Mesenchymal Stromal Cell Secretome: Influencing Therapeutic Potential by Cellular Pre-conditioning

Joana R Ferreira, Graciosa Q Teixeira, Susana G Santos, Mário A Barbosa, Graça Almeida-Porada, Raquel M Gonçalves, Joana R Ferreira, Graciosa Q Teixeira, Susana G Santos, Mário A Barbosa, Graça Almeida-Porada, Raquel M Gonçalves

Abstract

Mesenchymal stromal cells (MSCs) are self-renewing, culture-expandable adult stem cells that have been isolated from a variety of tissues, and possess multipotent differentiation capacity, immunomodulatory properties, and are relatively non-immunogenic. Due to this unique set of characteristics, these cells have attracted great interest in the field of regenerative medicine and have been shown to possess pronounced therapeutic potential in many different pathologies. MSCs' mode of action involves a strong paracrine component resulting from the high levels of bioactive molecules they secrete in response to the local microenvironment. For this reason, MSCs' secretome is currently being explored in several clinical contexts, either using MSC-conditioned media (CM) or purified MSC-derived extracellular vesicles (EVs) to modulate tissue response to a wide array of injuries. Rather than being a constant mixture of molecular factors, MSCs' secretome is known to be dependent on the diverse stimuli present in the microenvironment that MSCs encounter. As such, the composition of the MSCs' secretome can be modulated by preconditioning the MSCs during in vitro culture. This manuscript reviews the existent literature on how preconditioning of MSCs affects the therapeutic potential of their secretome, focusing on MSCs' immunomodulatory and regenerative features, thereby providing new insights for the therapeutic use of MSCs' secretome.

Keywords: MSCs (Mesenchymal Stromal Cells); immunomodulation; pre-conditioning; regeneration; secretome; therapeutic potential.

Figures

Figure 1
Figure 1
MSCs phenotype, differentiation potential, and immunological properties. Schematic representation of MSCs phenotype and immunological profile. (A) MSCs capacity of differentiation into osteogenic, chondrogenic and adipogenic lineages. (B) MSCs phenotype accordingly with the International Society for Stem Cell Research (ISSCR). (C) MSCs immunological profile. (D) Soluble factors families produced by MSCs and profile of interaction with immune cells.
Figure 2
Figure 2
The effect of different preconditioning stimuli in the MSCs response. Schematic representation of known effects of highly studied preconditioning factors—hypoxia (in blue), 3D culture (in blue), specific soluble factors (green), and inflammatory cytokines (red)—in the MSCs response. Blue pathway presents the effect of a hypoxic environment on the cells, which is mediated by specific signaling pathaways (Akt, ERK, p38MAPK) and culminates in the stimulation of the above signaled effects. Tridimensional culture is also represented in blue. MSCs preconditioning with specific soluble factors (SDF-1, TGF-α, and melatonin) seems to stimulate the same signaling pathways as a hypoxic environment and, thus, elicit the same general response from these cells. The use of inflammatory cytokines to influence the MSC response, as represented in red, besides promoting the specific above shown effects, also stimulates the production of factors that seem to be common to all the other preconditioning factors. The pathways that mediate this activity are still to be determined.

