Dysfunction of Mesenchymal Stem Cells Isolated from Metabolic Syndrome and Type 2 Diabetic Patients as Result of Oxidative Stress and Autophagy may Limit Their Potential Therapeutic Use

Katarzyna Kornicka, Jenny Houston, Krzysztof Marycz, Katarzyna Kornicka, Jenny Houston, Krzysztof Marycz

Abstract

Mesenchymal stem cells (MSC) have become a promising tool for therapeutic intervention. Their unique features, including self-renewal, multipotency and immunomodulatory properties draw the worldwide attention of researchers and physicians with respect to their application in disease treatment. However, the environment (so-called niche) from which MSCs are isolated may determine their usefulness. Many studies indicated the involvement of MSCs in ageing and disease. In this review, we have focused on how type 2 diabetes (T2D) and metabolic syndrome (MS) affect MSC properties, and thus limit their therapeutic potential. Herein, we mainly focus on apoptosis, autophagy and mitochondria deterioration processes that indirectly affect MSC fate. Based on the data presented, special attention should be paid when considering autologous MSC therapy in T2D or MS treatments, as their therapeutic potential may be restricted.

Keywords: Aging; Autophagy; Diabetes; Mesenchymal stem cells; Metabolic syndrome; Oxidative stress; Regenerative medicine; Senescence.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Mesenchymal stem cell dysfunction in metabolic syndrome

References

    1. IDF diabetes atlas - Home (n.d.). Retrieved January 2, 2017, from /.
    1. Friedenstein AJ, Chailakhjan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell and Tissue Kinetics. 1970;3(4):393–403.
    1. Friedenstein AJ, Chailakhyan RK, Latsinik NV, Panasyuk AF, Keiliss-Borok IV. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation. 1974;17(4):331–340. doi: 10.1097/00007890-197404000-00001.
    1. Zuk, P. A., Zhu, M., Ashjian, P., De Ugarte, D. A., Huang, J. I., Mizuno, H., … Hedrick, M. H. (2002). Human adipose tissue is a source of multipotent stem cells. Molecular Biology of the Cell, 13(12), 4279–4295. 10.1091/mbc.E02-02-0105.
    1. Marycz, K., Krzak, J., Urbański, W., Pezowicz, C. (2014). In vitro and in vivo evaluation of sol-gel derived TiO2 coatings based on a variety of precursors and synthesis conditions. Journal of Nanomaterials, 2014, e350579. 10.1155/2014/350579.
    1. Marycz, K., Grzesiak, J., Wrzeszcz, K., & Golonka, P. (2012). Adipose stem cell combined with plasma-based implant bone tissue differentiation in vitro and in a horse with a phalanx digitalis distalis fracture: a case report. Veterinarni Medicina (Czech Republic). Retrieved from .
    1. Grzesiak J, Krzysztof M, Karol W, Joanna C. Isolation and morphological characterisation of ovine adipose-derived mesenchymal stem cells in culture. International Journal of Stem Cells. 2011;4(2):99–104. doi: 10.15283/ijsc.2011.4.2.99.
    1. Kornicka K, Marycz K, Tomaszewski KA, Marędziak M, Śmieszek A. The effect of age on osteogenic and adipogenic differentiation potential of human adipose derived stromal stem cells (hASCs) and the impact of stress factors in the course of the differentiation process. Oxidative Medicine and Cellular Longevity. 2015;2015:309169. doi: 10.1155/2015/309169.
    1. Marędziak M, Marycz K, Lewandowski D, Siudzińska A, Śmieszek A. Static magnetic field enhances synthesis and secretion of membrane-derived microvesicles (MVs) rich in VEGF and BMP-2 in equine adipose-derived stromal cells (EqASCs)-a new approach in veterinary regenerative medicine. In Vitro Cellular & Developmental Biology. Animal. 2015;51(3):230–240. doi: 10.1007/s11626-014-9828-0.
    1. Nicpoń J, Marycz K, Grzesiak J. Therapeutic effect of adipose-derived mesenchymal stem cell injection in horses suffering from bone spavin. Polish Journal of Veterinary Sciences. 2013;16(4):753–754.
    1. Marędziak M, Marycz K, Tomaszewski KA, Kornicka K, Henry BM. The influence of aging on the regenerative potential of human adipose derived mesenchymal stem cells. Stem Cells International. 2016;2016:2152435.
