Biocompatibility of Bone Marrow-Derived Mesenchymal Stem Cells in the Rat Inner Ear following Trans-Tympanic Administration

Recent advancements in stem cell therapy have led to an increased interest within the auditory community in exploring the potential of mesenchymal stem cells (MSCs) in the treatment of inner ear disorders. However, the biocompatibility of MSCs with the inner ear, especially when delivered non-surgically and in the immunocompetent cochlea, is not completely understood. In this study, we determined the effect of intratympanic administration of rodent bone marrow MSCs (BM-MSCs) on the inner ear in an immunocompetent rat model. The administration of MSCs did not lead to the generation of any oxidative stress in the rat inner ear. There was no significant production of proinflammatory cytokines, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and IL-12, due to BM-MSCs administration into the rat cochlea. BM-MSCs do not activate caspase 3 pathway, which plays a central role in sensory cell damage. Additionally, transferase dUTP nick end labeling (TUNEL) staining determined that there was no significant cell death associated with the administration of BM-MSCs. The results of the present study suggest that trans-tympanic administration of BM-MSCs does not result in oxidative stress or inflammatory response in the immunocompetent rat cochlea.

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Tnfaip6 Secreted by Bone Marrow–Derived Mesenchymal Stem Cells Attenuates TNBS-Induced Colitis by Modulating Follicular Helper T Cells and Follicular Regulatory T Cells Balance in Mice

Frontiers in Pharmacology ◽

10.3389/fphar.2021.734040 ◽

2021 ◽

Vol 12 ◽

Author(s):

Guangli Gu ◽

Xiaodan Lv ◽

Gengfeng Liu ◽

Ruizhi Zeng ◽

Shiquan Li ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Weight Loss ◽

T Cells ◽

Mesenchymal Stem Cells ◽

Tumor Necrosis ◽

Helper T Cells ◽

Follicular Helper ◽

Tnf Α ◽

Necrosis Factor

Objective: To investigate the immunological mechanism of bone marrow–derived mesenchymal stem cells (BM-MSCs) in inflammatory bowel disease (IBD).Methods: Mice with 2,4,6-trinitrobenzene sulfonic acid (TNBS)–induced colitis were intraperitoneally injected with phosphate-buffered saline, BM-MSCs, BM-MSCs with tumor necrosis factor–induced protein 6 (Tnfaip6) knockdown mediated by RNA interference recombinant adenovirus, and BM-MSCs–infected with control adenovirus or recombinant mouse Tnfaip6. The disease activity index, weight loss, and histological scores were recorded. Serum levels of Tnfaip6 and pro- and anti-inflammatory cytokines, including interleukin (IL)-21, tumor necrosis factor-alpha (TNF-α), IL-10 were measured by enzyme-linked immunosorbent assay. The relative expression levels of these cytokines, B-cell lymphoma 6 (BCL-6) and fork-like transcription factor p3 (Foxp3) in the colon were determined by real-time quantitative PCR (RT-qPCR). BCL-6 and Foxp3 are the master regulators of follicular helper T cells (Tfh) and follicular regulatory T cells (Tfr), respectively. The infiltration of Tfh and Tfr in mesenteric lymph nodes (MLNs) and spleens was analyzed by flow cytometry.Results: Compared to the normal control group, the expression levels of BCL-6 and IL-21 in the colon, Tfh infiltration, and ratios of Tfh/Tfr in the MLNs and spleen, and the serum concentrations of IL-21 and TNF-α increased significantly in the colitis model group (p < 0.05). Intraperitoneal injection of BM-MSCs or Tnfaip6 ameliorated weight loss and clinical and histological severity of colitis, downregulated the expression of BCL-6, IL-21, and TNF-α, upregulated the expression of Foxp3, IL-10, and Tnfaip6 (p < 0.05), increased Tfr and reduced the infiltration of Tfh in the MLNs and spleen, and downregulated the Tfh/Tfr ratio (p < 0.05). On the other hand, BM-MSCs lost the therapeutic effect and immune regulatory functions on Tfh and Tfr after Tnfaip6 knockdown.Conclusion: Tfh increase in the inflamed colon, Tfh decrease and Tfr increase during the colitis remission phase, and the imbalance of the Tfh/Tfr ratio is closely related to the progression of IBD. Tnfaip6 secreted by BM-MSCs alleviates IBD by inhibiting Tfh differentiation, promoting Tfr differentiation, and improving the imbalance of Tfh/Tfr in mice.

