Inflammatory Cytokine Interleukin-6 (IL-6) Promotes the Proangiogenic
Ability of Adipose Stem Cells from Obese Subjects via the IL-6 Signaling
Pathway

Yuanyuan      Zhang; Pengju      Lv; Yalong      Li; Yonghui      Zhang; Chaofei      Cheng; Hongbo      Hao; Han      Yue

doi:10.2174/1574888X17666220429103935

Abstract

Background: The prevalence of obesity, as well as obesity-induced chronic inflammatory diseases, is increasing worldwide. Chronic inflammation is related to the complex process of angiogenesis, and we found that adipose-derived stem cells from obese subjects (obADSCs) had proangiogenic features, including higher expression levels of interleukin-6 (IL-6), Notch ligands and receptors, and proangiogenic cytokines, than those from control subjects. We hypothesized that IL-6 and Notch signaling pathways are essential for regulating the proangiogenic characteristics of obADSCs.

Objective: This study aimed to investigate whether the inflammatory cytokine interleukin 6 (IL-6) promotes the proangiogenic capacity of adipose stem cells in obese subjects via the IL-6 signaling pathway.

Methods: We compared the phenotype analysis as well as cell doubling time, proliferation, migration, differentiation, and proangiogenic properties of ADSCs in vitro. Moreover, we used small interfering RNAs to inhibit the gene and protein expression of IL-6.

Results: We found that ADSCs isolated from control individuals (chADSCs) and obADSCs had similar phenotypes and growth characteristics, and chADSCs had a stronger differentiation ability than obADSCs. However, obADSCs were more potent in promoting EA.hy926 cell migration and tube formation than chADSCs in vitro. We confirmed that IL-6 siRNA significantly reduced the transcriptional level of IL-6 in obADSCs, thereby reducing the expression of vascular endothelial growth factor (VEGF)- A, VEGF receptor 2, transforming growth factor β, and Notch ligands and receptors in obADSCs.

Conclusion: The finding suggests that inflammatory cytokine interleukin-6 (IL-6) promotes the proangiogenic ability of obADSCs via the IL-6 signaling pathway.

Keywords: Obesity, adipose-derived stem cells (ADSCs), inflammation, angiogenesis, interleukin-6 (IL-6), Notch signaling.

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[1]
Strong AL, Ohlstein JF, Biagas BA, et al. Leptin produced by obese adipose stromal/stem cells enhances proliferation and metastasis of estrogen receptor positive breast cancers. Breast Cancer Res  2015; 17: 112.
 [http://dx.doi.org/10.1186/s13058-015-0622-z] [PMID:  26286584]

[2]
Kim J, Lee J. Role of obesity-induced inflammation in the development of insulin resistance and type 2 diabetes: History of the research and remaining questions. Ann Pediatr Endocrinol Metab  2021; 26(1): 1-13.
 [http://dx.doi.org/10.6065/apem.2040188.094] [PMID:  33819954]

[3]
Gao X, Salomon C, Freeman DJ. Extracellular vesicles from adipose tissue-A potential role in obesity and type 2 diabetes? Front Endocrinol (Lausanne)  2017; 8: 202.
 [http://dx.doi.org/10.3389/fendo.2017.00202] [PMID:  28868048]

[4]
Herold J, Kalucka J. Angiogenesis in adipose tissue: The interplay between adipose and endothelial cells. Front Physiol  2021; 11: 624903.
 [http://dx.doi.org/10.3389/fphys.2020.624903] [PMID:  33633579]

[5]
Rosenwald M, Wolfrum C. The origin and definition of brite versus white and classical brown adipocytes. Adipocyte  2014; 3(1): 4-9.
 [http://dx.doi.org/10.4161/adip.26232] [PMID:  24575363]

[6]
Conese M, Annacontini L, Carbone A, et al. The role of adipose-derived stem cells, dermal regenerative templates, and platelet-rich plasma in tissue engineering-based treatments of chronic skin wounds. Stem Cells Int  2020; 2020: 7056261.
 [http://dx.doi.org/10.1155/2020/7056261]

[7]
Nguyen A, Guo J, Banyard DA, et al. Stromal vascular fraction: A regenerative reality? Part 1: Current concepts and review of the literature. J Plast Reconstr Aesthet Surg  2016; 69(2): 170-9.
 [http://dx.doi.org/10.1016/j.bjps.2015.10.015] [PMID:  26565755]

