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Current Stem Cell Research & Therapy

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ISSN (Print): 1574-888X
ISSN (Online): 2212-3946

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Research Article

Enhancing the Regenerative Potential of Adipose-Derived Mesenchymal Stem Cells Through TLR4-Mediated Signaling

Author(s): Demet Kaçaroğlu and Seher Yaylacı*

Volume 19, Issue 11, 2024

Published on: 09 January, 2024

Page: [1514 - 1524] Pages: 11

DOI: 10.2174/011574888X283664231219080535

Price: $65

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Abstract

Introduction: Toll-like receptor 4 (TLR4) is a receptor that traditionally plays an important role in immunomodulation (regulation of the immune system) and the initiation of proinflammatory responses. TLR4 is used in the body to recognize molecular patterns of pathogens or damaged cells from outside. However, in recent years, it has also become clear that TLR4 can affect the immune system and the function of stem cells, especially mesenchymal stem cells. Therefore, understanding how TLR4 signaling works at the cellular and molecular level and using this knowledge in regenerative medicine could be potentially useful, especially in the treatment of adipose- derived mesenchymal stem cells (ADMSCs). How these cells can use TLR4 signaling when used to increase their regenerative potential and repair tissues is an area of research.

Aims: This study aims to elucidate the multifaceted role of TLR4-mediated signaling in ADMSCs.

Methods: Employing a comprehensive set of assays, including MTT for cell viability, flow cytometry for surface marker expression, and gene expression analysis, we demonstrate that TLR4 activation significantly modulates key aspects of ADMSC biology. Specifically, TLR4 signaling was found to regulate ADMSCs proliferation, surface marker expression, and regenerative capacity in a dose- and time-dependent manner. Furthermore, TLR4 activation conferred cytoprotective effects against Doxorubicin (DOX)-induced cellular apoptosis.

Results: These findings suggest that TLR4 signaling could be used to enhance the regenerative abilities of ADMSCs and enable ADMSC-based therapies to be used more effectively for tissue engineering and therapeutic purposes.

Conclusion: However, it is important to note that research in this area needs more details and clinical studies.

Keywords: Toll-like receptor 4 (TLR4), mesenchymal stem cell, tissue regeneration, LPS, stemness, endocrine diseases.