References

    1. Ullah I, Subbarao RB, Rho GJ. Human mesenchymal stem cells - current trends and future prospective. Biosci Rep. (2015) 35:2. 10.1042/BSR20150025
    1. Squillaro T, Peluso G, Galderisi U. Clinical trials with mesenchymal stem cells: an update. Cell Trans. (2016) 25:829–48. 10.3727/096368915X689622
    1. Wang J, Liao L, Tan J. Mesenchymal-stem-cell-based experimental and clinical trials: current status and open questions. Expert Opin Biol Ther. (2011) 11:893–909. 10.1517/14712598.2011.574119
    1. Kim N, Cho SG. Clinical applications of mesenchymal stem cells. Korean J Intern Med. (2013) 28:387–402. 10.3904/kjim.2013.28.4.387
    1. Richardson SM, Hoyland JA, Mobasheri R, Csaki C, Shakibaei M, Mobasheri A. Mesenchymal stem cells in regenerative medicine: opportunities and challenges for articular cartilage and intervertebral disc tissue engineering. J Cell Physiol. (2010) 222:23–32. 10.1002/jcp.21915
    1. Rohban R, Pieber TR. Mesenchymal stem and progenitor cells in regeneration: tissue specificity and regenerative potential. Stem Cells Int. (2017) 2017:1–16. 10.1155/2017/5173732
    1. Christensen ME, Turner BE, Sinfield L, Kollar JK, Cullup H, Waterhouse NJ, et al. . Mesenchymal stromal cells transiently alter the inflammatory milieu post-transplant to delay graft-versus-host disease. Haematologica (2010) 95:2102–10. 10.3324/haematol.2010.028910
    1. Sun L, Akiyama K, Zhang H, Yamaza T, Hou Y, Zhao S, et al. Mesenchymal stem cell transplantation reverses multi-organ dysfunction in systemic lupus erythematosus mice and humans. Stem Cells (2009) 27:1421–32. 10.1002/stem.68
    1. Liang J, Zhang H, Hua B, Wang H, Lu L, Shi S, et al. . Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study. Ann Rheum Dis. (2010) 69:1423–9. 10.1136/ard.2009.123463
    1. Ciccocioppo R, Bernardo ME, Sgarella A, Maccario R, Avanzini MA, Ubezio C, et al. . Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn's disease. Gut (2011) 60:788–98. 10.1136/gut.2010.214841
    1. Amado LC, Saliaris AP, Schuleri KH, St John M, Xie JS, Cattaneo S, et al. . Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction Proc Natl Acad Sci USA. (2005) 102:11474–9. 10.1073/pnas.0504388102
    1. Cai M, Shen R, Song L, Lu M, Wang J, Zhao S, et al. Bone marrow mesenchymal stem cells (BM-MSCs) improve heart function in swine myocardial infarction model through paracrine effects. Sci Rep. (2016) 6:28250 10.1038/srep28250
    1. Bang OY, Lee JS, Lee PH, Lee G. Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol. 57:874–82. 10.1002/ana.20501
    1. Mohyeddin Bonab M, Yazdanbakhsh S, Lotfi J, Alimoghaddom K, Talebian F, Hooshmand F, et al. . Does mesenchymal stem cell therapy help multiple sclerosis patients? Rep Pilot Study Iran J Immunol. (2007) 4:50–7.
    1. Karussis D, Karageorgiou C, Vaknin-Dembinsky A, Gowda-Kurkalli B, Gomori J, Kassis IM, et al. . Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol. (2010) 67:1187–94. 10.1001/archneurol.2010.248
    1. Kharaziha P, Hellstrom PM, Noorinayer B, Farzaneh F, Aghajani K, Jafari F, et al. . Improvement of liver function in liver cirrhosis patients after autologous mesenchymal stem cell injection: a phase I-II clinical trial. Eur J Gastroenterol Hepatol. (2009) 21:1199–205. 10.1097/MEG.0b013e32832a1f6c
