Advertisement

Stem Cell Reviews and Reports

, Volume 14, Issue 4, pp 558–573 | Cite as

The Delta Opioid Peptide DADLE Represses Hypoxia-Reperfusion Mimicked Stress Mediated Apoptotic Cell Death in Human Mesenchymal Stem Cells in Part by Downregulating the Unfolded Protein Response and ROS along with Enhanced Anti-Inflammatory Effect

  • Madhubanti Mullick
  • Dwaipayan Sen
Article

Abstract

Hypoxia-reperfusion (H/R) emblems a plethora of pathological conditions which is potent in contributing to the adversities encountered by human mesenchymal stem cells (hMSCs) in post-transplant microenvironment, resulting in transplant failure. D-Alanine 2, Leucine 5 Enkephaline (DADLE)-mediated delta opioid receptor (DOR) activation is well-known for its recuperative properties in different cell types like neuronal and cardiomyocytes. In the current study its effectiveness in assuaging hMSC mortality under H/R-like insult has been delineated. The CoCl2 mimicked H/R conditions in vitro was investigated upon DOR activation, mediated via DADLE. hMSCs loss of viability, reactive oxygen species (ROS) production, inflammatory responses and disconcerted unfolded protein response (UPR) were assessed using AnnexinV/PI flow cytometry, fluorescence imaging, mitochondrial complex 1 assay, quantitative PCR, immunoblot analysis and ELISA. H/R like stress induced apoptosis of hMSCs was significantly mitigated by DADLE via modulation of the apoptotic regulators (Bcl-2/Bax) along with significant curtailment of ROS and mitochondrial complex 1 activity. DADLE concomitantly repressed the misfolded protein aggregation, alongside the major UPR sensors: PERK/BiP/IRE-1α /ATF-6, evoked due to the H/R mimicked endoplasmic reticulum stress. Undermined phosphorylation of the Akt signalling pathway was observed, which concerted its effect onto regulating both the pro and anti-inflammatory cytokines, actuated as a response to the H/R-like insult. The effects of DADLE were subdued by naltrindole (specific DOR antagonist) reaffirming the involvement of DOR in the process. Taken together these results promulgate the role of DADLE-induced DOR activation on improved hMSC survival, which signifies the plausible implications of DOR-activation in cell-transplantation therapies and tissue engineering aspect.

Keywords

DADLE Delta opioid peptide hMSCs Hypoxia-reperfusion Survival Transplantation 

Abbreviations

hMSC

human mesenchymal stem cells

H/R

Hypoxia-reperfusion

DADLE

d-Ala2, d-Leu5 enkephalin

DOR

Delta opioid receptor

ER

Endoplasmic reticulum

UPR

Unfolded protein response

CMH2DCFDA

chloro-methyl derivative 2′,7′-dichlorofluorescein

PERK

PRKR-like ER kinase

ATF-6

Activating transcription factor 6α

IRE-1α

Inositol-requiring protein 1α

BiP

immunoglobulin heavy-chain binding protein

MAPK

Mitogen activated protein kinase

Notes

Acknowledgements

Centre for Stem Cell Research, Christian Medical College, Vellore, India for providing access to flow cytometry and fluorescence microscope.

Authors’ contribution

MM has carried out experiments, analyzed data and wrote the paper. DS conceptualized, wrote the paper and analysed the data.

Funding

This work was supported by a start-up fund from VIT, Vellore given to DS. DS is also supported by a Indian Council of Medical Research (ICMR) Funded Project (Sanction Order No.NCD/Ad-hoc/66/2016–17) and a ‘Fast Track Young Scientist’ grant (YSS/2014/000027) from the Science and Engineering Research Board (SERB), Department of Science and Technology (DST), Government of India.

Compliance with Ethical Standards

Competing Interests

The authors declare that there are no conflicts of interest.

Consent for Publication

All authors have read the manuscript and agreed to the publication.

