OP0024 Synovial Activation Drives Efficacy of Anti-Inflammatory Effects of Adipose-Derived Stem Cells in Experimental OA Which is Reflected by Serum Levels of S100a8/A9

Rheumatoid arthritis (RA) is a disorder triggered by autoimmune reactions and related with chronic inflammation and severe disability. Bone Marrow-derived Mesenchymal Stem Cells (BM-MSCs) have shown a hopeful immunomodulatory effect towards repairing cartilage and restoring joint function. Additionally, indomethacin (IMC), a nonsteroidal compound, has been considered as a potent therapeutic agent that exhibits significant antipyretic properties and analgesic effects. The target of the current research is to assess the antiarthritic efficacy of BM-MSCs (106 cells/rat at 1, 6, 12 and 18 days) and IMC (2 mg/kg body weight/day for 3 weeks) either alone or concurrently administered against complete Freund’s adjuvant-induced arthritic rats. Changes in paw volume, body weight, gross lesions, and antioxidant defense system, as well as oxidative stress, were assessed. The Th1 cytokine (IL-1β) serum level and Th2 cytokine (IL-4) and Nrf-2 ankle joint expression were detected. In comparison to normal rats, it was found that the CFA-induced arthritic rats exhibited significant leukocytosis and increase in paw volume, LPO level, RF, and IL-1β serum levels. In parallel, arthritic rats that received BM-MSCs and/or IMC efficiently exhibited decrease in paw edema, leukocytosis, and enhancement in the antioxidant enzymatic levels of SOD, GPx, GST, and GSH in serum besides upregulation of Nrf-2 and anti-inflammatory IL-4 expression levels in the ankle articular joint. Likewise, these analyses were more evidenced by the histopathological sections and histological score. The data also revealed that the combined administration of BM-MSC and IMC was more potent in suppressing inflammation and enhancing the anti-inflammatory pathway than each agent alone. Thus, it can be concluded that the combined therapy with BM-MSC and IMC may be used as a promising therapeutic choice after assessing their efficacy and safety in human beings with RA, and the antiarthritic effects may be mediated via modulatory effects on Th1/Th2 cytokines, ozidative stress, and Nrf-2.

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Treatment efficacy of adipose-derived stem cells in experimental osteoarthritis is driven by high synovial activation and reflected by S100A8/A9 serum levels

Osteoarthritis and Cartilage ◽

10.1016/j.joca.2014.05.022 ◽

2014 ◽

Vol 22 (8) ◽

pp. 1158-1166 ◽

Cited By ~ 49

Author(s):

R.F. Schelbergen ◽

S. van Dalen ◽

M. ter Huurne ◽

J. Roth ◽

T. Vogl ◽

...

Keyword(s):

Stem Cells ◽

Treatment Efficacy ◽

Serum Levels ◽

Adipose Derived Stem Cells ◽

Experimental Osteoarthritis

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Oxidant therapy improves adipogenic differentiation of adipose-derived stem cells in human wound healing

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02336-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Christian Ploner ◽

Tina Rauchenwald ◽

Catherine E. Connolly ◽

Karin Joehrer ◽

Johannes Rainer ◽

...

Keyword(s):