    1. Shi M, Zhang Z, Xu R, Lin H, Fu J, Zou Z, et al. . Human mesenchymal stem cell transfusion is safe and improves liver function in acute-on-chronic liver failure patients. Stem Cells Transl Med. (2012) 1:725–31. 10.5966/sctm.2012-0034
    1. Chang C, Wang X, Niu D, Zhang Z, Zhao H, Gong F. Mesenchymal stem cells adopt beta-cell fate upon diabetic pancreatic microenvironment. Pancreas (2009) 38:275–81. 10.1097/MPA.0b013e318191521c
    1. Holmes D. Diabetes: MSC transplant prevents [beta]-cell dysfunction. Nat Rev Endocrinol. (2014) 10:701. 10.1038/nrendo.2014.172
    1. Kursova LV, Konoplyannikov AG, Pasov VV, Ivanova IN, Poluektova MV, Konoplyannikova OA. Possibilities for the use of autologous mesenchymal stem cells in the therapy of radiation-induced lung injuries. Bull Exp Biol Med. (2009) 147:542–6. 10.1007/s10517-009-0538-7
    1. Chamberlain G, Fox J, Ashton B, Middleton J. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells (2007) 25:2739–49. 10.1634/stemcells.2007-0197
    1. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood (2005) 105:1815–22. 10.1182/blood-2004-04-1559
    1. Casiraghi F, Azzollini N, Cassis P, Imberti B, Morigi M, Cugini D, et al. . Pretransplant infusion of mesenchymal stem cells prolongs the survival of a semiallogeneic heart transplant through the generation of regulatory T cells. J Immunol. (2008) 181:3933–46. 10.4049/jimmunol.181.6.3933
    1. Jarvinen L, Badri L, Wettlaufer S, Ohtsuka T, Standiford T, Toews GB, et al. . Lung resident mesenchymal stem cells isolated from human lung allografts inhibit T cell proliferation via a soluble mediator. J Immunol. (2008) 181:4389–96. 10.4049/jimmunol.181.6.4389
    1. Chan JL, Tang KC, Patel AP, Bonilla LM, Pierobon N, Ponzio NM, et al. . Antigen-presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-gamma. Blood (2006) 107:4817–24. 10.1182/blood-2006-01-0057
    1. Stagg J, Pommey S, Eliopoulos N, Galipeau J. Interferon-gamma-stimulated marrow stromal cells: a new type of nonhematopoietic antigen-presenting cell. Blood (2006) 107:2570–7. 10.1182/blood-2005-07-2793
    1. Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 98: 1076–84. 10.1002/jcb.20886
    1. Picinich SC, Mishra PJ, Mishra PJ, Glod J, Banerjee D. The therapeutic potential of mesenchymal stem cells. Cell- & tissue-based therapy. Expert Opin Biol Ther. (2007) 7:965–73. 10.1517/14712598.7.7.965
    1. Caplan AI. Why are MSCs therapeutic? J Pathol. (2009) 217:318–24. 10.1002/path.2469
    1. Vizoso FJ, Eiro N, Cid S, Schneider J, Perez-Fernandez R. Mesenchymal stem cell secretome: toward cell-free therapeutic strategies in regenerative medicine. Int J Mol Sci. (2017) 18:1852. 10.3390/ijms18091852
    1. Baraniak PR, McDevitt TC. Stem cell paracrine actions and tissue regeneration. Regenerat Med. (2010) 5:121–43. 10.2217/rme.09.74
    1. Madrigal M, Rao KS, Riordan NH. A review of therapeutic effects of mesenchymal stem cell secretions and induction of secretory modification by different culture methods. J Transl Med. (2014) 12:1–14. 10.1186/s12967-014-0260-8
    1. Lötvall J, Hill AF, Hochberg F, Buzás EI, Di Vizio D, Gardiner C, et al. . Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J Extracellu Vesicles (2014) 3, 1–6. 10.3402/jev.v3403.26913
    1. Stahl PD, Raposo G. Exosomes and extracellular vesicles: the path forward. Essays Biochem. (2018) 62:119–24. 10.1042/EBC20170088