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The let-7f-5p–Nme4 pathway mediates tumor necrosis factor α-induced impairment in osteogenesis of bone marrow-derived mesenchymal stem cells

Biochemistry and Cell Biology ◽

10.1139/bcb-2020-0281 ◽

2021 ◽

pp. 1-11

Author(s):

Ying-Jie Zhao ◽

Zheng-Chao Gao ◽

Xi-Jing He ◽

Jing Li

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Tumor Necrosis Factor ◽

Osteogenic Differentiation ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Tnf Α ◽

Factor Α ◽

Necrosis Factor

Although tumor necrosis factor α (TNF-α)-mediated inflammation significantly impacts osteoporosis, the mechanisms underlying the osteogenic differentiation defects of bone marrow-derived mesenchymal stem cells (BM-MSCs) caused by TNF-α remain poorly understood. We found that TNF-α stimulation of murine BM-MSCs significantly upregulated the expression levels of several microRNAs (miRNAs), including let-7f-5p, but this increase was significantly reversed by treatment with the kinase inhibitor BAY 11-7082. To study gain- or loss of function, we transfected cells with an miRNA inhibitor or miRNA mimic. We then demonstrated that let-7f-5p impaired osteogenic differentiation of BM-MSCs in the absence and presence of TNF-α, as evidenced by alkaline phosphatase and alizarin red staining as well as quantitative assays of the mRNA levels of bone formation marker genes in differentiated BM-MSCs. Moreover, let-7f-5p targets the 3′ untranslated region of Nucleoside diphosphate kinase 4 (Nme4) mRNA and negatively regulates Nme4 expression in mouse BM-MSCs. Ectopic expression of Nme4 completely reversed the inhibitory effects of the let-7f-5p mimic on osteogenic differentiation of mouse BM-MSCs. Furthermore, inhibition of let-7f-5p or overexpression of Nme4 in BM-MSCs restored in-vivo bone formation in an ovariectomized animal model. Collectively, our work indicates that let-7f-5p is involved in TNF-α-mediated reduction of BM-MSC osteogenesis via targeting Nme4.

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Inner ear progenitor cells can be generated in vitro from human bone marrow mesenchymal stem cells

Regenerative Medicine ◽

10.2217/rme.12.58 ◽

2012 ◽

Vol 7 (6) ◽

pp. 757-767 ◽

Cited By ~ 17

Author(s):

Sarah L Boddy ◽

Wei Chen ◽

Ricardo Romero-Guevara ◽

Lucksy Kottam ◽

Illaria Bellantuono ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Inner Ear ◽

Progenitor Cells ◽

Human Bone ◽

Human Bone Marrow ◽

Marrow Mesenchymal Stem Cells

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Bone marrow mesenchymal stem cells are progenitors in vitro for inner ear hair cells

Molecular and Cellular Neuroscience ◽

10.1016/j.mcn.2006.10.003 ◽

2007 ◽

Vol 34 (1) ◽

pp. 59-68 ◽

Cited By ~ 76

Author(s):

Sang-Jun Jeon ◽

Kazuo Oshima ◽

Stefan Heller ◽

Albert S.B. Edge

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Inner Ear ◽

Hair Cells ◽

Marrow Mesenchymal Stem Cells

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Lipocalin 2 decreases senescence of bone marrow-derived mesenchymal stem cells under sub-lethal doses of oxidative stress

Cell Stress and Chaperones ◽

10.1007/s12192-014-0496-5 ◽

2014 ◽

Vol 19 (5) ◽

pp. 685-693 ◽

Cited By ~ 19

Author(s):

Bahareh Bahmani ◽

Mehryar Habibi Roudkenar ◽

Raheleh Halabian ◽

Ali Jahanian-Najafabadi ◽

Fatemeh Amiri ◽

...

Keyword(s):

Oxidative Stress ◽

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Lipocalin 2 ◽

Lethal Doses

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Bone Marrow-Derived Mesenchymal Stem Cells Expressing Thioredoxin 1 Attenuate Bleomycin-Induced Skin Fibrosis and Oxidative Stress in Scleroderma

Journal of Investigative Dermatology ◽

10.1016/j.jid.2017.01.011 ◽

2017 ◽

Vol 137 (6) ◽

pp. 1223-1233 ◽

Cited By ~ 9

Author(s):

Miao Jiang ◽

Yiwu Yu ◽

Jingying Luo ◽

Qingyun Gao ◽

Lili Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Skin Fibrosis ◽

Thioredoxin 1 ◽

And Oxidative Stress

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HIGH GLUCOSE INDUCED BONE LOSS VIA ATTENUATING THE PROLIFERATION AND OSTEOBLASTOGENESIS AND ENHANCING ADIPOGENESIS OF BONE MARROW MESENCHYMAL STEM CELLS

Biomedical Engineering Applications Basis and Communications ◽

10.4015/s1016237213400103 ◽

2013 ◽

Vol 25 (05) ◽

pp. 1340010 ◽

Cited By ~ 1

Author(s):