References

  1. 1.
    Parekkadan, B., & Milwid, J. M. (2010). Mesenchymal stem cells as therapeutics. Annu Rev Biomed Eng, 12, 87–117.  https://doi.org/10.1146/annurev-bioeng-070909-105309.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Lee, S., Choi, E., Cha, M. J., & Hwang, K. C. (2015). Cell adhesion and long-term survival of transplanted mesenchymal stem cells: a prerequisite for cell therapy. Oxid Med Cell Longev, 2015, 632902.  https://doi.org/10.1155/2015/632902.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Murry, C. E., Soonpaa, M. H., Reinecke, H., Nakajima, H., Nakajima, H. O., Rubart, M., Pasumarthi, K. B., Virag, J. I., Bartelmez, S. H., Poppa, V., Bradford, G., Dowell, J. D., Williams, D. A., & Field, L. J. (2004). Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature, 428(6983), 664–668.  https://doi.org/10.1038/nature02446.CrossRefPubMedGoogle Scholar
  4. 4.
    Eltzschig, H. K., & Eckle, T. (2011). Ischemia and reperfusion--from mechanism to translation. Nature Medicine, 17(11), 1391–1401.  https://doi.org/10.1038/nm.2507.CrossRefPubMedGoogle Scholar
  5. 5.
    Feng, Y., Hu, L., Xu, Q., Yuan, H., Ba, L., He, Y., & Che, H. (2015). Cytoprotective Role of Alpha-1 Antitrypsin in Vascular Endothelial Cell Under Hypoxia/Reoxygenation Condition. Journal of Cardiovascular Pharmacology, 66(1), 96–107.  https://doi.org/10.1097/FJC.0000000000000250.CrossRefPubMedGoogle Scholar
  6. 6.
    Yellon, D. M., & Hausenloy, D. J. (2007). Myocardial reperfusion injury. The New England Journal of Medicine, 357(11), 1121–1135.CrossRefPubMedGoogle Scholar
  7. 7.
    Kvietys, P. R., & Granger, D. N. (2012). Role of reactive oxygen and nitrogen species in the vascular responses to inflammation. Free Radical Biology & Medicine, 52(3), 556–592.  https://doi.org/10.1016/j.freeradbiomed.2011.11.002.CrossRefGoogle Scholar
  8. 8.
    Qu, K., Shen, N. Y., Xu, X. S., Su, H. B., Wei, J. C., Tai, M. H., Meng, F. D., Zhou, L., Zhang, Y. L., & Liu, C. (2013). Emodin induces human T cell apoptosis in vitro by ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction. Acta Pharmacol Sin, 34(9), 1217–1228.  https://doi.org/10.1038/aps.2013.58.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Kim, I., Xu, W., & Reed, J. C. (2008). Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nature Reviews. Drug Discovery, 7(12), 1013–1030.  https://doi.org/10.1038/nrd2755.CrossRefPubMedGoogle Scholar
  10. 10.
    Minamino, T., Komuro, I., & Kitakaze, M. (2010). Endoplasmic reticulum stress as a therapeutic target in cardiovascular disease. Circulation Research, 107(9), 1071–1082.  https://doi.org/10.1038/aps.2015.CrossRefPubMedGoogle Scholar
  11. 11.
    Toko, H., Takahashi, H., Kayama, Y., Okada, S., Minamino, T., Terasaki, F., Kitaura, Y., & Komuro, I. (2010). ATF6 is important under both pathological and physiological states in the heart. Journal of Molecular and Cellular Cardiology, 49(1), 113–120.  https://doi.org/10.1016/j.yjmcc.2010.03.020.CrossRefPubMedGoogle Scholar
  12. 12.
    Grover, G. J., Atwal, K. S., Sleph, P. G., Wang, F. L., Monshizadegan, H., Monticello, T., & Green, D. W. (2004). Excessive ATP hydrolysis in ischemic myocardium by mitochondrial F1F0-ATPase: effect of selective pharmacological inhibition of mitochondrial ATPase hydrolase activity. American Journal of Physiology. Heart and Circulatory Physiology, 287(4), H1747–H1755.  https://doi.org/10.1152/ajpheart.01019.2003.CrossRefPubMedGoogle Scholar
  13. 13.