    1. Kornicka K, Nawrocka D, Lis-Bartos A, Marędziak M, Marycz K. Polyurethane–polylactide-based material doped with resveratrol decreases senescence and oxidative stress of adipose-derived mesenchymal stromal stem cell (ASCs) RSC Advances. 2017;7(39):24070–24084. doi: 10.1039/C7RA02334K.
    1. Kornicka K, Marycz K, Marędziak M, Tomaszewski KA, Nicpoń J. The effects of the DNA methyltranfserases inhibitor 5-Azacitidine on ageing, oxidative stress and DNA methylation of adipose derived stem cells. Journal of Cellular and Molecular Medicine. 2017;21(2):387–401. doi: 10.1111/jcmm.12972.
    1. Cislo-Pakuluk A, Marycz K. A promising tool in retina regeneration: current perspectives and challenges when using mesenchymal progenitor stem cells in veterinary and human ophthalmological applications. Stem Cell Reviews. 2017;13(5):598–602. doi: 10.1007/s12015-017-9750-4.
    1. Abdi R, Fiorina P, Adra CN, Atkinson M, Sayegh MH. Immunomodulation by mesenchymal stem cells: a potential therapeutic strategy for type 1 diabetes. Diabetes. 2008;57(7):1759–1767. doi: 10.2337/db08-0180.
    1. Sun, Y., Chen, L., Hou, X., Hou, W., Dong, J., Sun, L., … Wang, K. (2007). Differentiation of bone marrow-derived mesenchymal stem cells from diabetic patients into insulin-producing cells in vitro. Chinese Medical Journal, 120(9), 771–776.
    1. Phadnis SM, Ghaskadbi SM, Hardikar AA, Bhonde RR. Mesenchymal stem cells derived from bone marrow of diabetic patients portrait unique markers influenced by the diabetic microenvironment. The Review of Diabetic Studies : RDS. 2009;6(4):260–270. doi: 10.1900/RDS.2009.6.260.
    1. Ratajczak MZ. Microvesicles as immune orchestra conductors. Blood. 2008;111(10):4832–4833. doi: 10.1182/blood-2008-02-136028.
    1. Ratajczak J, Wysoczynski M, Hayek F, Janowska-Wieczorek A, Ratajczak MZ. Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia. 2006;20(9):1487–1495. doi: 10.1038/sj.leu.2404296.
    1. Ratajczak J, Miekus K, Kucia M, Zhang J, Reca R, Dvorak P, Ratajczak MZ. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia. 2006;20(5):847–856. doi: 10.1038/sj.leu.2404132.
    1. Huang Y-Z, Xie H-Q, Silini A, Parolini O, Zhang Y, Deng L, Huang Y-C. Mesenchymal stem/progenitor cells derived from articular cartilage, synovial membrane and synovial fluid for cartilage regeneration: current status and future perspectives. Stem Cell Reviews and Reports. 2017;13(5):575–586. doi: 10.1007/s12015-017-9753-1.
    1. Collino, F., Pomatto, M., Bruno, S., Lindoso, R. S., Tapparo, M., Sicheng, W., … Camussi, G. (2017). Exosome and microvesicle-enriched fractions isolated from mesenchymal stem cells by gradient separation showed different molecular signatures and functions on renal tubular epithelial cells. Stem Cell Reviews and Reports, 13(2), 226–243. 10.1007/s12015-016-9713-1.
    1. Wang Y, Chen L, Liu M. Microvesicles and diabetic complications--novel mediators, potential biomarkers and therapeutic targets. Acta Pharmacologica Sinica. 2014;35(4):433–443. doi: 10.1038/aps.2013.188.
    1. Marycz K, Kornicka K, Basinska K, Czyrek A. Equine metabolic syndrome affects viability, senescence, and stress factors of equine adipose-derived mesenchymal stromal stem cells: new insight into EqASCs isolated from EMS horses in the context of their aging. Oxidative Medicine and Cellular Longevity. 2016;2016:1–17.
    1. Sotiropoulou PA, Perez SA, Salagianni M, Baxevanis CN, Papamichail M. Characterization of the optimal culture conditions for clinical scale production of human mesenchymal stem cells. Stem Cells (Dayton, Ohio) 2006;24(2):462–471. doi: 10.1634/stemcells.2004-0331.
