Tumorigenic Aspects of MSC Senescence—Implication in Cancer Development and Therapy
Abstract
:1. Introduction
2. Inflammaging and Tumor Development
3. Immunomodulatory Functions of MSCs and Their Role in Tumorigenesis
4. MSC Senescence
5. Role of MSC SASP in Forming Tumor Microenvironment
6. Therapeutic Implications of MSC Senescence Targeting
Th Agent/Approach | MSC Type | Rejuvenating Effect | Reference |
---|---|---|---|
Senolytics | |||
Quercetin | rat BM-MSCs | Elimination of senescent cells in vitro; ↑ proliferation, ↑ osteogenesis, ↓ adipogenesis; no change in migration | [104] |
Quercetin + dasatinib | mouse BM-MSC | ↓ Number of senescent cells; ↑ proliferation, improving the osteogenic capacity of old BM-MSC in vitro and in vivo | [105] |
Dasatinib | human AT- MSC | ↓ Senescence in MSCs of patients with preeclampsia; improved MSC angiogenic potential | [106] |
Navitoclax (ABT-263) | mouse BM-MSC | ↓ Senescence cell burden, ↓ in vitro and in vivo osteogenic potential of MSCs | [107] |
human BM-MSCs | Mild ↓ proportion of senescent cells; no effect on telomere length or epigenetic senescence signature | [108] | |
Genetic manipulation | |||
NDNF overexpression | human BM-MSCs | ↓ Cell senescence and apoptosis ↑ proliferation and angiogenesis in old cells; improved cardiac function in mice after myocardial infarction | [109] |
human AT-MSCs | Improving proliferation and migration capacity; preserved cardiac function and reduced scar formation in vivo | [110] | |
Apelin overexpression | human AT-MSCs | ↑ Autophagy; enhanced paracrine effects; promoted cardioprotection following myocardial infarction in mice | [111] |
MIF overexpression | human BM-MSCs | Inhibiting cellular senescence of aged cells; activating autophagy improving their survival under serum deprivation/hypoxia in vitro; enhanced cardioprotection after myocardial infarction | [112] |
Silencing of miR-195 | mouse BM-MSCs | Reduced number of senescent cells in vitro, induced telomere re-lengthening, restored proliferation and expression of anti-aging factors Tert and Sirt1; reduced infarction size and improved left ventricular function | [113] |
Inhibition of miR-199a-5p | IPF-MSCs | Promoted autophagy and ameliorated senescence; transplantation of anti-miR-199a-5p-IPF-MSCs increased their capacity to prevent induced lung fibrosis progression in mice | [114] |
Inhibition of mir-188 | human and mouse BM-MSCs | Reduced age-associated processes, injection of antagomiR-188 into bone marrow stimulated bone formation and decreased bone marrow fat in aged mice | [115] |
Downregulating of lnc-CYP7A1-1 | human BM-MSCs | ↓ Cell senescence, ↑ proliferation, ↑ migration, ↑ survival; in vivo improved cardiac function in mice after MI | [116] |
Silencing lncRNA-p21 | mouse BM-MSCs | Enhanced cell growth and paracrine function, ↓ oxidative stress | [117] |
5-AZA | human AT-MSCs | ↑ Proliferation ↓ ROS accumulation, ↓ DNA methylation status ↑ BCL-2/BAX ratio | [118] |
human AT-MSCs | Improving proliferation and osteogenic differentiation potential; Induced Expression of TET2 and TET3, ↑ Nuclear 5 hmC Levels | [119] | |
Tetramethylpyrazine | mouse BM-MSCs | Inhibited senescence via histone-lysine N-methyltransferase enzyme EZH2; creating an anti-inflammatory and angiogenic environment in the bone marrow of aging mice | [120] |
Cytokine treatment | |||
MIF | rat BM-MSCs | Pretreatment enhanced growth, paracrine function and survival.; inhibited hypoxia/serum deprivation-induced apoptosis | [121] |
rat BM-MSCs | Pretreatment improved the proliferation rate, viability, paracrine function, telomere length, and telomerase activity of DOXO-treated MSCs; ↓ oxidative stress, ↑ activity of SOD. | [122] | |
Extracellular vesicles (EVs) | |||
Infant AT-MSC-derived EVs | human AT-MSCs | Promoting proliferation, ↓ number of β-gal-positive cells, inhibiting the elevation of ROS by upregulating the expression of SOD1 and SOD3; induced the ability of elderly MSCs to decrease necrotic area in type 1 and type 2 diabetic mice | [123] |
iPSC-derived EVs | human BM-MSCs | Reduced oxidative stress | [124] |
UC-MSCs-derived EVs | human BM-MSCs | Enhanced proliferation, mobility, and paracrine activity; better cardiac function, more neovascularization, and less scar formation after transplantation into infarct heart | [125] |
Mouse ESC-derived EVs | human PLAC-MSC | Enhanced proliferation and stemness; ↓ SA-β-gal activity; ↓ DNA damage foci, ↓ p16 and p53 mRNA expression; enhanced the retention of MSCs in the mouse cutaneous wound sites and facilitated the cutaneous wound healing process | [126] |
7. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Ferreira, J.R.; Teixeira, G.Q.; Santos, S.G.; Barbosa, M.A.; Almeida-Porada, G.; Gonçalves, R.M. Mesenchymal Stromal Cell Secretome: Influencing Therapeutic Potential by Cellular Pre-conditioning. Front. Immunol. 2018, 9, 2837. [Google Scholar] [CrossRef] [PubMed]