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[1]
Pountos, I.; Giannoudis, P.V. Biology of mesenchymal stem cells. Injury, 2005, 36(3), S8-S12.
[http://dx.doi.org/10.1016/j.injury.2005.07.028] [PMID: 16188553]
[2]
Berebichez-Fridman, R.; Montero-Olvera, P.R. Sources and clinical applications of mesenchymal stem cells. Sultan Qaboos Univ. Med. J., 2018, 18(3), 264.
[http://dx.doi.org/10.18295/squmj.2018.18.03.002] [PMID: 30607265]
[3]
Ding, D.C.; Shyu, W.C.; Lin, S.Z. Mesenchymal stem cells. Cell Transplant., 2011, 20(1), 5-14.
[http://dx.doi.org/10.3727/096368910X] [PMID: 21396235]
[4]
Lin, F. Adipose tissue-derived mesenchymal stem cells: A fat chance of curing kidney disease. Kidney Int, 2012, 82, 731-733.
[http://dx.doi.org/10.1038/ki.2012.158]
[5]
Strioga, M.; Viswanathan, S.; Darinskas, A.; Slaby, O.; Michalek, J. Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem Cells Dev., 2012, 21(14), 2724-2752.
[http://dx.doi.org/10.1089/scd.2011.0722] [PMID: 22468918]
[6]
Squillaro, T.; Peluso, G.; Galderisi, U. Clinical trials with mesenchymal stem cells: An update. Cell Transplant., 2016, 25(5), 829-848.
[http://dx.doi.org/10.3727/096368915X689622] [PMID: 26423725]
[7]
Parekkadan, B.; Milwid, J.M. Mesenchymal stem cells as therapeutics. Annu. Rev. Biomed. Eng., 2010, 12(1), 87-117.
[http://dx.doi.org/10.1146/annurev-bioeng-070909-105309] [PMID: 20415588]
[8]
Lee, B.C.; Kang, K.S. Functional enhancement strategies for immunomodulation of mesenchymal stem cells and their therapeutic application. Stem Cell Res. Ther., 2020, 11(1), 397.
[http://dx.doi.org/10.1186/s13287-020-01920-3] [PMID: 32928306]
[9]
Yuk, J.M.; Jo, E.K. Toll-like receptors and innate immunity. J. Bacteriol. Virol., 2011, 41(4), 225-235.
[http://dx.doi.org/10.4167/jbv.2011.41.4.225]
[10]
Frederiksen, H.R.; Haukedal, H.; Freude, K.; Muthuraju, S. Cell type specific expression of toll-like receptors in human brains and implications in Alzheimer’s disease. BioMed Res. Int., 2019, 2019, 1-18.
[http://dx.doi.org/10.1155/2019/7420189] [PMID: 31396533]
[11]
Kawasaki, T.; Kawai, T. Toll-like receptor signaling pathways. Front. Immunol., 2014, 5, 461.
[http://dx.doi.org/10.3389/FIMMU.2014.00461/BIBTEX] [PMID: 25309543]
[12]
Waterman, R.S.; Tomchuck, S.L.; Henkle, S.L.; Betancourt, A.M. A new mesenchymal stem cell (MSC) paradigm: Polarization into a pro-inflammatory MSC1 or an Immunosuppressive MSC2 phenotype. PLoS One, 2010, 5(4), e10088.
[http://dx.doi.org/10.1371/journal.pone.0010088] [PMID: 20436665]
[13]
Qu, G.; Xie, X.; Li, X.; Chen, Y.; Isla, N.D.; Huselstein, C.; Stoltz, J-F.; Li, Y. Immunomodulatory function of mesenchymal stem cells: regulation and application. J. Cell. Immunother., 2018, 4(1), 1-3.
[http://dx.doi.org/10.1016/j.jocit.2018.09.001]
[14]
He, X.; Wang, H.; Jin, T.; Xu, Y.; Mei, L.; Yang, J. TLR4 activation promotes bone marrow MSC proliferation and osteogenic differentiation via Wnt3a and Wnt5a signaling. PLoS One, 2016, 11(3), e0149876.
[http://dx.doi.org/10.1371/journal.pone.0149876]
[15]
Yao, Y.; Zhang, F.; Wang, L.; Zhang, G.; Wang, Z.; Chen, J.; Gao, X. Lipopolysaccharide preconditioning enhances the efficacy of mesenchymal stem cells transplantation in a rat model of acute myocardial infarction. J. Biomed. Sci., 2009, 16(1), 74.
[http://dx.doi.org/10.1186/1423-0127-16-74] [PMID: 19691857]
[16]
Bunnell, B.; Flaat, M.; Gagliardi, C.; Patel, B.; Ripoll, C. Adipose-derived stem cells: Isolation, expansion and differentiation. Methods, 2008, 45(2), 115-120.
[http://dx.doi.org/10.1016/j.ymeth.2008.03.006] [PMID: 18593609]
[17]
Kouokam, J.C.; Huskens, D.; Schols, D.; Johannemann, A.; Riedell, S.K.; Walter, W.; Walker, J.M.; Matoba, N.; O’Keefe, B.R.; Palmer, K.E. Investigation of griffithsin’s interactions with human cells confirms its outstanding safety and efficacy profile as a microbicide candidate. PLoS One, 2011, 6(8), e22635.
[http://dx.doi.org/10.1371/journal.pone.0022635] [PMID: 21829638]
[18]
Li, N.; Du, H.; Mao, L.; Xu, G.; Zhang, M.; Fan, Y.; Dong, X.; Zheng, L.; Wang, B.; Qin, X.; Jiang, X.; Chen, C.; Zou, Z.; Zhang, J. Reciprocal regulation of NRF2 by autophagy and ubiquitin–proteasome modulates vascular endothelial injury induced by copper oxide nanoparticles. J. Nanobiotechnology, 2022, 20(1), 270.
[http://dx.doi.org/10.1186/s12951-022-01486-7] [PMID: 35690781]
[19]
Bourin, P.; Bunnell, B.A.; Casteilla, L.; Dominici, M.; Katz, A.J.; March, K.L.; Redl, H.; Rubin, J.P.; Yoshimura, K.; Gimble, J.M. Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: A joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy, 2013, 15(6), 641-648.