Stem Cells ◽

Wound Healing ◽

Granulation Tissue ◽

Adipogenic Differentiation ◽

Adipose Derived Stem Cells ◽

Activated Macrophages ◽

Fat Tissue ◽

Differentiation Potential ◽

Anti Inflammatory ◽

Wound Tissue

Abstract Background Adipose-derived stem cells (ASC) and adipocytes are involved in numerous physiological and pathophysiological conditions, which have been extensively described in subcutaneous and visceral fat depots over the past two decades. However, much less is known about ASC and adipocytes outside classical fat tissue depots and their necessity in tissue remodeling after injury. Therefore, we investigated the etiology of adipocytes in human granulation tissue and define their possible role wound healing. Methods Identification of human wound tissue adipocytes was determined by immunohistochemical staining of granulation tissue sections from patients undergoing surgical debridement. Stromal cell fractions from granulation tissue and subcutaneous fat tissue were generated by collagenase type II-based protocols. Pro- and anti-inflammatory wound bed conditions were mimicked by THP1- and CD14+ monocyte-derived macrophage models in vitro. Effects of macrophage secretome on ASC differentiation and metabolism were determined by immunoblotting, flow cytometry, and microscopy assessing early and late adipocyte differentiation states. Functional rescuing experiments were conducted by lentiviral transduction of wildtype PPARG, IL1RA, and N-chlorotaurine (NCT) treatment. Results Single and clustered adipocyte populations were detected in 11 out of 13 granulation tissue specimens and single-cell suspensions from granulation tissue showed adipogenic differentiation potential. Pro-inflammatory signaling by IFNG/LPS-stimulated macrophages (M (IFNG/LPS)) inhibited the maturation of lipid droplets in differentiated ASC. In contrast, anti-inflammatory IL4/IL13-activated macrophages (M (IL4/IL13)) revealed minor effects on adipocyte development. The M (IFNG/LPS)-induced phenotype was associated with a switch from endogenous fatty acid synthesis to glycolysis-dominated cell metabolism and increased pro-inflammatory cytokine production. Impaired adipogenesis was associated with increased, but seemingly non-functional, CEBPB levels, which failed to induce downstream PPARG and CEBPA. Neither transgenic PPARG overexpression, nor inhibition of IL1B was sufficient to rescue the anti-adipogenic effects induced by IFNG/LPS-activated macrophages. Instead, macrophage co-treatment during stimulation with NCT, a mild oxidant produced by activated granulocytes present in human wounds in vivo, significantly attenuated the anti-adipogenic effects. Conclusions In conclusion, the appearance of adipocytes in wound tissue indicates a prevailing anti-inflammatory environment that could be promoted by NCT treatment and may be associated with improved healing outcomes. Graphical abstract

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Human adipose‐derived stem cells attenuate cigarette smoke induced bone marrow hypoplasia via secretion of anti‐inflammatory cytokine TSG‐6

The FASEB Journal ◽

10.1096/fasebj.26.1_supplement.856.6 ◽

2012 ◽

Vol 26 (S1) ◽

Author(s):

Jie Xie ◽

Kelly Schweitzer ◽

Brian Johnstone ◽

Todd Cook ◽

Dongni Feng ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Cigarette Smoke ◽

Inflammatory Cytokine ◽

Adipose Derived Stem Cells ◽

Bone Marrow Hypoplasia ◽

Anti Inflammatory ◽

Anti Inflammatory Cytokine

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Adipose Tissue-Derived Stem Cells: Immunomodulatory Effects and Therapeutic Potential

Physiology ◽

10.1152/physiol.00021.2019 ◽

2020 ◽

Vol 35 (2) ◽

pp. 125-133 ◽

Cited By ~ 4

Author(s):

Sara Al-Ghadban ◽

Bruce A. Bunnell

Keyword(s):

Stem Cells ◽

Therapeutic Potential ◽

Mechanisms Of Action ◽

Adipose Derived Stem Cells ◽

Immunomodulatory Effects ◽

Graft Versus Host ◽

Cell Lineages ◽

Pathological Conditions ◽

Multiple Cell ◽

Anti Inflammatory

Adipose-derived stem cells (ASCs) can self-renew and differentiate along multiple cell lineages. ASCs are also potently anti-inflammatory due to their inherent ability to regulate the immune system by secreting anti-inflammatory cytokines and growth factors that play a crucial role in the pathology of many diseases, including multiple sclerosis, diabetes mellitus, Crohn’s, SLE, and graft-versus-host disease. The immunomodulatory effects and mechanisms of action of ASCs on pathological conditions are reviewed here.

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Anti-inflammatory Effects of Adipose-Derived Stem Cells (ASCs)

Stem Cell Biology and Regenerative Medicine - Mesenchymal Stem Cells and Immunomodulation ◽

10.1007/978-3-319-46733-7_4 ◽

2016 ◽

pp. 43-60 ◽

Cited By ~ 1

Author(s):

A. C. Bowles ◽

R. M. Wise ◽

B. A. Bunnell

Keyword(s):

Stem Cells ◽

Adipose Derived Stem Cells ◽

Anti Inflammatory

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Immunomodulatory Properties of Adipose-Derived Stem Cells Treated with 5-Azacytydine and Resveratrol on Peripheral Blood Mononuclear Cells and Macrophages in Metabolic Syndrome Animals

Journal of Clinical Medicine ◽

10.3390/jcm7110383 ◽

2018 ◽

Vol 7 (11) ◽

pp. 383 ◽

Cited By ~ 11

Author(s):

Katarzyna Kornicka ◽

Agnieszka Śmieszek ◽

Agnieszka Węgrzyn ◽

Michael Röcken ◽

Krzysztof Marycz

Keyword(s):