- Rustad, K.C.; Gurtner, G.C. Mesenchymal Stem Cells Home to Sites of Injury and Inflammation. Adv. Wound Care 2012, 1, 147–152. [Google Scholar] [CrossRef] [Green Version]
- Merimi, M.; El-Majzoub, R.; Lagneaux, L.; Agha, D.M.; Bouhtit, F.; Meuleman, N.; Fahmi, H.; Lewalle, P.; Fayyad-Kazan, M.; Najar, M. The Therapeutic Potential of Mesenchymal Stromal Cells for Regenerative Medicine: Current Knowledge and Future Understandings. Front. Cell Dev. Biol. 2021, 9, 661532. [Google Scholar] [CrossRef]
- Neri, S.; Borzì, R.M. Molecular Mechanisms Contributing to Mesenchymal Stromal Cell Aging. Biomolecules 2020, 10, 340. [Google Scholar] [CrossRef] [Green Version]
- Rodier, F.; Campisi, J. Four faces of cellular senescence. J. Cell Biol. 2011, 192, 547–556. [Google Scholar] [CrossRef] [PubMed]
- Menendez, J.A.; Alarcón, T. Senescence-Inflammatory Regulation of Reparative Cellular Reprogramming in Aging and Cancer. Front. Cell Dev. Biol. 2017, 5, 1–14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Coppé, J.-P.; Desprez, P.-Y.; Krtolica, A.; Campisi, J. The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression. Annu. Rev. Pathol. Mech. Dis. 2010, 5, 99–118. [Google Scholar] [CrossRef] [Green Version]
- Franceschi, C.; Campisi, J. Chronic Inflammation (Inflammaging) and Its Potential Contribution to Age-Associated Diseases. J. Gerontol. Ser. A Boil. Sci. Med Sci. 2014, 69, S4–S9. [Google Scholar] [CrossRef] [PubMed]
- Salminen, A. Immunosuppressive network promotes immunosenescence associated with aging and chronic inflammatory conditions. J. Mol. Med. 2021, 99, 1553–1569. [Google Scholar] [CrossRef]
- Zheng, P.; Li, W. Crosstalk Between Mesenchymal Stromal Cells and Tumor-Associated Macrophages in Gastric Cancer. Front. Oncol. 2020, 10, 571516. [Google Scholar] [CrossRef]
- Chan, T.-S.; Shaked, Y.; Tsai, K.K. Targeting the Interplay Between Cancer Fibroblasts, Mesenchymal Stem Cells, and Cancer Stem Cells in Desmoplastic Cancers. Front. Oncol. 2019, 9, 688. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lee, B.-C.; Yu, K.R. Impact of Mesenchymal Stem Cell Senescence on Inflammaging. BMB Rep. 2020, 53, 65–73. [Google Scholar] [CrossRef] [Green Version]
- Medzhitov, R. Origin and physiological roles of inflammation. Nature 2008, 454, 428–435. [Google Scholar] [CrossRef] [PubMed]
- Aran, D.; Lasry, A.; Zinger, A.; Biton, M.; Pikarsky, E.; Hellman, A.; Butte, A.J.; Ben-Neriah, Y. Widespread parainflammation in human cancer. Genome Biol. 2016, 17, 1–14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Freire, M.O.; Van Dyke, T.E. Natural resolution of inflammation. Periodontol. 2000 2013, 63, 149–164. [Google Scholar] [CrossRef] [Green Version]
- Qu, X.; Tang, Y.; Hua, S. Immunological Approaches Towards Cancer and Inflammation: A Cross Talk. Front. Immunol. 2018, 9, 563. [Google Scholar] [CrossRef] [Green Version]
- Franceschi, C.; Capri, M.; Monti, D.; Giunta, S.; Olivieri, F.; Sevini, F.; Panourgia, M.P.; Invidia, L.; Celani, L.; Scurti, M.; et al. Inflammaging and anti-inflammaging: A systemic perspective on aging and longevity emerged from studies in humans. Mech. Ageing Dev. 2007, 128, 92–105. [Google Scholar] [CrossRef] [PubMed]
- Franceschi, C.; Bonafè, M.; Valensin, S.; Olivieri, F.; De Luca, M.; Ottaviani, E.; De Benedictis, G. Inflamm-aging: An Evolutionary Perspective on Immunosenescence. Ann. N. Y. Acad. Sci. 2000, 908, 244–254. [Google Scholar] [CrossRef] [PubMed]
- Vasto, S.; Candore, G.; Balistreri, C.R.; Caruso, M.; Colonna-Romano, G.; Grimaldi, M.P.; Listi, F.; Nuzzo, D.; Lio, D.; Caruso, C. Inflammatory networks in ageing, age-related diseases and longevity. Mech. Ageing Dev. 2007, 128, 83–91. [Google Scholar] [CrossRef] [PubMed]
- Salminen, A.; Kaarniranta, K.; Kauppinen, A. Inflammaging: Disturbed interplay between autophagy and inflammasomes. Aging 2012, 4, 166–175. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Balkwill, F.; Mantovani, A. Inflammation and cancer: Back to Virchow? Lancet 2001, 357, 539–545. [Google Scholar] [CrossRef]
- Chimal-Ramírez, G.K.; Espinoza-Sánchez, N.A.; Fuentes-Pananá, E.M. Protumor Activities of the Immune Response: Insights in the Mechanisms of Immunological Shift, Oncotraining, and Oncopromotion. J. Oncol. 2013, 2013, 835956. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mantovani, A.; Allavena, P.; Sica, A.; Balkwill, F. Cancer-related inflammation. Nature 2008, 454, 436–444. [Google Scholar] [CrossRef] [PubMed]
- Coussens, L.M.; Werb, Z. Inflammation and cancer. Nature 2002, 420, 860–867. [Google Scholar] [CrossRef] [PubMed]
- Song, N.; Scholtemeijer, M.; Shah, K. Mesenchymal Stem Cell Immunomodulation: Mechanisms and Therapeutic Potential. Trends Pharmacol. Sci. 2020, 41, 653–664. [Google Scholar] [CrossRef] [PubMed]