    1. Baker N, Boyette LB, Tuan RS. Characterization of bone marrow-derived mesenchymal stem cells in aging. Bone. 2015;70:37–47. doi: 10.1016/j.bone.2014.10.014.
    1. Duggal S, Brinchmann JE. Importance of serum source for the in vitro replicative senescence of human bone marrow derived mesenchymal stem cells. Journal of Cellular Physiology. 2011;226(11):2908–2915. doi: 10.1002/jcp.22637.
    1. Cmielova, J., Havelek, R., Soukup, T., Jiroutová, A., Visek, B., Suchánek, J., … Rezacova, M. (2012). Gamma radiation induces senescence in human adult mesenchymal stem cells from bone marrow and periodontal ligaments. International Journal of Radiation Biology, 88(5), 393–404. 10.3109/09553002.2012.666001.
    1. Muthna, D., Soukup, T., Vavrova, J., Mokry, J., Cmielova, J., Visek, B., … Rezacova, M. (2010). Irradiation of adult human dental pulp stem cells provokes activation of p53, cell cycle arrest, and senescence but not apoptosis. Stem Cells and Development, 19(12), 1855–1862. 10.1089/scd.2009.0449.
    1. Seifrtova M, Havelek R, Soukup T, Filipova A, Mokry J, Rezacova M. Mitoxantrone ability to induce premature senescence in human dental pulp stem cells and human dermal fibroblasts. Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society. 2013;64(2):255–266.
    1. Stolzing A, Scutt A. Age-related impairment of mesenchymal progenitor cell function. Aging Cell. 2006;5(3):213–224. doi: 10.1111/j.1474-9726.2006.00213.x.
    1. Stolzing A, Jones E, McGonagle D, Scutt A. Age-related changes in human bone marrow-derived mesenchymal stem cells: consequences for cell therapies. Mechanisms of Ageing and Development. 2008;129(3):163–173. doi: 10.1016/j.mad.2007.12.002.
    1. Ko E, Lee KY, Hwang DS. Human umbilical cord blood-derived mesenchymal stem cells undergo cellular senescence in response to oxidative stress. Stem Cells and Development. 2012;21(11):1877–1886. doi: 10.1089/scd.2011.0284.
    1. Burova E, Borodkina A, Shatrova A, Nikolsky N. Sublethal oxidative stress induces the premature senescence of human mesenchymal stem cells derived from endometrium. Oxidative Medicine and Cellular Longevity. 2013;2013:474931. doi: 10.1155/2013/474931.
    1. Kim J-S, Kim E-J, Kim H-J, Yang J-Y, Hwang G-S, Kim C-W. Proteomic and metabolomic analysis of H2O2-induced premature senescent human mesenchymal stem cells. Experimental Gerontology. 2011;46(6):500–510. doi: 10.1016/j.exger.2011.02.012.
    1. Skolekova, S., Matuskova, M., Bohac, M., Toro, L., Durinikova, E., Tyciakova, S., … Kucerova, L. (2016). Cisplatin-induced mesenchymal stromal cells-mediated mechanism contributing to decreased antitumor effect in breast cancer cells. Cell Communication and Signaling: CCS, 14, 4. 10.1186/s12964-016-0127-0.
    1. Minieri, V., Saviozzi, S., Gambarotta, G., Lo Iacono, M., Accomasso, L., Cibrario Rocchietti, E., … Giachino, C. (2015). Persistent DNA damage-induced premature senescence alters the functional features of human bone marrow mesenchymal stem cells. Journal of Cellular and Molecular Medicine, 19(4), 734–743. 10.1111/jcmm.12387.
    1. Kornicka K, Babiarczuk B, Krzak J, Marycz K. The effect of a sol–gel derived silica coating doped with vitamin E on oxidative stress and senescence of human adipose-derived mesenchymal stem cells (AMSCs) RSC Advances. 2016;6(35):29524–29537. doi: 10.1039/C6RA00029K.
    1. Hemeda H, Jakob M, Ludwig A-K, Giebel B, Lang S, Brandau S. Interferon-gamma and tumor necrosis factor-alpha differentially affect cytokine expression and migration properties of mesenchymal stem cells. Stem Cells and Development. 2010;19(5):693–706. doi: 10.1089/scd.2009.0365.