    Solaini, G., & Harris, D. A. (2005). Biochemical dysfunction in heart mitochondria exposed to ischaemia and reperfusion. The Biochemical Journal, 390(Pt 2), 377–394.  https://doi.org/10.1042/BJ20042006.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Xu, M., Bi, X., He, X., Yu, X., Zhao, M., & Zang, W. (2016). Inhibition of the mitochondrial unfolded protein response by acetylcholine alleviated hypoxia/reoxygenation-induced apoptosis of endothelial cells. Cell Cycle, 15(10), 1331–1343.  https://doi.org/10.1080/15384101.2016.1160985.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Ong, S. B., & Gustafsson, A. B. (2012). New roles for mitochondria in cell death in the reperfused myocardium. Cardiovascular Research, 94(2), 190–196.  https://doi.org/10.1093/cvr/cvr312.CrossRefPubMedGoogle Scholar
  16. 16.
    Satoh, M., & Minami, M. (1995). Molecular pharmacology of the opioid receptors. Pharmacology & Therapeutics, 68(3), 343–364.CrossRefGoogle Scholar
  17. 17.
    Tian, X., Guo, J., Zhu, M., Li, M., Wu, G., & Xia, Y. (2013). delta-Opioid receptor activation rescues the functional TrkB receptor and protects the brain from ischemia-reperfusion injury in the rat. PLoS One, 8(7), e69252.  https://doi.org/10.1371/journal.pone.0069252PONE-D-11-22093.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Tanaka, K., Kersten, J. R., & Riess, M. L. (2014). Opioid-induced cardioprotection. Curr Pharm Des, 20(36), 5696–5705.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Crowley MG, Liska MG, Lippert T, Coreya S, Borlongan CV (2017) Utilizing Delta Opioid Receptors and Peptides for Cytoprotection: Implications in Stroke and Other Neurological Disorders. CNS Neurol Disord Drug Targets.  https://doi.org/10.2174/1871527316666170320150659
  20. 20.
    Kaneko, Y., Tajiri, N., Su, T. P., Wang, Y., & Borlongan, C. V. (2012). Combination treatment of hypothermia and mesenchymal stromal cells amplifies neuroprotection in primary rat neurons exposed to hypoxic-ischemic-like injury in vitro: role of the opioid system. PLoS One, 7(10), e47583.  https://doi.org/10.1371/journal.pone.0047583PONE-D-12-14071.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Mullick, M., Venkatesh, K., & Sen, D. (2017). d-Alanine 2, Leucine 5 Enkephaline (DADLE)-mediated DOR activation augments human hUCB-BFs viability subjected to oxidative stress via attenuation of the UPR. Stem Cell Research, 22, 20–28.  https://doi.org/10.1016/j.scr.2017.05.009.CrossRefPubMedGoogle Scholar
  22. 22.
    Reddy, L. V. K., & Sen, D. (2017). DADLE enhances viability and anti-inflammatory effect of human MSCs subjected to 'serum free' apoptotic condition in part via the DOR/PI3K/AKT pathway. Life Sciences, 191, 195–204.  https://doi.org/10.1016/j.lfs.2017.10.024.CrossRefPubMedGoogle Scholar
  23. 23.
    Jaiswal, N., Haynesworth, S. E., Caplan, A. I., & Bruder, S. P. (1997). Osteogenic differentiation of purified, culture-expanded human mesenchymal stem cells in vitro. J Cell Biochem, 64(2), 295–312.  https://doi.org/10.1002/(SICI)1097-4644(199702)64:2<295::AID-JCB12>3.0.CO;2-I.CrossRefPubMedGoogle Scholar
  24. 24.
    Nakamura, T., Shiojima, S., Hirai, Y., Iwama, T., Tsuruzoe, N., Hirasawa, A., Katsuma, S., & Tsujimoto, G. (2003). Temporal gene expression changes during adipogenesis in human mesenchymal stem cells. Biochemical and Biophysical Research Communications, 303(1), 306–312.  https://doi.org/10.1016/S0006-291X(03)00325-5.CrossRefPubMedGoogle Scholar
  25. 25.
    Lopez-Sanchez, L. M., Jimenez, C., Valverde, A., Hernandez, V., Penarando, J., Martinez, A., Lopez-Pedrera, C., Munoz-Castaneda, J. R., De la Haba-Rodriguez, J. R., Aranda, E., & Rodriguez-Ariza, A. (2014). CoCl2, a mimic of hypoxia, induces formation of polyploid giant cells with stem characteristics in colon cancer. PLoS One, 9(6), e99143.  https://doi.org/10.1371/journal.pone.0099143PONE-D-14-14287.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Zhang, Y. B., Wang, X., Meister, E. A., Gong, K. R., Yan, S. C., Lu, G. W., Ji, X. M., & Shao, G. (2014). The effects of CoCl2 on HIF-1alpha protein under experimental conditions of autoprogressive hypoxia using mouse models. International Journal of Molecular Sciences, 15(6), 10999–11012.  