- Weiss, A.R.R.; Dahlke, M.H. Immunomodulation by Mesenchymal Stem Cells (MSCs): Mechanisms of Action of Living, Apoptotic, and Dead MSCs. Front. Immunol. 2019, 10, 1191. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wu, X.; Jiang, J.; Gu, Z.; Zhang, J.; Chen, Y.; Liu, X. Mesenchymal stromal cell therapies: Immunomodulatory properties and clinical progress. Stem Cell Res. Ther. 2020, 11, 345. [Google Scholar] [CrossRef] [PubMed]
- Lee, H.J.; Ko, J.H.; Kim, H.J.; Jeong, H.J.; Oh, J.Y. Mesenchymal stromal cells induce distinct myeloid-derived suppressor cells in inflammation. JCI Insight 2020, 5, e136059. [Google Scholar] [CrossRef]
- Chen, H.-W.; Chen, M.-Y.; Wang, L.-T.; Wang, F.-H.; Fang, L.-W.; Lai, H.-Y.; Chen, H.-H.; Lu, J.; Hung, M.-S.; Cheng, Y.; et al. Mesenchymal Stem Cells Tune the Development of Monocyte-Derived Dendritic Cells Toward a Myeloid-Derived Suppressive Phenotype through Growth-Regulated Oncogene Chemokines. J. Immunol. 2013, 190, 5065–5077. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fan, X.-L.; Zhang, Y.; Li, X.; Fu, Q.-L. Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy. Cell. Mol. Life Sci. 2020, 77, 2771–2794. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- English, K. Mechanisms of mesenchymal stromal cell immunomodulation. Immunol. Cell Biol. 2013, 91, 19–26. [Google Scholar] [CrossRef] [Green Version]
- Matheakakis, A.; Batsali, A.; Papadaki, H.A.; Pontikoglou, C.G. Therapeutic Implications of Mesenchymal Stromal Cells and Their Extracellular Vesicles in Autoimmune Diseases: From Biology to Clinical Applications. Int. J. Mol. Sci. 2021, 22, 10132. [Google Scholar] [CrossRef] [PubMed]
- Harrell, C.R.; Fellabaum, C.; Jovicic, N.; Djonov, V.; Arsenijevic, N.; Volarevic, V. Molecular Mechanisms Responsible for Therapeutic Potential of Mesenchymal Stem Cell-Derived Secretome. Cells 2019, 8, 467. [Google Scholar] [CrossRef] [Green Version]
- Krampera, M. Mesenchymal stromal cell ‘licensing’: A multistep process. Leukemia 2011, 25, 1408–1414. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- 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, e10088. [Google Scholar] [CrossRef] [PubMed]
- Romieu-Mourez, R.; Francois, M.; Boivin, M.-N.; Bouchentouf, M.; Spaner, D.E.; Galipeau, J. Cytokine Modulation of TLR Expression and Activation in Mesenchymal Stromal Cells Leads to a Proinflammatory Phenotype. J. Immunol. 2009, 182, 7963–7973. [Google Scholar] [CrossRef] [PubMed]
- Renner, P.; Eggenhofer, E.; Rosenauer, A.; Popp, F.C.; Steinmann, J.F.; Slowik, P.; Geissler, E.K.; Piso, P.; Schlitt, H.J.; Dahlke, M.H. Mesenchymal Stem Cells Require a Sufficient, Ongoing Immune Response to Exert Their Immunosuppressive Function. Transplant. Proc. 2009, 41, 2607–2611. [Google Scholar] [CrossRef]
- Zhang, Y.; Ravikumar, M.; Ling, L.; Nurcombe, V.; Cool, S.M. Age-Related Changes in the Inflammatory Status of Human Mesenchymal Stem Cells: Implications for Cell Therapy. Stem Cell Rep. 2021, 16, 694–707. [Google Scholar] [CrossRef] [PubMed]
- Nwabo Kamdje, A.H.; Kamga, P.T.; Simo, R.T.; Vecchio, L.; Seke Etet, P.F.; Muller, J.M.; Bassi, G.; Lukong, E.; Goel, R.K.; Amvene, J.M.; et al. Mesenchymal stromal cells’ role in tumor microenvironment: Involvement of signaling pathways. Cancer Biol. Med. 2017, 14, 129–141. [Google Scholar] [CrossRef] [PubMed]
- Waterman, R.S.; Henkle, S.L.; Betancourt, A.M. Mesenchymal Stem Cell 1 (MSC1)-Based Therapy Attenuates Tumor Growth Whereas MSC2-Treatment Promotes Tumor Growth and Metastasis. PLoS ONE 2012, 7, e45590. [Google Scholar] [CrossRef] [Green Version]
- Liang, W.; Chen, X.; Zhang, S.; Fang, J.; Chen, M.; Xu, Y.; Chen, X. Mesenchymal stem cells as a double-edged sword in tumor growth: Focusing on MSC-derived cytokines. Cell. Mol. Biol. Lett. 2021, 26, 3. [Google Scholar] [CrossRef]
- Dörnen, J.; Myklebost, O.; Dittmar, T. Cell Fusion of Mesenchymal Stem/Stromal Cells and Breast Cancer Cells Leads to the Formation of Hybrid Cells Exhibiting Diverse and Individual (Stem Cell) Characteristics. Int. J. Mol. Sci. 2020, 21, 9636. [Google Scholar] [CrossRef]
- Hass, R.; Von Der Ohe, J.; Ungefroren, H. Potential Role of MSC/Cancer Cell Fusion and EMT for Breast Cancer Stem Cell Formation. Cancers 2019, 11, 1432. [Google Scholar] [CrossRef] [Green Version]
- Banimohamad-Shotorbani, B.; Kahroba, H.; Sadeghzadeh, H.; Wilson, D.M.; Maadi, H.; Samadi, N.; Hejazi, M.S.; Farajpour, H.; Onari, B.N.; Sadeghi, M.R. DNA damage repair response in mesenchymal stromal cells: From cellular senescence and aging to apoptosis and differentiation ability. Ageing Res. Rev. 2020, 62, 101125. [Google Scholar] [CrossRef] [PubMed]
- Turinetto, V.; Vitale, E.; Giachino, C. Senescence in Human Mesenchymal Stem Cells: Functional Changes and Implications in Stem Cell-Based Therapy. Int. J. Mol. Sci. 2016, 17, 1164. [Google Scholar] [CrossRef] [PubMed]