    1. Camussi G, Deregibus MC, Bruno S, Cantaluppi V, Biancone L. Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney Int. (2010) 78:838–48. 10.1038/ki.2010.278
    1. Polacek M, Bruun JA, Elvenes J, Figenschau Y, Martinez I. The secretory profiles of cultured human articular chondrocytes and mesenchymal stem cells: implications for autologous cell transplantation strategies. Cell Trans. (2011) 20:1381–93. 10.3727/096368910X550215
    1. Kyurkchiev D, Bochev I, Ivanova-Todorova E, Mourdjeva M, Oreshkova T, Belemezova K, et al. . Secretion of immunoregulatory cytokines by mesenchymal stem cells. World J Stem Cells (2014) 6:552–70. 10.4252/wjsc.v6.i5.552
    1. Linero I, Chaparro O. Paracrine effect of mesenchymal stem cells derived from human adipose tissue in bone regeneration. PLoS ONE (2014) 9:e107001. 10.1371/journal.pone.0107001
    1. Pereira T, Ivanova G, Caseiro AR, Barbosa P, Bártolo PJ, Santos JD, et al. . MSCs conditioned media and umbilical cord blood plasma metabolomics and composition. PLoS ONE (2014) 9:e113769. 10.1371/journal.pone.0113769
    1. Wang M, Crisostomo PR, Herring C, Meldrum KK, Meldrum DR. Human progenitor cells from bone marrow or adipose tissue produce VEGF, HGF, and IGF-I in response to TNF by a p38 MAPK-dependent mechanism. Am J Physiol Regul Integr Comp Physiol. (2006) 291:R880–4. 10.1152/ajpregu.00280.2006
    1. Inukai T, Katagiri W, Yoshimi R, Osugi M, Kawai T, Hibi H, et al. . Novel application of stem cell-derived factors for periodontal regeneration. Biochem Biophys Res Commun. (2013) 430:763–8. 10.1016/j.bbrc.2012.11.074
    1. Liu CH, Hwang S-M. Cytokine interactions in mesenchymal stem cells from cord blood. Cytokine (2005) 32:270–9. 10.1016/j.cyto.2005.11.003
    1. Osugi M, Katagiri W, Yoshimi R, Inukai T, Hibi H, Ueda M. Conditioned media from mesenchymal stem cells enhanced bone regeneration in rat calvarial bone defects. Tissue Eng Part A (2012) 18:1479–89. 10.1089/ten.tea.2011.0325
    1. Teng X, Chen L, Chen W, Yang J, Yang Z, Shen Z. Mesenchymal stem cell-derived exosomes improve the microenvironment of infarcted myocardium contributing to angiogenesis and anti-inflammation. Cell Physiol Biochem. (2015) 37:2415–24. 10.1159/000438594
    1. Li T, Yan Y, Wang B, Qian H, Zhang X, Shen L, et al. . Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem Cells Dev. (2012) 22:845–54. 10.1089/scd.2012.0395
    1. Teixeira FG, Carvalho MM, Neves-Carvalho A, Panchalingam KM, Behie LA, Pinto L, et al. . Secretome of mesenchymal progenitors from the umbilical cord acts as modulator of neural/glial proliferation and differentiation. Stem Cell Rev. (2015) 11:288–97. 10.1007/s12015-014-9576-2
    1. Chen L, Xu Y, Zhao J, Zhang Z, Yang R, Xie J. Conditioned medium from hypoxic bone marrow-derived mesenchymal stem cells enhances wound healing in mice. PLoS ONE (2014) 9:e96161. 10.1371/journal.pone.0096161
    1. Ando Y, Matsubara K, Ishikawa J, Fujio M, Shohara R, Hibi H, et al. . Stem cell-conditioned medium accelerates distraction osteogenesis through multiple regenerative mechanisms. Bone (2014) 61:82–90. 10.1016/j.bone.2013.12.029
    1. Parekkadan B, van Poll D, Suganuma K, Carter EA, Berthiaume F, Tilles AW, et al. . Mesenchymal stem cell-derived molecules reverse fulminant hepatic failure. PLoS ONE (2007) 2:e941. 10.1371/journal.pone.0000941