    1. Mansilla, E., Marín, G. H., Drago, H., Sturla, F., Salas, E., Gardiner, C., … Soratti, C. (2006). Bloodstream cells phenotypically identical to human mesenchymal bone marrow stem cells circulate in large amounts under the influence of acute large skin damage: new evidence for their use in regenerative medicine. Transplantation Proceedings, 38(3), 967–969. 10.1016/j.transproceed.2006.02.053.
    1. Gálvez, B. G., San Martín, N., & Rodríguez, C. (2009). TNF-alpha is required for the attraction of mesenchymal precursors to white adipose tissue in Ob/ob mice. PLoS One, 4(2). 10.1371/journal.pone.0004444.
    1. Rizvi AA. Hypertension, obesity, and inflammation: the complex designs of a deadly trio. Metabolic Syndrome and Related Disorders. 2010;8(4):287–294. doi: 10.1089/met.2009.0116.
    1. Kočí, Z., Turnovcová, K., Dubský, M., Baranovičová, L., Holáň, V., Chudíčková, M., … Kubinová, S. (2014). Characterization of human adipose tissue-derived stromal cells isolated from diabetic patient’s distal limbs with critical ischemia. Cell Biochemistry and Function, 32(7), 597–604. 10.1002/cbf.3056.
    1. Wu C-L, Diekman BO, Jain D, Guilak F. Diet-induced obesity alters the differentiation potential of stem cells isolated from bone marrow, adipose tissue and infrapatellar fat pad: the effects of free fatty acids. International Journal of Obesity (2005) 2013;37(8):1079–1087. doi: 10.1038/ijo.2012.171.
    1. Liu, L. F., Kodama, K., Wei, K., Tolentino, L. L., Choi, O., Engleman, E. G., … McLaughlin, T. (2015). The receptor CD44 is associated with systemic insulin resistance and proinflammatory macrophages in human adipose tissue. Diabetologia, 58(7), 1579–1586. 10.1007/s00125-015-3603-y.
    1. Kodama K, Toda K, Morinaga S, Yamada S, Butte AJ. Anti-CD44 antibody treatment lowers hyperglycemia and improves insulin resistance, adipose inflammation, and hepatic steatosis in diet-induced obese mice. Diabetes. 2015;64(3):867–875. doi: 10.2337/db14-0149.
    1. Kodama, K., Horikoshi, M., Toda, K., Yamada, S., Hara, K., Irie, J., … Butte, A. J. (2012). Expression-based genome-wide association study links the receptor CD44 in adipose tissue with type 2 diabetes. Proceedings of the National Academy of Sciences of the United States of America, 109(18), 7049–7054. 10.1073/pnas.1114513109.
    1. Pérez, L. M., Bernal, A., de Lucas, B., San Martin, N., Mastrangelo, A., García, A., … Gálvez, B. G. (2015). Altered metabolic and stemness capacity of adipose tissue-derived stem cells from obese mouse and human. PloS One, 10(4), e0123397. 10.1371/journal.pone.0123397.
    1. Marycz K, Śmieszek A, Grzesiak J, Donesz-Sikorska A, Krzak-Roś J. Application of bone marrow and adipose-derived mesenchymal stem cells for testing the biocompatibility of metal-based biomaterials functionalized with ascorbic acid. Biomedical Materials (Bristol, England) 2013;8(6):065004. doi: 10.1088/1748-6041/8/6/065004.
    1. Marycz K, Kornicka K, Marędziak M, Golonka P, Nicpoń J. Equine metabolic syndrome impairs adipose stem cells osteogenic differentiation by predominance of autophagy over selective mitophagy. Journal of Cellular and Molecular Medicine. 2016;20(12):2384–2404. doi: 10.1111/jcmm.12932.
    1. Marycz K, Kornicka K, Grzesiak J, Śmieszek A, Szłapka J. Macroautophagy and selective mitophagy ameliorate chondrogenic differentiation potential in adipose stem cells of equine metabolic syndrome: new findings in the field of progenitor cells differentiation. Oxidative Medicine and Cellular Longevity. 2016;2016:e3718468.
    1. Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. The American Journal of Physiology. 1996;271(5 Pt 1):C1424–C1437. doi: 10.1152/ajpcell.1996.271.5.C1424.