- Prendergast, M.; Cruet-Hennequart, S.; Shaw, G.; Barry, F.P.; Carty, M.P. Activation of DNA damage response pathways in human mesenchymal stem cells exposed to cisplatin or ?-irradiation. Cell Cycle 2011, 10, 3768–3777. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Münz, F.; Lopez Perez, R.; Trinh, T.; Sisombath, S.; Weber, K.-J.; Wuchter, P.; Debus, J.; Saffrich, R.; Huber, P.E.; Nicolay, N.H. Human mesenchymal stem cells lose their functional properties after paclitaxel treatment. Sci. Rep. 2018, 8, 312. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kuilman, T.; Michaloglou, C.; Vredeveld, L.C.W.; Douma, S.; van Doorn, R.; Desmet, C.J.; Aarden, L.A.; Mooi, W.J.; Peeper, D.S. Oncogene-Induced Senescence Relayed by an Interleukin-Dependent Inflammatory Network. Cell 2008, 133, 1019–1031. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wagner, W.; Bork, S.; Horn, P.; Krunic, D.; Walenda, T.; Diehlmann, A.; Benes, V.; Blake, J.; Huber, F.-X.; Eckstein, V.; et al. Aging and Replicative Senescence Have Related Effects on Human Stem and Progenitor Cells. PLoS ONE 2009, 4, e5846. [Google Scholar] [CrossRef]
- Peffers, M.J.; Collins, J.; Fang, Y.; Goljanek-Whysall, K.; Rushton, M.; Loughlin, J.; Proctor, C.; Clegg, P. Age-related changes in mesenchymal stem cells identified using a multi-omics approach. Eur. Cells Mater. 2016, 31, 136–159. [Google Scholar] [CrossRef] [PubMed]
- Sepúlveda, J.C.; Tomé, M.; Fernández, M.E.; Delgado, M.; Campisi, J.; Bernad, A.; González, M.A. Cell Senescence Abrogates the Therapeutic Potential of Human Mesenchymal Stem Cells in the Lethal Endotoxemia Model. Stem Cells 2014, 32, 1865–1877. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tchkonia, T.; Zhu, Y.; Van Deursen, J.; Campisi, J.; Kirkland, J.L. Cellular senescence and the senescent secretory phenotype: Therapeutic opportunities. J. Clin. Investig. 2013, 123, 966–972. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lepperdinger, G. Inflammation and mesenchymal stem cell aging. Curr. Opin. Immunol. 2011, 23, 518–524. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lin, H.; Shen, H.; Tuan, R.S. Chapter 71—Aging of human mesenchymal stem cells. In Conn’s Handbook of Models for Human Aging, 2nd ed.; Ram, J.L., Conn, P.M., Eds.; Academic Press: Cambridge, MA, USA, 2018; pp. 975–994. [Google Scholar] [CrossRef]
- Choudhery, M.S.; Khan, M.; Mahmood, R.; Mehmood, A.; Khan, S.N.; Riazuddin, S. Bone marrow derived mesenchymal stem cells from aged mice have reduced wound healing, angiogenesis, proliferation and anti-apoptosis capabilities. Cell Biol. Int. 2012, 36, 747–753. [Google Scholar] [CrossRef]
- Kapetanos, K.; Asimakopoulos, D.; Christodoulou, N.; Vogt, A.; Khan, W. Chronological Age Affects MSC Senescence In Vitro—A Systematic Review. Int. J. Mol. Sci. 2021, 22, 7945. [Google Scholar] [CrossRef]
- Shang, J.; Yao, Y.; Fan, X.; Shangguan, L.; Li, J.; Liu, H.; Zhou, Y. miR-29c-3p promotes senescence of human mesenchymal stem cells by targeting CNOT6 through p53–p21 and p16–pRB pathways. Biochim. Biophys. Acta Mol. Cell Res. 2016, 1863, 520–532. [Google Scholar] [CrossRef]
- Minieri, V.; Saviozzi, S.; Gambarotta, G.; Lo Iacono, M.; Accomasso, L.; Cibrario Rocchietti, E.; Gallina, C.; Turinetto, V.; Giachino, C. Persistent DNA damage-induced premature senescence alters the functional features of human bone marrow mesenchymal stem cells. J. Cell. Mol. Med. 2015, 19, 734–743. [Google Scholar] [CrossRef] [Green Version]
- Wagner, W.; Ho, A.D.; Zenke, M. Different Facets of Aging in Human Mesenchymal Stem Cells. Tissue Eng. Part B Rev. 2010, 16, 445–453. [Google Scholar] [CrossRef]
- Ghosh, D.; Mejia-Pena, C.; Quach, N.; Xuan, B.; Lee, A.H.; Dawson, M.R. Senescent mesenchymal stem cells remodel extracellular matrix driving breast cancer cells to more invasive phenotype. J. Cell Sci. 2020, 133, jcs232470. [Google Scholar] [CrossRef]
- Singh, L.; Brennan, T.A.; Russell, E.; Kim, J.-H.; Chen, Q.; Brad Johnson, F.; Pignolo, R.J. Aging alters bone-fat reciprocity by shifting in vivo mesenchymal precursor cell fate towards an adipogenic lineage. Bone 2016, 85, 29–36. [Google Scholar] [CrossRef] [Green Version]
- Kim, M.; Kim, C.; Choi, Y.S.; Kim, M.; Park, C.; Suh, Y. Age-related alterations in mesenchymal stem cells related to shift in differentiation from osteogenic to adipogenic potential: Implication to age-associated bone diseases and defects. Mech. Ageing Dev. 2012, 133, 215–225. [Google Scholar] [CrossRef] [PubMed]
- Geissler, S.; Textor, M.; Kühnisch, J.; Könnig, D.; Klein, O.; Ode, A.; Pfitzner, T.; Adjaye, J.; Kasper, G.; Duda, G.N. Functional Comparison of Chronological and In Vitro Aging: Differential Role of the Cytoskeleton and Mitochondria in Mesenchymal Stromal Cells. PLoS ONE 2012, 7, e52700. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Khanh, V.C.; Zulkifli, A.F.; Tokunaga, C.; Yamashita, T.; Hiramatsu, Y.; Ohneda, O. Aging impairs beige adipocyte differentiation of mesenchymal stem cells via the reduced expression of Sirtuin 1. Biochem. Biophys. Res. Commun. 2018, 500, 682–690. [Google Scholar] [CrossRef] [PubMed]