Wen-Tyng Li ◽

Wen-Kai Hu ◽

Feng-Ming Ho

Keyword(s):

Oxidative Stress ◽

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Bone Loss ◽

High Glucose ◽

Chromatin Condensation ◽

Diabetic Rats ◽

Peroxisome Proliferator ◽

Bone Marrow Mscs

Diabetes mellitus (DM) is associated with bone loss and leads to osteopenia and osteoporosis. This study was undertaken to investigate whether the impaired functions of mesenchymal stem cells (MSCs) derived from bone marrow play a role in pathogenesis of DM-associated bone loss. Bone marrow MSCs were taken from the alloxan-induced diabetic rats and normal rats. Bone mineral densities of tibias and femurs in diabetic rats decreased compared to those of normal rats as shown by dual energy X-ray absorptiometry. MSCs from diabetic rats exhibited reduced colony formation activity. The in vitro effects of high glucose (HG) (20 or 33 mM) on the growth, oxidative stress, apoptosis, and differentiation MSCs were next assessed. The viability and proliferation of MSCs derived from diabetic rats decreased significantly compared with that from normal rats. HG further suppressed the proliferation and viability of MSCs from both diabetic and normal rats. HG was associated with 38–40% increase in reactive oxygen species level and had significantly downregulated the activities of superoxide dismutase (SOD) and catalase (CAT) which could be recovered by the addition of L-ascorbic acid. The phenomena of apoptosis such as chromatin condensation and DNA fragmentation were found in cells cultured under HG conditions. As compared with 5.5 mM glucose, exposure of MSCs to HG enhanced adipogenic induction of triacylglycerol accumulation and inhibited osteogenic induction of alkaline phosphatase activity. HG increased peroxisome proliferator-activated receptor gamma expression during adipogenesis and reduced RUNX2 expression during osteoblastogenesis. These results indicate that MSCs derived from diabetic rats exhibited the inhibitory effects on cell growth and osteogenic ability. The oxidative stress, apoptosis, and adipogenic capability of MSCs were increased by HG. Furthermore, it is suggested that HG induces bone loss via attenuating the proliferation and osteoblastogenesis and enhancing adipogenesis mediated by the oxidative stress in rat bone marrow MSCs.

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1,25(OH)2D3 Differently Affects Immunomodulatory Activities of Mesenchymal Stem Cells Depending on the Presence of TNF-α, IL-1β and IFN-γ

Journal of Clinical Medicine ◽

10.3390/jcm8122211 ◽

2019 ◽

Vol 8 (12) ◽

pp. 2211 ◽

Cited By ~ 4

Author(s):

Christian Behm ◽

Alice Blufstein ◽

Johannes Gahn ◽

Barbara Kubin ◽

Michael Nemec ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Inflammatory Cytokines ◽

T Lymphocyte ◽

T Lymphocyte Proliferation ◽

Tnf Α ◽

Ifn Γ ◽

Anti Inflammatory ◽

Anti Inflammatory Cytokine ◽

Necrosis Factor

Periodontal ligament-derived mesenchymal stem cells (hPDLSCs) possess immunomodulatory abilities which are strongly enhanced by various inflammatory cytokines. Vitamin D3 has anti-inflammatory effects on hPDLSCs and immune cells. However, no study to date has directly compared the influence of 1,25(OH)2D3 on the immunomodulatory activities of hPDLSCs in the presence of different cytokines. In the present study, the effects of hPDLSCs treated with tumor necrosis factor (TNF)-α, interleukin (IL)-1β, or interferon (IFN)-γ in the presence of 1,25(OH)2D3 on the proliferation of allogenic CD4+ T lymphocyte or on the functional status of primary CD68+ macrophages were analyzed in coculture models. Additionally, the effects of 1,25(OH)2D3 on TNF-α-, IL-1β-, and IFN-γ-induced gene expression of some immunomodulatory factors in hPDLSCs were compared. Under coculture conditions, 1,25(OH)2D3 increased or decreased CD4+ T lymphocyte proliferation via hPDLSCs, depending on the cytokine. hPDLSCs primed with 1,25(OH)2D3 and different cytokines affected pro- and anti-inflammatory cytokine expression in macrophages variably, depending on the priming cytokine. With one exception, 1,25(OH)2D3 significantly reduced TNF-α-, IL-1β-, and IFN-γ-induced expression of all the investigated immunomediators in hPDLSCs, albeit to different extents. These results suggest that 1,25(OH)2D3 influences the immunomodulatory activities of hPDLSCs depending qualitatively and quantitatively on the presence of certain inflammatory cytokines.

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