[8]
Scholz T, Sumarto A, Krichevsky A, Evans GR. Neuronal differentiation of human adipose tissue-derived stem cells for peripheral nerve regeneration in vivo. Arch Surg  2011; 146(6): 666-74.
 [http://dx.doi.org/10.1001/archsurg.2011.148] [PMID:  21690442]

[9]
Cheng NC, Wang S, Young TH. The influence of spheroid formation of human adipose-derived stem cells on chitosan films on stemness and differentiation capabilities. Biomaterials  2012; 33(6): 1748-58.
 [http://dx.doi.org/10.1016/j.biomaterials.2011.11.049] [PMID:  22153870]

[10]
Marino G, Rosso F, Ferdinando P, et al. Growth and endothelial differentiation of adipose stem cells on polycaprolactone. J Biomed Mater Res A  2012; 100(3): 543-8.
 [http://dx.doi.org/10.1002/jbm.a.33296] [PMID:  22162251]

[11]
Kim M, Kim I, Lee SK, Bang SI, Lim SY. Clinical trial of autologous differentiated adipocytes from stem cells derived from human adipose tissue. Dermatol Surg  2011; 37(6): 750-9.
 [http://dx.doi.org/10.1111/j.1524-4725.2011.01765.x]

[12]
Salgado AJ, Reis RL, Sousa NJ, Gimble JM. Adipose tissue derived stem cells secretome: Soluble factors and their roles in regenerative medicine. Curr Stem Cell Res Ther  2010; 5(2): 103-10.
 [http://dx.doi.org/10.2174/157488810791268564] [PMID:  19941460]

[13]
Barry FP, Murphy JM. Mesenchymal stem cells: Clinical applications and biological characterization. Int J Biochem Cell Biol  2004; 36(4): 568-84.
 [http://dx.doi.org/10.1016/j.biocel.2003.11.001] [PMID:  15010324]

[14]
Elahi KC, Klein G, Avci-Adali M, Sievert KD, MacNeil S, Aicher WK. Human mesenchymal stromal cells from different sources diverge in their expression of cell surface proteins and display distinct differentiation patterns. Stem Cells Int  2016; 2016: 5646384.
 [http://dx.doi.org/10.1155/2016/5646384]

[15]
Pu CM, Liu CW, Liang CJ, et al. Adipose-derived stem cells protect skin flaps against ischemia/reperfusion injury via IL-6 expression. J Invest Dermatol  2017; 137(6): 1353-62.
 [http://dx.doi.org/10.1016/j.jid.2016.12.030] [PMID:  28163069]

[16]
Kim EH, Heo CY. Current applications of adipose-derived stem cells and their future perspectives. World J Stem Cells  2014; 6(1): 65-8.
 [http://dx.doi.org/10.4252/wjsc.v6.i1.65] [PMID:  24567789]

[17]
Bora P, Majumdar AS. Adipose tissue-derived stromal vascular fraction in regenerative medicine: A brief review on biology and translation. Stem Cell Res Ther  2017; 8(1): 145.
 [http://dx.doi.org/10.1186/s13287-017-0598-y] [PMID:  28619097]

[18]
Miranville A, Heeschen C, Sengenès C, Curat CA, Busse R, Bouloumié A. Improvement of postnatal neovascularization by human adipose tissue-derived stem cells. Circulation  2004; 110(3): 349-55.
 [http://dx.doi.org/10.1161/01.CIR.0000135466.16823.D0] [PMID:  15238461]

[19]
Wong DE, Banyard DA, Santos PJF, Sayadi LR, Evans GRD, Widgerow AD. Adipose-derived stem cell extracellular vesicles: A systematic review✰ J Plast Reconstr Aesthet Surg  2019; 72(7): 1207-18.
 [http://dx.doi.org/10.1016/j.bjps.2019.03.008] [PMID:  30952587]

[20]
Hsiao ST, Lokmic Z, Peshavariya H, et al. Hypoxic conditioning enhances the angiogenic paracrine activity of human adipose-derived stem cells. Stem Cells Dev  2013; 22(10): 1614-23.
 [http://dx.doi.org/10.1089/scd.2012.0602] [PMID:  23282141]

[21]
Matsuda K, Falkenberg KJ, Woods AA, Choi YS, Morrison WA, Dilley RJ. Adipose-derived stem cells promote angiogenesis and tissue formation for in vivo tissue engineering. Tissue Eng Part A  2013; 19(11-12): 1327-35.
 [http://dx.doi.org/10.1089/ten.tea.2012.0391] [PMID:  23394225]