- Zoico, E.; Rubele, S.; De Caro, A.; Nori, N.; Mazzali, G.; Fantin, F.; Rossi, A.; Zamboni, M. Brown and Beige Adipose Tissue and Aging. Front. Endocrinol. 2019, 10, 368. [Google Scholar] [CrossRef] [Green Version]
- Starr, M.E.; Evers, B.M.; Saito, H. Age-Associated Increase in Cytokine Production During Systemic Inflammation: Adipose Tissue as a Major Source of IL-6. J. Gerontol. Ser. A Boil. Sci. Med Sci. 2009, 64, 723–730. [Google Scholar] [CrossRef]
- Lago, F.; Diéguez, C.; Gómez-Reino, J.; Gualillo, O. Adipokines as emerging mediators of immune response and inflammation. Nat. Clin. Pract. Rheumatol. 2007, 3, 716–724. [Google Scholar] [CrossRef] [PubMed]
- Li, X.-Y.; Ding, J.; Zheng, Z.-H.; Li, X.-Y.; Wu, Z.-B.; Zhu, P. Long-term culture in vitro impairs the immunosuppressive activity of mesenchymal stem cells on T cells. Mol. Med. Rep. 2012, 6, 1183–1189. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- De Witte, S.F.H.; Lambert, E.E.; Merino, A.; Strini, T.; Douben, H.J.; O’Flynn, L.; Elliman, S.J.; de Klein, A.J.; Newsome, P.N.; Baan, C.; et al. Aging of bone marrow– and umbilical cord–derived mesenchymal stromal cells during expansion. Cytotherapy 2017, 19, 798–807. [Google Scholar] [CrossRef]
- Yu, K.-R.; Lee, J.Y.; Kim, H.-S.; Hong, I.-S.; Choi, S.W.; Seo, Y.; Kang, I.; Kim, J.-J.; Lee, B.-C.; Lee, S.; et al. A p38 MAPK-Mediated Alteration of COX-2/PGE2 Regulates Immunomodulatory Properties in Human Mesenchymal Stem Cell Aging. PLoS ONE 2014, 9, e102426. [Google Scholar] [CrossRef]
- Wu, L.W.; Wang, Y.-L.; Christensen, J.M.; Khalifian, S.; Schneeberger, S.; Raimondi, G.; Cooney, D.S.; Lee, W.A.; Brandacher, G. Donor age negatively affects the immunoregulatory properties of both adipose and bone marrow derived mesenchymal stem cells. Transpl. Immunol. 2014, 30, 122–127. [Google Scholar] [CrossRef] [PubMed]
- Li, X.; Zhang, B.; Wang, H.; Zhao, X.; Zhang, Z.; Ding, G.; Wei, F. The effect of aging on the biological and immunological characteristics of periodontal ligament stem cells. Stem Cell Res. Ther. 2020, 11, 326. [Google Scholar] [CrossRef] [PubMed]
- Oishi, Y.; Manabe, I. Macrophages in age-related chronic inflammatory diseases. npj Aging Mech. Dis. 2016, 2, 16018. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yin, Y.; Wu, R.-X.; He, X.-T.; Xu, X.-Y.; Wang, J.; Chen, F.-M. Influences of age-related changes in mesenchymal stem cells on macrophages during in-vitro culture. Stem Cell Res. Ther. 2017, 8, 153. [Google Scholar] [CrossRef] [Green Version]
- Ruhland, M.K.; Loza, A.J.; Capietto, A.-H.; Luo, X.; Knolhoff, B.L.; Flanagan, K.C.; Belt, B.A.; Alspach, E.; Leahy, K.; Luo, J.; et al. Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nat. Commun. 2016, 7, 11762. [Google Scholar] [CrossRef] [PubMed]
- Lee, H.-J.; Lee, W.-J.; Hwang, S.-C.; Choe, Y.; Kim, S.; Bok, E.; Lee, S.; Kim, S.-J.; Kim, H.-O.; Ock, S.-A.; et al. Chronic inflammation-induced senescence impairs immunomodulatory properties of synovial fluid mesenchymal stem cells in rheumatoid arthritis. Stem Cell Res. Ther. 2021, 12, 502. [Google Scholar] [CrossRef]
- Valletta, S.; Thomas, A.; Meng, Y.; Ren, X.; Drissen, R.; Sengül, H.; Di Genua, C.; Nerlov, C. Micro-environmental sensing by bone marrow stroma identifies IL-6 and TGFβ1 as regulators of hematopoietic ageing. Nat. Commun. 2020, 11, 4075. [Google Scholar] [CrossRef] [PubMed]
- O’Hagan-Wong, K.; Nadeau, S.; Carrier-Leclerc, A.; Apablaza, F.; Hamdy, R.; Shum-Tim, D.; Rodier, F.; Colmegna, I. Increased IL-6 secretion by aged human mesenchymal stromal cells disrupts hematopoietic stem and progenitor cells’ homeostasis. Oncotarget 2016, 7, 13285–13296. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gnani, D.; Crippa, S.; della Volpe, L.; Rossella, V.; Conti, A.; Lettera, E.; Rivis, S.; Ometti, M.; Fraschini, G.; Bernardo, M.E.; et al. An early-senescence state in aged mesenchymal stromal cells contributes to hematopoietic stem and progenitor cell clonogenic impairment through the activation of a pro-inflammatory program. Aging Cell 2019, 18, e12933. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Massaro, F.; Corrillon, F.; Stamatopoulos, B.; Meuleman, N.; Lagneaux, L.; Bron, D. Aging of Bone Marrow Mesenchymal Stromal Cells: Hematopoiesis Disturbances and Potential Role in the Development of Hematologic Cancers. Cancers 2020, 13, 68. [Google Scholar] [CrossRef] [PubMed]
- Mattiucci, D.; Maurizi, G.; Leoni, P.; Poloni, A. Aging- and Senescence-associated Changes of Mesenchymal Stromal Cells in Myelodysplastic Syndromes. Cell Transplant. 2018, 27, 754–764. [Google Scholar] [CrossRef] [Green Version]