    1. Imberti B, Morigi M, Tomasoni S, Rota C, Corna D, Longaretti L, et al. . Insulin-like growth factor-1 sustains stem cell mediated renal repair. J Am Soc Nephrol. (2007) 18:2921–8. 10.1681/ASN.2006121318
    1. Iso Y, Spees JL, Serrano C, Bakondi B, Pochampally R, Song YH, et al. . Multipotent human stromal cells improve cardiac function after myocardial infarction in mice without long-term engraftment. Biochem Biophys Res Commun. (2007) 354:700–6. 10.1016/j.bbrc.2007.01.045
    1. Javazon EH, Keswani SG, Badillo AT, Crombleholme TM, Zoltick PW, Radu AP, et al. . Enhanced epithelial gap closure and increased angiogenesis in wounds of diabetic mice treated with adult murine bone marrow stromal progenitor cells Wound Repair Regen. (2007) 15:350–9. 10.1111/j.1524-475X.2007.00237.x
    1. Yang SH, Wu CC, Shih TT, Sun YH, Lin FH. In Vitro study on interaction between human nucleus pulposus cells and mesenchymal stem cells through paracrine stimulation. Spine (2008) 33:1951–7. 10.1097/BRS.0b013e31817e6974
    1. Brisby H, Papadimitriou N, Brantsing C, Bergh P, Lindahl A, Barreto Henriksson H. The presence of local mesenchymal progenitor cells in human degenerated intervertebral discs and possibilities to influence these in vitro: a descriptive study in humans. Stem Cells Dev. (2013) 22:804–14. 10.1089/scd.2012.0179
    1. Pereira CL, Teixeira GQ, Ribeiro-Machado C, Caldeira J, Costa M, Figueiredo F, et al. . Mesenchymal stem/stromal cells seeded on cartilaginous endplates promote intervertebral disc regeneration through extracellular matrix remodeling. Sci Rep. (2016) 6:33836. 10.1038/srep33836
    1. Teixeira GQ, Pereira CL, Ferreira JR, Maia AF, Gomez-Lazaro M, Barbosa MA, et al. . Immunomodulation of human mesenchymal stem/stromal cells in intervertebral disc degeneration: insights from a proinflammatory/degenerative ex vivo model. Spine (2017) 43:E673–82. 10.1097/BRS.0000000000002494
    1. Zheng ZM, Lu MM, Zhou L, Sun Y, Lv F, Leung VYL, et al. The potential of umbilical cord derived mesenchymal stem cells in intervertebral disc repair. Global Spine J. Germany, Georg Thieme Verlag; (2014) 4:S81 10.1055/s-0034-1376649
    1. Strassburg S, Hodson NW, Hill PI, Richardson SM, Hoyland JA. Bi-directional exchange of membrane components occurs during co-culture of mesenchymal stem cells and nucleus pulposus cells. PLoS ONE (2012) 7:e33739. 10.1371/journal.pone.0033739
    1. Dai W, Hale SL, Kloner RA. Role of a paracrine action of mesenchymal stem cells in the improvement of left ventricular function after coronary artery occlusion in rats. Regenet Med. (2007) 2:63–8. 10.2217/17460751.2.1.63
    1. Li Y, Chen J, Zhang CL, Wang L, Lu D, Katakowski M, et al. . Gliosis and brain remodeling after treatment of stroke in rats with marrow stromal cells. Glia (2005) 49:407–17. 10.1002/glia.20126
    1. Salgado AJ, Reis RL, Sousa NJ, Gimble JM. Adipose tissue derived stem cells secretome: soluble factors and their roles in regenerative medicine. Curr Stem Cell Res Ther. (2010) 5:103–10. 10.2174/157488810791268564
    1. van Koppen A, Joles JA, van Balkom BWM, Lim SK, de Kleijn D, Giles RH, et al. . Human embryonic mesenchymal stem cell-derived conditioned medium rescues kidney function in rats with established chronic kidney disease. PLoS ONE (2012) 7:e38746. 10.1371/journal.pone.0038746
    1. Silva AM, Teixeira JH, Almeida MI, Goncalves RM, Barbosa MA, Santos SG. Extracellular Vesicles: Immunomodulatory messengers in the context of tissue repair/regeneration. Eur J Pharm Sci. (2017) 98:86–95. 10.1016/j.ejps.2016.09.017
