight, blood glucose, and insulin levels were measured every week. Glucose tolerance tests (GTT) and insulin tolerance tests (ITT) were performed every 2 weeks. All the animals were sacrificed at week 6 and the blood and liver tissues were collected for biochemical and histological examinations. Results UC-MSCs showed the strongest efficacy in reducing fasting glucose levels, increasing fasting insulin levels, and improving GTT and ITT in a dose-dependent manner, whereas PU-MSCs showed an intermediate efficacy and AD-MSCs showed the least efficacy on these parameters. Moreover, UC-MSCs also reduced the serum low-density lipoprotein cholesterol (LDL-C) levels with the most prominent potency and AD-MSCs had only very weak effect on LDL-C. In contrast, AD-MSCs substantially reduced the lipid content and histological lesion of liver and accompanying biomarkers of liver injury such as serum aspartate transaminase (AST) and alanine aminotransferase (ALT) levels, whereas UC-MSCs and PU-MSCs displayed no or modest effects on these parameters, respectively. Conclusions Taken together, our results demonstrated that MSCs of different tissue origins can confer substantially different therapeutic efficacy in ameliorating glucose and lipid metabolic disorders in type II diabetes. MSCs with different therapeutic characteristics could be selected according to the purpose of the treatment in the future clinical practice.

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Mesenchymal stem cells immortalization's and state-of-art: a systematic review and meta-analysis

European Journal of Public Health ◽

10.1093/eurpub/ckab120.058 ◽

2021 ◽

Vol 31 (Supplement_2) ◽

Author(s):

P E F Stricker ◽

A C Irioda ◽

B F Mogharbel ◽

E Abdelwaid ◽

L R Cavalli ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Gene Transfection ◽

Meta Analysis ◽

Total N ◽

Htert Gene ◽

Cell Immortalization ◽

Immortalized Cell ◽

Experimental Strategies ◽

Established Technique

Abstract Background The immortalization of mesenchymal stem cells (MSCs) allows them to avoid senescence and be cultured through limitless cell passages. Thus, several experimental strategies, such as retrovirus-mediated gene transfer or viral oncogenesis, have been applied for the immortalization of MSCs. The aim was to identifier the most commonly used methodologies and their particularities for the immortalization of human and animal MSCs. Methods The search was conducted in June 2019 and developed in SCOPUS, PUBMED, and SCIENCE DIRECT. Statistical analysis was performed, obtaining the values of total n, mean and standard deviation, confidence interval (CI), and percentage (frequency) for all the predictors. Results The most used immortalization methodology was viral transfection, being the most common immortalized cell type was the bone marrow-derived MSC, and the most used gene for immortalizing both human and animal MSCs was hTERT (39.3%) and SV40T (54.5%). Among the articles analyzed in this review, only 39.3% and 36.4% of human and animal MSCs immortalization protocols, respectively, underwent the tumorigenicity test. Conclusions The virus-mediated gene transfection was observed as the most used and established technique. The insertion of the hTERT gene is still the most used gene for cell immortalization, suggesting that the maintenance of telomerase is efficient for maintaining cell proliferation and bypassing cell senescence. The review concluded that the tumorigenicity tests should become mandatory in order to safely use the immortalized MSCs for translation.

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Self-assembled GFFYK peptide hydrogel enhances the therapeutic efficacy of mesenchymal stem cells in a mouse hindlimb ischemia model

Acta Biomaterialia ◽

10.1016/j.actbio.2018.12.015 ◽

2019 ◽

Vol 85 ◽

pp. 94-105 ◽

Cited By ~ 5

Author(s):

Anan Huang ◽

Danni Liu ◽

Xin Qi ◽

Zhiwei Yue ◽

Hongmei Cao ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Therapeutic Efficacy ◽

Hindlimb Ischemia ◽

Self Assembled ◽

Peptide Hydrogel

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Mesenchymal Stem Cells and NF-κB Sensing Interleukin-4 Over-Expressing Mesenchymal Stem Cells Are Equally Effective in Mitigating Particle-Associated Chronic Inflammatory Bone Loss in Mice

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.757830 ◽

2021 ◽

Vol 9 ◽

Author(s):

Ning Zhang ◽

Takeshi Utsunomiya ◽

Tzuhua Lin ◽

Yusuke Kohno ◽

Masaya Ueno ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Bone Loss ◽

Chronic Inflammation ◽

Local Injection ◽

Interleukin 4 ◽

M2 Macrophage ◽

Mineral Density ◽

Primary Surgery ◽

Polyethylene Particle

Wear particles from total joint arthroplasties (TJAs) induce chronic inflammation, macrophage infiltration and lead to bone loss by promoting bone destruction and inhibiting bone formation. Inhibition of particle-associated chronic inflammation and the associated bone loss is critical to the success and survivorship of TJAs. The purpose of this study is to test the hypothesis that polyethylene particle induced chronic inflammatory bone loss could be suppressed by local injection of NF-κB sensing Interleukin-4 (IL-4) over-expressing MSCs using the murine continuous polyethylene particle infusion model. The animal model was generated with continuous infusion of polyethylene particles into the intramedullary space of the femur for 6 weeks. Cells were locally injected into the intramedullary space 3 weeks after the primary surgery. Femurs were collected 6 weeks after the primary surgery. Micro-computational tomography (μCT), histochemical and immunohistochemical analyses were performed. Particle-infusion resulted in a prolonged pro-inflammatory M1 macrophage dominated phenotype and a decrease of the anti-inflammatory M2 macrophage phenotype, an increase in TRAP positive osteoclasts, and lower alkaline phosphatase staining area and bone mineral density, indicating chronic particle-associated inflammatory bone loss. Local injection of MSCs or NF-κB sensing IL-4 over-expressing MSCs reversed the particle-associated chronic inflammatory bone loss and facilitated bone healing. These results demonstrated that local inflammatory bone loss can be effectively modulated via MSC-based treatments, which could be an efficacious therapeutic strategy for periprosthetic osteolysis.

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