- Zambetti, N.A.; Ping, Z.; Chen, S.; Kenswil, K.J.G.; Mylona, M.A.; Sanders, M.A.; Hoogenboezem, R.M.; Bindels, E.M.; Adisty, M.N.; Van Strien, P.M.; et al. Mesenchymal Inflammation Drives Genotoxic Stress in Hematopoietic Stem Cells and Predicts Disease Evolution in Human Pre-leukemia. Cell Stem Cell 2016, 19, 613–627. [Google Scholar] [CrossRef] [Green Version]
- Zhang, P.; Chen, Z.; Li, R.; Guo, Y.; Shi, H.; Bai, J.; Yang, H.; Sheng, M.; Li, Z.; Li, Z.; et al. Loss of ASXL1 in the bone marrow niche dysregulates hematopoietic stem and progenitor cell fates. Cell Discov. 2018, 4, 1–17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, R.; Zhou, Y.; Cao, Z.; Liu, L.; Wang, J.; Chen, Z.; Xing, W.; Chen, S.; Bai, J.; Yuan, W.; et al. TET2 Loss Dysregulates the Behavior of Bone Marrow Mesenchymal Stromal Cells and Accelerates Tet2-Driven Myeloid Malignancy Progression. Stem Cell Rep. 2018, 10, 166–179. [Google Scholar] [CrossRef] [Green Version]
- Naveiras, O.; Nardi, V.; Wenzel, P.L.; Hauschka, P.V.; Fahey, F.; Daley, G.Q. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 2009, 460, 259–263. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ambrosi, T.H.; Scialdone, A.; Graja, A.; Gohlke, S.; Jank, A.-M.; Bocian, C.; Woelk, L.; Fan, H.; Logan, D.W.; Schurmann, A.; et al. Adipocyte Accumulation in the Bone Marrow during Obesity and Aging Impairs Stem Cell-Based Hematopoietic and Bone Regeneration. Cell Stem Cell 2017, 20, 771–784. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Baghban, R.; Roshangar, L.; Jahanban-Esfahlan, R.; Seidi, K.; Ebrahimi-Kalan, A.; Jaymand, M.; Kolahian, S.; Javaheri, T.; Zare, P. Tumor microenvironment complexity and therapeutic implications at a glance. Cell Commun. Signal. 2020, 18, 59. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wei, R.; Liu, S.; Zhang, S.; Min, L.; Zhu, S. Cellular and Extracellular Components in Tumor Microenvironment and Their Application in Early Diagnosis of Cancers. Anal. Cell. Pathol. 2020, 2020, 6283796. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Brassart-Pasco, S.; Brézillon, S.; Brassart, B.; Ramont, L.; Oudart, J.-B.; Monboisse, J.C. Tumor Microenvironment: Extracellular Matrix Alterations Influence Tumor Progression. Front. Oncol. 2020, 10, 397. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ridge, S.M.; Sullivan, F.J.; Glynn, S.A. Mesenchymal stem cells: Key players in cancer progression. Mol. Cancer 2017, 16, 31. [Google Scholar] [CrossRef] [Green Version]
- Papait, A.; Stefani, F.R.; Cargnoni, A.; Magatti, M.; Parolini, O.; Silini, A.R. The Multifaceted Roles of MSCs in the Tumor Microenvironment: Interactions with Immune Cells and Exploitation for Therapy. Front. Cell Dev. Biol. 2020, 8, 447. [Google Scholar] [CrossRef] [PubMed]
- Di, G.-H.; Liu, Y.; Lu, Y.; Liu, J.; Wu, C.; Duan, H.-F. IL-6 Secreted from Senescent Mesenchymal Stem Cells Promotes Proliferation and Migration of Breast Cancer Cells. PLoS ONE 2014, 9, e113572. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, Y.; Xu, X.; Wang, L.; Liu, G.; Li, Y.; Wu, X.; Jing, Y.; Li, H.; Wang, G. Senescent mesenchymal stem cells promote colorectal cancer cells growth via galectin-3 expression. Cell Biosci. 2015, 5, 21. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ruvolo, P.P. Galectin 3 as a guardian of the tumor microenvironment. Biochim. Biophys. Acta 2016, 1863, 427–437. [Google Scholar] [CrossRef] [PubMed]
- Kasper, G.; Mao, L.; Geissler, S.; Draycheva, A.; Trippens, J.; Kühnisch, J.; Tschirschmann, M.; Kaspar, K.; Perka, C.; Duda, G.N.; et al. Insights into Mesenchymal Stem Cell Aging: Involvement of Antioxidant Defense and Actin Cytoskeleton. Stem Cells 2009, 27, 1288–1297. [Google Scholar] [CrossRef] [PubMed]
- Özcan, S.; Alessio, N.; Acar, M.B.; Toprak, G.; Gönen, Z.B.; Peluso, G.; Galderisi, U. Myeloma cells can corrupt senescent mesenchymal stromal cells and impair their anti-tumor activity. Oncotarget 2015, 6, 39482–39492. [Google Scholar] [CrossRef] [PubMed]
- Özcan, S.; Alessio, N.; Acar, M.B.; Mert, E.; Omerli, F.; Peluso, G.; Galderisi, U. Unbiased analysis of senescence associated secretory phenotype (SASP) to identify common components following different genotoxic stresses. Aging 2016, 8, 1316–1329. [Google Scholar] [CrossRef] [Green Version]
- Alessio, N.; Aprile, D.; Squillaro, T.; Di Bernardo, G.; Finicelli, M.; Melone, M.A.; Peluso, G.; Galderisi, U. The senescence-associated secretory phenotype (SASP) from mesenchymal stromal cells impairs growth of immortalized prostate cells but has no effect on metastatic prostatic cancer cells. Aging 2019, 11, 5817–5828. [Google Scholar] [CrossRef] [PubMed]