[22]
Shoji T, Ii M, Mifune Y, et al. Local transplantation of human multipotent adipose-derived stem cells accelerates fracture healing via enhanced osteogenesis and angiogenesis. Lab Invest  2010; 90(4): 637-49.
 [http://dx.doi.org/10.1038/labinvest.2010.39] [PMID:  20157290]

[23]
Sabol RA, Bowles AC, Cote A, Wise R, Pashos N, Bunnell BA. Therapeutic potential of adipose stem cells. Adv Exp Med Biol 2018.
 [http://dx.doi.org/10.1007/5584_2018_248] [PMID:  30051318]

[24]
Sabol RA, Villela VA, Denys A, et al. Obesity-altered adipose stem cells promote radiation resistance of estrogen receptor positive breast cancer through paracrine signaling. Int J Mol Sci  2020; 21(8): E2722.
 [http://dx.doi.org/10.3390/ijms21082722] [PMID:  32326381]

[25]
Hotamisligil GS. Inflammation and metabolic disorders. Nature  2006; 444(7121): 860-7.
 [http://dx.doi.org/10.1038/nature05485] [PMID:  17167474]

[26]
Powell K. Obesity: The two faces of fat. Nature  2007; 447(7144): 525-7.
 [http://dx.doi.org/10.1038/447525a] [PMID:  17538594]

[27]
Guo S, Gonzalez-Perez RR. Notch, IL-1 and leptin crosstalk outcome (NILCO) is critical for leptin-induced proliferation, migration and VEGF/VEGFR-2 expression in breast cancer. PLoS One  2011; 6(6): e21467.
 [http://dx.doi.org/10.1371/journal.pone.0021467] [PMID:  21731759]

[28]
Zhu H, Zhang Y, Zhong Y, et al. Inflammation-Mediated Angiogenesis in Ischemic Stroke. Front Cell Neurosci  2021; 15: 652647.
 [http://dx.doi.org/10.3389/fncel.2021.652647] [PMID:  33967696]

[29]
Nilsson MB, Langley RR, Fidler IJ. Interleukin-6, secreted by human ovarian carcinoma cells, is a potent proangiogenic cytokine. Cancer Res  2005; 65(23): 10794-800.
 [http://dx.doi.org/10.1158/0008-5472.CAN-05-0623] [PMID:  16322225]

[30]
Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med  1995; 1(1): 27-31.
 [http://dx.doi.org/10.1038/nm0195-27] [PMID:  7584949]

[31]
Zuk PA, Zhu M, Ashjian P, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell  2002; 13(12): 4279-95.
 [http://dx.doi.org/10.1091/mbc.e02-02-0105] [PMID:  12475952]

[32]
Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy  2006; 8(4): 315-7.
 [http://dx.doi.org/10.1080/14653240600855905] [PMID:  16923606]

[33]
Zhang Y, Lv P, Li Y, et al. Comparison of the biological characteristics of umbilical cord mesenchymal stem cells derived from the human heterosexual twins. Differentiation  2020; 114: 1-12.
 [http://dx.doi.org/10.1016/j.diff.2020.05.005]

[34]
Dabrowski FA, Burdzinska A, Kulesza A, et al. Comparison of the paracrine activity of mesenchymal stem cells derived from human umbilical cord, amniotic membrane and adipose tissue. J Obstet Gynaecol Res  2017; 43(11): 1758-68.
 [http://dx.doi.org/10.1111/jog.13432] [PMID:  28707770]

[35]
Luo Y, Yi X, Liang T, et al. Autograft microskin combined with adipose-derived stem cell enhances wound healing in a full-thickness skin defect mouse model. Stem Cell Res Ther  2019; 10(1): 279.
 [http://dx.doi.org/10.1186/s13287-019-1389-4] [PMID:  31470890]

[36]
Lu H, Wang F, Mei H, Wang S, Cheng L. Human adipose mesenchymal stem cells show more efficient angiogenesis promotion on endothelial colony-forming cells than umbilical cord and endometrium. Stem Cells Int  2018; 2018: 7537589.
 [http://dx.doi.org/10.1155/2018/7537589]

[37]
Frei K, Gramatzki D, Tritschler I, et al. Transforming growth factor-β pathway activity in glioblastoma. Oncotarget  2015; 6(8): 5963-77.
 [http://dx.doi.org/10.18632/oncotarget.3467] [PMID:  25849941]

[38]
Saltiel AR, Olefsky JM. Inflammatory mechanisms linking obesity and metabolic disease. J Clin Invest  2017; 127(1): 1-4.
 [http://dx.doi.org/10.1172/JCI92035] [PMID:  28045402]