https://doi.org/10.3390/ijms150610999.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Sen, D., Huchital, M., & Chen, Y. L. (2013). Crosstalk between delta opioid receptor and nerve growth factor signaling modulates neuroprotection and differentiation in rodent cell models. International Journal of Molecular Sciences, 14(10), 21114–21139.  https://doi.org/10.3390/ijms141021114.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Wen, A., Guo, A., & Chen, Y. L. (2013). Mu-opioid signaling modulates biphasic expression of TrkB and IkappaBalpha genes and neurite outgrowth in differentiating and differentiated human neuroblastoma cells. Biochemical and Biophysical Research Communications, 432(4), 638–642.  https://doi.org/10.1016/j.bbrc.2013.02.031.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Fang, S., Xu, H., Lu, J., Zhu, Y., & Jiang, H. (2013). Neuroprotection by the kappa-opioid receptor agonist, BRL52537, is mediated via up-regulating phosphorylated signal transducer and activator of transcription-3 in cerebral ischemia/reperfusion injury in rats. Neurochemical Research, 38(11), 2305–2312.  https://doi.org/10.1007/s11064-013-1139-4.CrossRefPubMedGoogle Scholar
  30. 30.
    Delgado-Camprubi, M., Esteras, N., Soutar, M. P., Plun-Favreau, H., & Abramov, A. Y. (2017). Deficiency of Parkinson's disease-related gene Fbxo7 is associated with impaired mitochondrial metabolism by PARP activation. Cell Death and Differentiation, 24(1), 120–131.  https://doi.org/10.1038/cdd.2016.104.CrossRefPubMedGoogle Scholar
  31. 31.
    Xin, G., Wei, Z., Ji, C., Zheng, H., Gu, J., Ma, L., Huang, W., Morris-Natschke, S. L., Yeh, J. L., Zhang, R., Qin, C., Wen, L., Xing, Z., Cao, Y., Xia, Q., Lu, Y., Li, K., Niu, H., & Lee, K. H. (2016). Metformin Uniquely Prevents Thrombosis by Inhibiting Platelet Activation and mtDNA Release. Science Reporter, 6, 36222.  https://doi.org/10.1038/srep36222.CrossRefGoogle Scholar
  32. 32.
    Fischer, T., Elenko, E., McCaffery, J. M., DeVries, L., & Farquhar, M. G. (1999). Clathrin-coated vesicles bearing GAIP possess GTPase-activating protein activity in vitro. Proceedings of the National Academy of Sciences of the United States of America, 96(12), 6722–6727.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Sarugaser, R., Hanoun, L., Keating, A., Stanford, W. L., & Davies, J. E. (2009). Human mesenchymal stem cells self-renew and differentiate according to a deterministic hierarchy. PLoS One, 4(8), e6498.  https://doi.org/10.1371/journal.pone.0006498.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Li, C. D., Zhang, W. Y., Li, H. L., Jiang, X. X., Zhang, Y., Tang, P. H., & Mao, N. (2005). Mesenchymal stem cells derived from human placenta suppress allogeneic umbilical cord blood lymphocyte proliferation. Cell Research, 15(7), 539–547.  https://doi.org/10.1038/sj.cr.7290323.CrossRefPubMedGoogle Scholar
  35. 35.
    Singh, A., & Sen, D. (2016). Mesenchymal stem cells in cardiac regeneration: a detailed progress report of the last 6 years (2010-2015). Stem Cell Res Ther, 7(1), 82.  https://doi.org/10.1186/s13287-016-0341-0.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Saraswati, S., Guo, Y., Atkinson, J., & Young, P. P. (2015). Prolonged hypoxia induces monocarboxylate transporter-4 expression in mesenchymal stem cells resulting in a secretome that is deleterious to cardiovascular repair. Stem Cells, 33(4), 1333–1344.  https://doi.org/10.1002/stem.1935.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Chouchani, E. T., Pell, V. R., Gaude, E., Aksentijevic, D., Sundier, S. Y., Robb, E. L., Logan, A., Nadtochiy, S. M., Ord, E. N., Smith, A. C., Eyassu, F., Shirley, R., Hu, C. H., Dare, A. J., James, A. M., Rogatti, S., Hartley, R. C., Eaton, S., Costa, A. S., Brookes, P. S., Davidson, S. M., Duchen, M. R., Saeb-Parsy, K., Shattock, M. J., Robinson, A. J., Work, L. M., Frezza, C., Krieg, T., & Murphy, M. P. (2014). Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature, 515(7527), 431–435.  https://doi.org/10.1038/nature13909.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Kalogeris, T., Baines, C. P., Krenz, M., & Korthuis, R. J. (2012). Cell biology of ischemia/reperfusion injury. International Review of Cell and Molecular Biology, 298, 229–317.  https://doi.org/10.1016/B978-0-12-394309-5.00006-7.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Kalogeris, T., Bao, Y., & Korthuis, R. J. (2014). Mitochondrial reactive oxygen species: a double edged sword in ischemia/reperfusion vs preconditioning. Redox Biology, 2, 702–714.  https://doi.org/10.1016/j.redox.2014.05.006.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Mahfoudh-Boussaid, A., Zaouali, M. A., Hauet, T., Hadj-Ayed, K., Miled, A. H., Ghoul-Mazgar, S., Saidane-Mosbahi, D., Rosello-Catafau, J., & Ben Abdennebi, H. (2012). Attenuation of endoplasmic reticulum stress and mitochondrial injury in kidney with ischemic postconditioning application and trimetazidine treatment. Journal of Biomedical Science, 19, 71.  https://doi.org/10.1186/1423-0127-19-71.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Chen, J., Crawford, R., Chen, C., & Xiao, Y. (2013). The key regulatory roles of the PI3K/Akt signaling pathway in the functionalities of mesenchymal stem cells and applications in tissue regeneration. Tissue Eng Part B Rev, 19(6), 516–528.  https://doi.org/10.1089/ten.TEB.2012.0672.CrossRefPubMedGoogle Scholar
  42. 42.
    Hamel, D., Sanchez, M., Duhamel, F., Roy, O., Honore, J. C., Noueihed, B., Zhou, T., Nadeau-Vallee, M., Hou, X., Lavoie, J. C., Mitchell, G., Mamer, O. A., & Chemtob, S. (2014). G-protein-coupled receptor 91 and succinate are key contributors in neonatal postcerebral hypoxia-ischemia recovery. Arteriosclerosis, Thrombosis, and Vascular Biology, 34(2), 285–293.  https://doi.org/10.1161/ATVBAHA.113.302131.CrossRefPubMedGoogle Scholar
  43. 43.
    Zheng, Z., & Yenari, M. A. (2004). Post-ischemic inflammation: molecular mechanisms and therapeutic implications. Neurological Research, 26(8), 884–892.  https://doi.org/10.1179/016164104X2357.CrossRefPubMedGoogle Scholar
  44. 44.
    Gnecchi, M., Zhang, Z., Ni, A., & Dzau, V. J. (2008). Paracrine mechanisms in adult stem cell signaling and therapy. Circulation Research, 103(11), 1204–1219.  https://doi.org/10.1161/CIRCRESAHA.108.176826. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Chavakis, E., Urbich, C., & Dimmeler, S. (2008). Homing and engraftment of progenitor cells: a prerequisite for cell therapy. Journal of Molecular and Cellular Cardiology, 45(4), 514–522.  https://doi.org/10.1016/j.yjmcc.2008.01.004.CrossRefPubMedGoogle Scholar
  46. 46.
    Ingber, D. E. (2002). Mechanical signaling and the cellular response to extracellular matrix in angiogenesis and cardiovascular physiology. Circulation Research, 91(10), 877–887.CrossRefPubMedGoogle Scholar
  47. 47.
    Wang, J. A., Chen, T. L., Jiang, J., Shi, H., Gui, C., Luo, R. H., Xie, X. J., Xiang, M. X., & Zhang, X. (2008). Hypoxic preconditioning attenuates hypoxia/reoxygenation-induced apoptosis in mesenchymal stem cells. Acta Pharmacologica Sinica, 29(1), 74–82.  https://doi.org/10.1111/j.1745-7254.2008.00716.x.CrossRefPubMedGoogle Scholar
  48. 48.
    Peng, G., Yuan, Y., He, Q., Wu, W., & Luo, B. Y. (2011). MicroRNA let-7e regulates the expression of caspase-3 during apoptosis of PC12 cells following anoxia/reoxygenation injury. Brain Research Bulletin, 86(3-4), 272–276.  https://doi.org/10.1016/j.brainresbull.2011.07.017.CrossRefPubMedGoogle Scholar
  49. 49.