- Ridge, S.M.; Bhattacharyya, D.; Dervan, E.; Naicker, S.D.; Burke, A.J.; Murphy, J.M.; O’Leary, K.; Greene, J.; Ryan, A.E.; Sullivan, F.J.; et al. Secreted factors from metastatic prostate cancer cells stimulate mesenchymal stem cell transition to a pro-tumourigenic ‘activated’ state that enhances prostate cancer cell migration. Int. J. Cancer 2018, 142, 2056–2067. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- André, T.; Meuleman, N.; Stamatopoulos, B.; De Bruyn, C.; Pieters, K.; Bron, D.; Lagneaux, L. Evidences of Early Senescence in Multiple Myeloma Bone Marrow Mesenchymal Stromal Cells. PLoS ONE 2013, 8, e59756. [Google Scholar] [CrossRef] [PubMed]
- Wang, B.; Kohli, J.; Demaria, M. Senescent Cells in Cancer Therapy: Friends or Foes? Trends Cancer 2020, 6, 838–857. [Google Scholar] [CrossRef] [PubMed]
- DeMaria, M.; O’Leary, M.N.; Chang, J.; Shao, L.; Liu, S.; Alimirah, F.; Koenig, K.; Le, C.; Mitin, N.; Deal, A.M.; et al. Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. Cancer Discov. 2016, 7, 165–176. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kirkland, J.L.; Tchkonia, T. Senolytic drugs: From discovery to translation. J. Intern. Med. 2020, 288, 518–536. [Google Scholar] [CrossRef] [PubMed]
- Zhang, D.; Yu, K.; Yang, J.; Xie, S.; Yang, J.; Tan, L. Senolytic controls bone marrow mesenchymal stem cells fate improving bone formation. Am. J. Transl. Res. 2020, 12, 3078–3088. [Google Scholar] [PubMed]
- Zhou, Y.; Xin, X.; Wang, L.; Wang, B.; Chen, L.; Liu, O.; Rowe, D.W.; Xu, M. Senolytics improve bone forming potential of bone marrow mesenchymal stem cells from aged mice. npj Regen. Med. 2021, 6, 34. [Google Scholar] [CrossRef] [PubMed]
- Suvakov, S.; Cubro, H.; White, W.M.; Butler Tobah, Y.S.; Weissgerber, T.L.; Jordan, K.L.; Zhu, X.Y.; Woollard, J.R.; Chebib, F.T.; Milic, N.M.; et al. Targeting senescence improves angiogenic potential of adipose-derived mesenchymal stem cells in patients with preeclampsia. Biol. Sex Differ. 2019, 10, 1–13. [Google Scholar] [CrossRef] [PubMed]
- Sharma, A.K.; Roberts, R.L.; Benson, R.D., Jr.; Pierce, J.L.; Yu, K.; Hamrick, M.W.; McGee-Lawrence, M.E. The Senolytic Drug Navitoclax (ABT-263) Causes Trabecular Bone Loss and Impaired Osteoprogenitor Function in Aged Mice. Front. Cell Dev. Biol. 2020, 8, 354. [Google Scholar] [CrossRef]
- Grezella, C.; Fernandez-Rebollo, E.; Franzen, J.; Ventura Ferreira, M.S.; Beier, F.; Wagner, W. Effects of senolytic drugs on human mesenchymal stromal cells. Stem Cell Res. Ther. 2018, 9, 1–6. [Google Scholar] [CrossRef] [Green Version]
- Song, H.-F.; He, S.; Li, S.-H.; Yin, W.-J.; Wu, J.; Guo, J.; Shao, Z.-B.; Zhai, X.-Y.; Gong, H.; Lu, L.; et al. Aged Human Multipotent Mesenchymal Stromal Cells Can Be Rejuvenated by Neuron-Derived Neurotrophic Factor and Improve Heart Function After Injury. JACC Basic Transl. Sci. 2017, 2, 702–716. [Google Scholar] [CrossRef]
- Yang, K.; Song, H.F.; He, S.; Yin, W.J.; Fan, X.M.; Ru, F.; Gong, H.; Zhai, X.Y.; Zhang, J.; Peng, Z.X.; et al. Effect of neuron-derived neurotrophic factor on rejuvenation of human adipose-derived stem cells for cardiac repair after myocardial infarction. J. Cell. Mol. Med. 2019, 23, 5981–5993. [Google Scholar] [CrossRef] [Green Version]
- Zhang, H.; Zhao, C.; Jiang, G.; Hu, B.; Zheng, H.; Hong, Y.; Cui, Z.; Shi, L.; Li, X.; Lin, F.; et al. Apelin Rejuvenates Aged Human Mesenchymal Stem Cells by Regulating Autophagy and Improves Cardiac Protection After Infarction. Front. Cell Dev. Biol. 2021, 9, 628463. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Y.; Zhu, W.; He, H.; Fan, B.; Deng, R.; Hong, Y.; Liang, X.; Zhao, H.; Li, X.; Zhang, F. Macrophage migration inhibitory factor rejuvenates aged human mesenchymal stem cells and improves myocardial repair. Aging 2019, 11, 12641–12660. [Google Scholar] [CrossRef] [PubMed]
- Okada, M.; Kim, H.W.; Matsu-Ura, K.; Wang, Y.-G.; Xu, M.; Ashraf, M. Abrogation of Age-Induced MicroRNA-195 Rejuvenates the Senescent Mesenchymal Stem Cells by Reactivating Telomerase. Stem Cells 2015, 34, 148–159. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shi, L.; Han, Q.; Hong, Y.; Li, W.; Gong, G.; Cui, J.; Mao, M.; Liang, X.; Hu, B.; Li, X.; et al. Inhibition of miR-199a-5p rejuvenates aged mesenchymal stem cells derived from patients with idiopathic pulmonary fibrosis and improves their therapeutic efficacy in experimental pulmonary fibrosis. Stem Cell Res. Ther. 2021, 12, 147. [Google Scholar] [CrossRef] [PubMed]
- Li, C.-J.; Cheng, P.; Liang, M.-K.; Chen, Y.-S.; Lu, Q.; Wang, J.-Y.; Xia, Z.Y.; Zhou, H.-D.; Cao, X.; Xie, H.; et al. MicroRNA-188 regulates age-related switch between osteoblast and adipocyte differentiation. J. Clin. Investig. 2015, 125, 1509–1522. [Google Scholar] [CrossRef] [Green Version]
- Dong, J.; Liu, J.; Wen, Y.; Tobin, S.W.; Zhang, C.; Zheng, H.; Huang, Z.; Feng, Y.; Zhang, D.; Liu, S.; et al. Down-Regulation of Lnc-CYP7A1-1 Rejuvenates Aged Human Mesenchymal Stem Cells to Improve Their Efficacy for Heart Repair Through SYNE1. Front. Cell Dev. Biol. 2020, 8, 1–15. [Google Scholar] [CrossRef]