Metabolic Syndrome ◽

Stem Cells ◽

Mononuclear Cells ◽

Adipose Derived Stem Cells ◽

Peripheral Blood Mononuclear ◽

Raw264.7 Macrophages ◽

Tnf Α ◽

Blood Mononuclear Cells ◽

Immunomodulatory Properties ◽

Anti Inflammatory

Endocrine disorders, including equine metabolic syndrome (EMS), are a serious issue in veterinary medicine and horse breeding. Furthermore, EMS was shown to affect the cytophysiological properties of adipose-derived stem cells, reducing their therapeutic potential. However, it was shown that those cells can be rejuvenated while using a combination of two chemicals: 5-azacytydine (AZA) and resveratrol (RES). In the present study, we decided to evaluate the immunomodulatory properties of AZA/RES-treated adipose-derived stem cells (ASC) isolated from EMS horses (ASCEMS). Thus, we co-cultured ASC with peripheral blood mononuclear cells (PBMC) and RAW264.7 macrophages. Most attention was placed on regulatory T lymphocytes (TREG), as well as the messenger RNA (mRNA) and protein levels of several cytokines (tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-10, and IL-1β). Moreover, we also investigated the expression of genes related to auto- and mitophagy in both PBMCs and ASCs. PBMCs were obtained from healthy and EMS-suffering individuals and were co-cultured with ASCs that were isolated from healthy and EMS horses cultured in control conditions and with AZA/RES. We discovered that cells treated with AZA/RES increase the TREG number while co-cultured with PBMCs. Moreover, the co-culture of PBMCs with AZA/RES-treated ASCEMS induced mitophagy in PBMCs. Furthermore, ASCEMS pre-treated with AZA/RES displayed anti-inflammatory properties, as decreased levels of TNF-α, nitric oxide (NO), and IL-6 were observed in those cells in comparison with their untreated counterparts in the co-culture with RAW264.7 macrophages. In summary, we demonstrated that ASCEMS treated with AZA/RES displayed increased anti-inflammatory properties, and was able to regulate and activate the TREG-related anti-inflammatory response.

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A Novel Hepatic Anti-Fibrotic Strategy Utilizing the Secretome Released from Etanercept-Synthesizing Adipose-Derived Stem Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20246302 ◽

2019 ◽

Vol 20 (24) ◽

pp. 6302

Author(s):

Jae Hyun Han ◽

Ok-Hee Kim ◽

Sang Chul Lee ◽

Kee-Hwan Kim ◽

Jung Hyun Park ◽

...

Keyword(s):

Stem Cells ◽

Liver Fibrosis ◽

Serum Levels ◽

Genetically Engineered ◽

Control Group ◽

Adipose Derived Stem Cells ◽

Tnf Α ◽

Factor Α

Tumor necrosis factor-α (TNF-α)-driven inflammatory reaction plays a crucial role in the initiation of liver fibrosis. We herein attempted to design genetically engineered adipose-derived stem cells (ASCs) producing etanercept (a potent TNF-α inhibitor), and to determine the anti-fibrotic potential of the secretome released from the etanercept-synthesizing ASCs (etanercept-secretome). First, we generated the etanercept-synthesizing ASCs by transfecting the ASCs with mini-circle plasmids containing the gene insert encoding for etanercept. We subsequently collected the secretory material released from the etanercept-synthesizing ASCs and determined its anti-fibrotic effects both in vitro (in thioacetamide [TAA]-treated AML12 and LX2 cells) and in vivo (in TAA-treated mice) models of liver fibrosis. We observed that while etanercept-secretome increased the viability of the TAA-treated AML12 hepatocytes (p = 0.021), it significantly decreased the viability of the TAA-treated LX2 HSCs (p = 0.021). In the liver of mice with liver fibrosis, intravenous administration of the etanercept-secretome induced significant reduction in the expression of both fibrosis-related and inflammation-related markers compared to the control group (all Ps < 0.05). The etanercept-secretome group also showed significantly lower serum levels of liver enzymes as well as pro-inflammatory cytokines, such as TNF-α (p = 0.020) and IL-6 (p = 0.021). Histological examination of the liver showed the highest reduction in the degree of fibrosis in the entanercept-secretome group (p = 0.006). Our results suggest that the administration of etanercept-secretome improves liver fibrosis by inhibiting TNF-α-driven inflammation in the mice with liver fibrosis. Thus, blocking TNF-α-driven inflammation at the appropriate stage of liver fibrosis could be an efficient strategy to prevent fibrosis.

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