    Konstantinidis, K., Whelan, R. S., & Kitsis, R. N. (2012). Mechanisms of cell death in heart disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 32(7), 1552–1562.  https://doi.org/10.1161/ATVBAHA.111.224915.CrossRefPubMedGoogle Scholar
  50. 50.
    Okada, K., Minamino, T., Tsukamoto, Y., Liao, Y., Tsukamoto, O., Takashima, S., Hirata, A., Fujita, M., Nagamachi, Y., Nakatani, T., Yutani, C., Ozawa, K., Ogawa, S., Tomoike, H., Hori, M., & Kitakaze, M. (2004). Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis. Circulation, 110(6), 705–712.  https://doi.org/10.1161/01.CIR.0000137836.95625.D4.CrossRefPubMedGoogle Scholar
  51. 51.
    Martindale, J. J., Fernandez, R., Thuerauf, D., Whittaker, R., Gude, N., Sussman, M. A., & Glembotski, C. C. (2006). Endoplasmic reticulum stress gene induction and protection from ischemia/reperfusion injury in the hearts of transgenic mice with a tamoxifen-regulated form of ATF6. Circulation Research, 98(9), 1186–1193.  https://doi.org/10.1161/01.RES.0000220643.65941.8d.CrossRefPubMedGoogle Scholar
  52. 52.
    Yamamoto, K., Sato, T., Matsui, T., Sato, M., Okada, T., Yoshida, H., Harada, A., & Mori, K. (2007). Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1. Developmental Cell, 13(3), 365–376.  https://doi.org/10.1016/j.devcel.2007.07.018.CrossRefPubMedGoogle Scholar
  53. 53.
    Chen, J. (2011). Multiple signal pathways in obesity-associated cancer. Obes Rev, 12(12), 1063–1070.  https://doi.org/10.1111/j.1467-789X.2011.00917.x.CrossRefPubMedGoogle Scholar
  54. 54.
    Tautenhahn, H. M., Bruckner, S., Uder, C., Erler, S., Hempel, M., von Bergen, M., Brach, J., Winkler, S., Pankow, F., Gittel, C., Baunack, M., Lange, U., Broschewitz, J., Dollinger, M., Bartels, M., Pietsch, U., Amann, K., & Christ, B. (2017). Mesenchymal stem cells correct haemodynamic dysfunction associated with liver injury after extended resection in a pig model. Science Reporter, 7(1), 2617.  https://doi.org/10.1038/s41598-017-02670-8.CrossRefGoogle Scholar
  55. 55.
    Wise, A. F., Williams, T. M., Kiewiet, M. B., Payne, N. L., Siatskas, C., Samuel, C. S., & Ricardo, S. D. (2014). Human mesenchymal stem cells alter macrophage phenotype and promote regeneration via homing to the kidney following ischemia-reperfusion injury. American Journal of Physiology. Renal Physiology, 306(10), F1222–F1235.  https://doi.org/10.1152/ajprenal.00675.2013.CrossRefPubMedGoogle Scholar
  56. 56.
    Eggenhofer, E., & Hoogduijn, M. J. Mesenchymal stem cell-educated macrophages. Transplant Research, 1(1), 12.  https://doi.org/10.1186/2047-1440-1-12.
  57. 57.
    Lim, J. Y., Im, K. I., Lee, E. S., Kim, N., Nam, Y. S., Jeon, Y. W., & Cho, S. G. (2016). Enhanced immunoregulation of mesenchymal stem cells by IL-10-producing type 1 regulatory T cells in collagen-induced arthritis. Science Reporter, 6, 26851.  https://doi.org/10.1038/srep26851.
  58. 58.
    Hou, Y., Ryu, C. H., Jun, J. A., Kim, S. M., Jeong, C. H., & Jeun, S. S. (2014). IL-8 enhances the angiogenic potential of human bone marrow mesenchymal stem cells by increasing vascular endothelial growth factor. Cell Biology International, 38(9), 1050–1059.  https://doi.org/10.1002/cbin.10294.PubMedGoogle Scholar
  59. 59.
    Bernardo, M. E., & Fibbe, W. E. (2013). Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell, 13(4), 392–402.  https://doi.org/10.1016/j.stem.2013.09.006z.CrossRefPubMedGoogle Scholar
  60. 60.
    Kyurkchiev, D., Bochev, I., Ivanova-Todorova, E., Mourdjeva, M., Oreshkova, T., Belemezova, K., & Kyurkchiev, S. (2014). Secretion of immunoregulatory cytokines by mesenchymal stem cells. World Journal Stem Cells, 6(5), 552–570.  https://doi.org/10.4252/wjsc.v6.i5.552.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Cellular and Molecular Therapeutics Laboratory, Centre for Biomaterials Cellular and Molecular Theranostics (CBCMT)Vellore Institute of Technology (VIT)VelloreIndia

Personalised recommendations