    1. Allen CL, Bayraktutan U. Oxidative stress and its role in the pathogenesis of ischaemic stroke. International Journal of Stroke: Official Journal of the International Stroke Society. 2009;4(6):461–470. doi: 10.1111/j.1747-4949.2009.00387.x.
    1. De Duve C. The lysosome. Scientific American. 1963;208:64–72. doi: 10.1038/scientificamerican0563-64.
    1. De Duve C, Wattiaux R. Functions of lysosomes. Annual Review of Physiology. 1966;28:435–492. doi: 10.1146/annurev.ph.28.030166.002251.
    1. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annual Review of Genetics. 2009;43:67–93. doi: 10.1146/annurev-genet-102808-114910.
    1. Chen Y, Klionsky DJ. The regulation of autophagy - unanswered questions. Journal of Cell Science. 2011;124(Pt 2):161–170. doi: 10.1242/jcs.064576.
    1. Saftig P, Beertsen W, Eskelinen E-L. LAMP-2: a control step for phagosome and autophagosome maturation. Autophagy. 2008;4(4):510–512. doi: 10.4161/auto.5724.
    1. Mizushima, N., Yamamoto, A., Hatano, M., Kobayashi, Y., Kabeya, Y., Suzuki, K., … Yoshimori, T. (2001). Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. The Journal of Cell Biology, 152(4), 657–668.
    1. Vessoni AT, Muotri AR, Okamoto OK. Autophagy in stem cell maintenance and differentiation. Stem Cells and Development. 2012;21(4):513–520. doi: 10.1089/scd.2011.0526.
    1. Coller HA, Sang L, Roberts JM. A new description of cellular quiescence. PLoS Biology. 2006;4(3):e83. doi: 10.1371/journal.pbio.0040083.
    1. Rambold AS, Kostelecky B, Elia N, Lippincott-Schwartz J. Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(25):10190–10195. doi: 10.1073/pnas.1107402108.
    1. Sanchez, C. G., Penfornis, P., Oskowitz, A. Z., Boonjindasup, A. G., Cai, D. Z., Dhule, S. S., … Pochampally, R. R. (2011). Activation of autophagy in mesenchymal stem cells provides tumor stromal support. Carcinogenesis, 32(7), 964–972. 10.1093/carcin/bgr029.
    1. Zhang, Z., Yang, M., Wang, Y., Wang, L., Jin, Z., Ding, L., … Hu, T. (2016). Autophagy regulates the apoptosis of bone marrow-derived mesenchymal stem cells under hypoxic condition via AMP-activated protein kinase/mammalian target of rapamycin pathway. Cell Biology International, 40(6), 671–685. 10.1002/cbin.10604.
    1. Gao, L., Cen, S., Wang, P., Xie, Z., Liu, Z., Deng, W., et al. (2016). Autophagy improves the immunosuppression of CD4+ T cells by mesenchymal stem cells through transforming growth factor-β1. Stem Cells Translational Medicine. 10.5966/sctm.2015-0420.
    1. Gonzalez, C. D., Lee, M.-S., Marchetti, P., Pietropaolo, M., Towns, R., Vaccaro, M. I., … Wiley, J. W. (2011). The emerging role of autophagy in the pathophysiology of diabetes mellitus. Autophagy, 7(1), 2–11. :10.4161/auto.7.1.13044.
    1. Jung, H. S., Chung, K. W., Won Kim, J., Kim, J., Komatsu, M., Tanaka, K., … Lee, M.-S. (2008). Loss of autophagy diminishes pancreatic beta cell mass and function with resultant hyperglycemia. Cell Metabolism, 8(4), 318–324. 10.1016/j.cmet.2008.08.013.
    1. Marsh, B. J., Soden, C., Alarcón, C., Wicksteed, B. L., Yaekura, K., Costin, A. J., … Rhodes, C. J. (2007). Regulated autophagy controls hormone content in secretory-deficient pancreatic endocrine beta-cells. Molecular Endocrinology (Baltimore, Md.), 21(9), 2255–2269. 10.1210/me.2007-0077.
    1. Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes. 1999;48(1):1–9. doi: 10.2337/diabetes.48.1.1.
    1. Weir GC, Laybutt DR, Kaneto H, Bonner-Weir S, Sharma A. Beta-cell adaptation and decompensation during the progression of diabetes. Diabetes. 2001;50(Suppl 1):S154–S159. doi: 10.2337/diabetes.50.2007.S154.