[http://dx.doi.org/10.1016/j.jcyt.2013.02.006] [PMID: 23570660]
[20]
Sautter, N.B.; Delaney, K.L.; Hausman, F.A.; Trune, D.R. Tissue remodeling gene expression in a murine model of chronic rhinosinusitis. Laryngoscope, 2012, 122(4), 711-717.
[http://dx.doi.org/10.1002/lary.22148] [PMID: 22294478]
[21]
Najar, M.; Krayem, M.; Meuleman, N.; Bron, D.; Lagneaux, L. Mesenchymal stromal cells and toll-like receptor priming: A critical review. Immune Netw., 2017, 17(2), 89-102.
[http://dx.doi.org/10.4110/in.2017.17.2.89] [PMID: 28458620]
[22]
Wu, S.; Wang, Y.; Yuan, Z.; Wang, S.; Du, H.; Liu, X.; Wang, Q.; Zhu, X. Human adipose-derived mesenchymal stem cells promote breast cancer MCF7 cell epithelial-mesenchymal transition by cross interacting with the TGF-β/Smad and PI3K/AKT signaling pathways. Mol. Med. Rep., 2019, 19(1), 177-186.
[http://dx.doi.org/10.3892/MMR.2018.9664/HTML] [PMID: 30483746]
[23]
Wang, Y.; Abarbanell, A.M.; Herrmann, J.L.; Weil, B.R.; Manukyan, M.C.; Poynter, J.A.; Meldrum, D.R. TLR4 inhibits mesenchymal stem cell (MSC) STAT3 activation and thereby exerts deleterious effects on MSC-mediated cardioprotection. PLoS One, 2010, 5(12), e14206.
[http://dx.doi.org/10.1371/journal.pone.0014206] [PMID: 21151968]
[24]
Herzmann, N.; Salamon, A.; Fiedler, T.; Peters, K. Lipopolysaccharide induces proliferation and osteogenic differentiation of adipose-derived mesenchymal stromal cells in vitro via TLR4 activation. Exp. Cell Res., 2017, 350(1), 115-122.
[http://dx.doi.org/10.1016/j.yexcr.2016.11.012] [PMID: 27865937]
[25]
Gaikwad, S.; Agrawal-Rajput, R. Lipopolysaccharide from rhodobacter sphaeroides attenuates microglia-mediated inflammation and phagocytosis and directs regulatory T cell response. Int. J. Inflamm., 2015, 2015, 1-13.
[http://dx.doi.org/10.1155/2015/361326] [PMID: 26457222]
[26]
Mei, Y.B.; Zhou, W.Q.; Zhang, X.Y.; Wei, X.J.; Feng, Z.C. Lipopolysaccharides shapes the human Wharton’s jelly-derived mesenchymal stem cells in vitro. Cell. Physiol. Biochem., 2013, 32(2), 390-401.
[http://dx.doi.org/10.1159/000354446] [PMID: 23988491]
[27]
Li, H.; Xu, H.; Liu, S. Toll-like receptors 4 induces expression of matrix metalloproteinase-9 in human aortic smooth muscle cells. Mol. Biol. Rep., 2011, 38(2), 1419-1423.
[http://dx.doi.org/10.1007/s11033-010-0246-4] [PMID: 20725790]
[28]
Lee, S.C.; Jeong, H.J.; Lee, S.K.; Kim, S.J. Lipopolysaccharide preconditioning of adipose-derived stem cells improves liver-regenerating activity of the secretome. Stem Cell Res. Ther., 2015, 6(1), 75.
[http://dx.doi.org/10.1186/s13287-015-0072-7] [PMID: 25890074]
[29]
Rusanov, A.L.; Biryukova, Y.K.; Shonina, O.O.; Luzgina, E.D.; Luzgina, N.G. TLR4 activation of mesenchymal stem cells enhances the regenerative properties of their secretome. Cell Technol. Biol. Med., 2020, (4), 255-261.
[http://dx.doi.org/10.47056/1814-3490-2020-4-255-261] [PMID: 33725255]
[30]
Baxter-Holland, M.; Dass, C.R. Doxorubicin, mesenchymal stem cell toxicity and antitumour activity: implications for clinical use. J. Pharm. Pharmacol., 2018, 70, 320-327.
[http://dx.doi.org/10.1111/jphp.12869]
[31]
Yang, X.; Chen, G.; Wang, Y.; Xian, S.; Zhang, L.; Zhu, S.; Pan, F.; Cheng, Y. TLR4 promotes the expression of HIF-1α by triggering reactive oxygen species in cervical cancer cells in�vitro-implications for therapeutic intervention. Mol. Med. Rep., 2017, 17(2), 2229-2238.
[http://dx.doi.org/10.3892/mmr.2017.8108] [PMID: 29207048]
[32]
Franken, N.A.P.; Rodermond, H.M.; Stap, J.; Haveman, J.; van Bree, C. Clonogenic assay of cells in vitro. Nat Protoc, 2006, 1(5), 2315-2319.
[http://dx.doi.org/10.1038/nprot.2006.339]
[33]
Moraes, D.A.; Sibov, T.T.; Pavon, L.F.; Alvim, P.Q.; Bonadio, R.S.; Da Silva, J.R.; Pic-Taylor, A.; Toledo, O.A.; Marti, L.C.; Azevedo, R.B.; Oliveira, D.M. 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]
[34]
Pham, L.H.; Vu, N.B.; Van Pham, P.; Van Pham, P. The subpopulation of CD105 negative mesenchymal stem cells show strong immunomodulation capacity compared to CD105 positive mesenchymal stem cells. Biomed. Res. Ther., 2019, 6(4), 3131-3140.
[http://dx.doi.org/10.15419/bmrat.v6i4.538]
[35]
Ode, A.; Kopf, J.; Kurtz, A.; Schmidt-Bleek, K.; Schrade, P.; Kolar, P.; Buttgerei, F.; Lehmann, K.; Hutmacher, D.W.; Duda, G.N.; Kasper, G. CD73 and CD29 concurrently mediate the mechanically induced decrease of migratory capacity of mesenchymal stromal cells. Eur. Cell. Mater., 2011, 22, 26-42.
[http://dx.doi.org/10.22203/eCM.v022a03] [PMID: 21732280]

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