- Xia, W.; Zhuang, L.; Deng, X.; Hou, M. Long noncoding RNA-p21 modulates cellular senescence via the Wnt/β-catenin signaling pathway in mesenchymal stem cells. Mol. Med. Rep. 2017, 16, 7039–7047. [Google Scholar] [CrossRef] [Green Version]
- Kornicka, K.; Marycz, K.; Marędziak, M.; Tomaszewski, K.A.; Nicpoń, J. The effects of the DNA methyltranfserases inhibitor 5-Azacitidine on ageing, oxidative stress and DNA methylation of adipose derived stem cells. J. Cell. Mol. Med. 2016, 21, 387–401. [Google Scholar] [CrossRef]
- Yan, X.; Ehnert, S.; Culmes, M.; Bachmann, A.; Seeliger, C.; Schyschka, L.; Wang, Z.; Rahmanian-Schwarz, A.; Stöckle, U.; De Sousa, P.A.; et al. 5-Azacytidine Improves the Osteogenic Differentiation Potential of Aged Human Adipose-Derived Mesenchymal Stem Cells by DNA Demethylation. PLoS ONE 2014, 9, e90846. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gao, B.; Lin, X.; Jing, H.; Fan, J.; Ji, C.; Jie, Q.; Zheng, C.; Wang, D.; Xu, X.; Hu, Y.; et al. Local delivery of tetramethylpyrazine eliminates the senescent phenotype of bone marrow mesenchymal stromal cells and creates an anti-inflammatory and angiogenic environment in aging mice. Aging Cell 2018, 17, e12741. [Google Scholar] [CrossRef] [PubMed]
- Xia, W.; Zhang, F.; Xie, C.; Jiang, M.; Hou, M. Macrophage migration inhibitory factor confers resistance to senescence through CD74-dependent AMPK-FOXO3a signaling in mesenchymal stem cells. Stem Cell Res. Ther. 2015, 6, 1–17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Xia, W.; Hou, M. Macrophage migration inhibitory factor rescues mesenchymal stem cells from doxorubicin-induced senescence though the PI3K-Akt signaling pathway. Int. J. Mol. Med. 2018, 41, 1127–1137. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Khanh, V.C.; Yamashita, T.; Ohneda, K.; Tokunaga, C.; Kato, H.; Osaka, M.; Hiramatsu, Y.; Ohneda, O. Rejuvenation of mesenchymal stem cells by extracellular vesicles inhibits the elevation of reactive oxygen species. Sci. Rep. 2020, 10, 17315. [Google Scholar] [CrossRef] [PubMed]
- Liu, S.; Mahairaki, V.; Bai, H.; Ding, Z.; Li, J.; Witwer, K.W.; Cheng, L. Highly Purified Human Extracellular Vesicles Produced by Stem Cells Alleviate Aging Cellular Phenotypes of Senescent Human Cells. Stem Cells 2019, 37, 779–790. [Google Scholar] [CrossRef] [Green Version]
- Zhang, N.; Zhu, J.; Ma, Q.; Zhao, Y.; Wang, Y.; Hu, X.; Chen, J.; Zhu, W.; Han, Z.; Yu, H. Exosomes derived from human umbilical cord MSCs rejuvenate aged MSCs and enhance their functions for myocardial repair. Stem Cell Res. Ther. 2020, 11, 1–15. [Google Scholar] [CrossRef]
- Zhang, Y.; Xu, J.; Liu, S.; Lim, M.; Zhao, S.; Cui, K.; Zhang, K.; Wang, L.; Ji, Q.; Han, Z.; et al. Embryonic stem cell-derived extracellular vesicles enhance the therapeutic effect of mesenchymal stem cells. Theranostics 2019, 9, 6976–6990. [Google Scholar] [CrossRef]
- Thakur, A.; Ke, X.; Chen, Y.-W.; Motallebnejad, P.; Zhang, K.; Lian, Q.; Chen, H.J. The mini player with diverse functions: Extracellular vesicles in cell biology, disease, and therapeutics. Protein Cell 2021, 1–24. [Google Scholar] [CrossRef]
- Maggiorani, D.; Beauséjour, C. Senescence and Aging: Does It Impact Cancer Immunotherapies? Cells 2021, 10, 1568. [Google Scholar] [CrossRef]
- Cuollo, L.; Antonangeli, F.; Santoni, A.; Soriani, A. The Senescence-Associated Secretory Phenotype (SASP) in the Challenging Future of Cancer Therapy and Age-Related Diseases. Biology 2020, 9, 485. [Google Scholar] [CrossRef]
- Xu, Q.; Long, Q.; Zhu, D.; Fu, D.; Zhang, B.; Han, L.; Qian, M.; Guo, J.; Xu, J.; Cao, L.; et al. Targeting amphiregulin (AREG) derived from senescent stromal cells diminishes cancer resistance and averts programmed cell death 1 ligand (PD-L1)-mediated immunosuppression. Aging Cell 2019, 18, 1–25. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Calcinotto, A.; Kohli, J.; Zagato, E.; Pellegrini, L.; Demaria, M.; Alimonti, A. Cellular Senescence: Aging, Cancer, and Injury. Physiol. Rev. 2019, 99, 1047–1078. [Google Scholar] [CrossRef] [PubMed]
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Mojsilović, S.; Jauković, A.; Kukolj, T.; Obradović, H.; Okić Đorđević, I.; Petrović, A.; Bugarski, D. Tumorigenic Aspects of MSC Senescence—Implication in Cancer Development and Therapy. J. Pers. Med. 2021, 11, 1133. https://doi.org/10.3390/jpm11111133
Mojsilović S, Jauković A, Kukolj T, Obradović H, Okić Đorđević I, Petrović A, Bugarski D. Tumorigenic Aspects of MSC Senescence—Implication in Cancer Development and Therapy. Journal of Personalized Medicine. 2021; 11(11):1133. https://doi.org/10.3390/jpm11111133
Chicago/Turabian StyleMojsilović, Slavko, Aleksandra Jauković, Tamara Kukolj, Hristina Obradović, Ivana Okić Đorđević, Anđelija Petrović, and Diana Bugarski. 2021. "Tumorigenic Aspects of MSC Senescence—Implication in Cancer Development and Therapy" Journal of Personalized Medicine 11, no. 11: 1133. https://doi.org/10.3390/jpm11111133