    1. Prentki M, Nolan CJ. Islet beta cell failure in type 2 diabetes. The Journal of Clinical Investigation. 2006;116(7):1802–1812. doi: 10.1172/JCI29103.
    1. Poitout V, Robertson RP. Minireview: secondary beta-cell failure in type 2 diabetes--a convergence of glucotoxicity and lipotoxicity. Endocrinology. 2002;143(2):339–342. doi: 10.1210/endo.143.2.8623.
    1. Lenzen S, Drinkgern J, Tiedge M. Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues. Free Radical Biology & Medicine. 1996;20(3):463–466. doi: 10.1016/0891-5849(96)02051-5.
    1. Kaneto, H., Kajimoto, Y., Miyagawa, J., Matsuoka, T., Fujitani, Y., Umayahara, Y., … Hori, M. (1999). Beneficial effects of antioxidants in diabetes: possible protection of pancreatic beta-cells against glucose toxicity. Diabetes, 48(12), 2398–2406.
    1. Nawrocka, D., Kornicka, K., Śmieszek, A., & Marycz, K. (2017). Spirulina platensis improves mitochondrial function impaired by elevated oxidative stress in adipose-derived mesenchymal stromal cells (ASCs) and intestinal epithelial cells (IECs), and enhances insulin sensitivity in equine metabolic syndrome (EMS) horses. Marine Drugs, 15(8). 10.3390/md15080237.
    1. Marycz, K., Michalak, I., Kocherova, I., Marędziak, M., & Weiss, C. (2017). The cladophora glomerata enriched by biosorption process in Cr(III) improves viability, and reduces oxidative stress and apoptosis in equine metabolic syndrome derived adipose mesenchymal stromal stem cells (ASCs) and their extracellular vesicles (MV’s). Marine Drugs, 15(12). 10.3390/md15120385.
    1. Prowse, A. B. J., Chong, F., Elliott, D. A., Elefanty, A. G., Stanley, E. G., Gray, P. P., … Osborne, G. W. (2012). Analysis of mitochondrial function and localisation during human embryonic stem cell differentiation in vitro. PloS One, 7(12), e52214. 10.1371/journal.pone.0052214.
    1. Chen C-T, Shih Y-RV, Kuo TK, Lee OK, Wei Y-H. Coordinated changes of mitochondrial biogenesis and antioxidant enzymes during osteogenic differentiation of human mesenchymal stem cells. Stem Cells. 2008;26(4):960–968. doi: 10.1634/stemcells.2007-0509.
    1. Galkowski D, Ratajczak MZ, Kocki J, Darzynkiewicz Z. Of cytometry, stem cells and fountain of youth. Stem Cell Reviews and Reports. 2017;13(4):465–481. doi: 10.1007/s12015-017-9733-5.
    1. Prathipati P, Nandi SS, Mishra PK. Stem cell-derived exosomes, autophagy, extracellular matrix turnover, and miRNAs in cardiac regeneration during stem cell therapy. Stem Cell Reviews and Reports. 2017;13(1):79–91. doi: 10.1007/s12015-016-9696-y.
    1. Lei L-T, Chen J-B, Zhao Y-L, Yang S-P, He L. Resveratrol attenuates senescence of adipose-derived mesenchymal stem cells and restores their paracrine effects on promoting insulin secretion of INS-1 cells through Pim-1. European Review for Medical and Pharmacological Sciences. 2016;20(6):1203–1213.
    1. Yuan, H.-F., Zhai, C., Yan, X.-L., Zhao, D.-D., Wang, J.-X., Zeng, Q., … Pei, X.-T. (2012). SIRT1 is required for long-term growth of human mesenchymal stem cells. Journal of Molecular Medicine, 90(4), 389–400. 10.1007/s00109-011-0825-4.
    1. Gu, Z., Tan, W., Ji, J., Feng, G., Meng, Y., Da, Z., … Cheng, C. (2016). Rapamycin reverses the senescent phenotype and improves immunoregulation of mesenchymal stem cells from MRL/lpr mice and systemic lupus erythematosus patients through inhibition of the mTOR signaling pathway. Aging, 8(5), 1102–1114. 10.18632/aging.100925.

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