[39]
Harper JW, Zisman TL. Interaction of obesity and inflammatory bowel disease. World J Gastroenterol  2016; 22(35): 7868-81.
 [http://dx.doi.org/10.3748/wjg.v22.i35.7868] [PMID:  27672284]

[40]
Liu R, Nikolajczyk BS. Tissue immune cells fuel obesity-associated inflammation in adipose tissue and beyond. Front Immunol  2019; 10: 1587.
 [http://dx.doi.org/10.3389/fimmu.2019.01587] [PMID:  31379820]

[41]
Kern S, Eichler H, Stoeve J, Klüter H, Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells  2006; 24(5): 1294-301.
 [http://dx.doi.org/10.1634/stemcells.2005-0342] [PMID:  16410387]

[42]
Moraes DA, Sibov TT, Pavon LF, et al. A reduction in CD90 (THY-1) expression results in increased differentiation of mesenchymal stromal cells. Stem Cell Res Ther  2016; 7(1): 97.
 [http://dx.doi.org/10.1186/s13287-016-0359-3] [PMID:  27465541]

[43]
Sullivan CB, Porter RM, Evans CH, et al. TNFα and IL-1β influence the differentiation and migration of murine MSCs independently of the NF-κB pathway. Stem Cell Res Ther  2014; 5(4): 104.
 [http://dx.doi.org/10.1186/scrt492] [PMID:  25163844]

[44]
McFadden TM, Duffy GP, Allen AB, et al. The delayed addition of human mesenchymal stem cells to pre-formed endothelial cell networks results in functional vascularization of a collagen-glycosaminoglycan scaffold in vivo. Acta Biomater  2013; 9(12): 9303-16.
 [http://dx.doi.org/10.1016/j.actbio.2013.08.014] [PMID:  23958783]

[45]
Bianco P, Robey PG, Simmons PJ. Mesenchymal stem cells: Revisiting history, concepts, and assays. Cell Stem Cell  2008; 2(4): 313-9.
 [http://dx.doi.org/10.1016/j.stem.2008.03.002] [PMID:  18397751]

[46]
Liang L, Li Z, Ma T, et al. Transplantation of human placenta-derived mesenchymal stem cells alleviates critical limb ischemia in diabetic nude rats. Cell Transplant  2017; 26(1): 45-61.
 [http://dx.doi.org/10.3727/096368916X692726] [PMID:  27501782]

[47]
Xu Y, Liu L, Zhang L, et al. Efficient commitment to functional CD34+ progenitor cells from human bone marrow mesenchymal stem-cell-derived induced pluripotent stem cells. PLoS One  2012; 7(4): e34321.
 [http://dx.doi.org/10.1371/journal.pone.0034321] [PMID:  22496789]

[48]
Zhou Z, Tian X, Mo B, et al. Adipose mesenchymal stem cell transplantation alleviates spinal cord injury-induced neuroinflammation partly by suppressing the Jagged1/Notch pathway. Stem Cell Res Ther  2020; 11(1): 212.
 [http://dx.doi.org/10.1186/s13287-020-01724-5] [PMID:  32493480]

[49]
Nagasaki T, Hara M, Nakanishi H, Takahashi H, Sato M, Takeyama H. Interleukin-6 released by colon cancer-associated fibroblasts is critical for tumour angiogenesis: Anti-interleukin-6 receptor antibody suppressed angiogenesis and inhibited tumour-stroma interaction. Br J Cancer  2014; 110(2): 469-78.
 [http://dx.doi.org/10.1038/bjc.2013.748] [PMID:  24346288]

[50]
Costa C, Incio J, Soares R. Angiogenesis and chronic inflammation: Cause or consequence? Angiogenesis  2007; 10(3): 149-66.
 [http://dx.doi.org/10.1007/s10456-007-9074-0] [PMID:  17457680]

[51]
Jackson JR, Seed MP, Kircher CH, Willoughby DA, Winkler JD. The codependence of angiogenesis and chronic inflammation. FASEB J  1997; 11(6): 457-65.
 [http://dx.doi.org/10.1096/fasebj.11.6.9194526] [PMID:  9194526]

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DOI https://dx.doi.org/10.2174/1574888X17666220429103935	Print ISSN 1574-888X
Publisher Name Bentham Science Publisher	Online ISSN 2212-3946

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Inflammatory Cytokine Interleukin-6 (IL-6) Promotes the Proangiogenic Ability of Adipose Stem Cells from Obese Subjects via the IL-6 Signaling Pathway

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