    1. Lai RC, Arslan F, Lee MM, Sze NS, Choo KA, Chen TS, et al. . Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res. (2010) 4:214–22. 10.1016/j.scr.2009.12.003
    1. Doeppner TR, Herz J, Gorgens A, Schlechter J, Ludwig A, Radtke KS, et al. . Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression. Stem Cells Transl Med. (2015) 4:1131–43. 10.5966/sctm.2015-0078
    1. Xin H, Li Y, Liu Z, Wang X, Shang X, Cui Y, et al. . MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles. Stem Cells (2013) 31:2737–46. 10.1002/stem.1409
    1. Ophelders DR, Wolfs TG, Jellema RK, Zwanenburg A, Andriessen P, Delhaas T, et al. . Mesenchymal stromal cell-derived extracellular vesicles protect the fetal brain after hypoxia-ischemia. Stem Cells Transl Med. (2016) 5:754–63. 10.5966/sctm.2015-0197
    1. Gangadaran P, Rajendran RL, Lee HW, Kalimuthu S, Hong CM, Jeong SY, et al. . Extracellular vesicles from mesenchymal stem cells activates VEGF receptors and accelerates recovery of hindlimb ischemia J Control Rel. (2017) 264:112–26. 10.1016/j.jconrel.2017.08.022
    1. Gatti S, Bruno S, Deregibus MC, Sordi A, Cantaluppi V, Tetta C, et al. . Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia–reperfusion-induced acute and chronic kidney injury. Nephrol Dial Trans. (2011) 26:1474–83. 10.1093/ndt/gfr015
    1. Bruno S, Grange C, Collino F, Deregibus MC, Cantaluppi V, Biancone L, et al. . Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury. PLoS ONE (2012) 7:e33115. 10.1371/journal.pone.0033115
    1. Zhou BR, Xu Y, Guo SL, Xu Y, Wang Y, Zhu F, et al. . The effect of conditioned media of adipose-derived stem cells on wound healing after ablative fractional carbon dioxide laser resurfacing. Biomed Res Int. (2013) 2013:519126. 10.1155/2013/519126
    1. Kordelas L, Rebmann V, Ludwig AK, Radtke S, Ruesing J, Doeppner TR, et al. . MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease Leukemia (2014) 28:970–3. 10.1038/leu.2014.41
    1. Fukuoka H, Suga H. Hair regeneration treatment using adipose-derived stem cell conditioned medium: follow-up with trichograms. Eplasty (2015) 15:e10.
    1. Shin H, Ryu HH, Kwon O, Park BS, Jo SJ. Clinical use of conditioned media of adipose tissue-derived stem cells in female pattern hair loss: a retrospective case series study. Int J Dermatol. (2015) 54:730–5. 10.1111/ijd.12650
    1. Katagiri W, Osugi M, Kawai T, Hibi H. First-in-human study and clinical case reports of the alveolar bone regeneration with the secretome from human mesenchymal stem cells. Head Face Med. (2016) 12:5. 10.1186/s13005-016-0101-5
    1. Amos PJ, Kapur SK, Stapor PC, Shang H, Bekiranov S, Khurgel M, et al. . Human adipose-derived stromal cells accelerate diabetic wound healing: impact of cell formulation and delivery. Tissue Eng Part A (2010) 16:1595–606. 10.1089/ten.tea.2009.0616
    1. Hemeda H, Jakob M, Ludwig AK, 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 Dev. (2010) 19:693–706. 10.1089/scd.2009.0365
    1. Hagmann S, Moradi B, Frank S, Dreher T, Kämmerer P, Richter WW, et al. . Different culture media affect growth characteristics, surface marker distribution and chondrogenic differentiation of human bone marrow-derived mesenchymal stromal cells. BMC Musculoskeletal Disord. (2013) 14:223. 10.1186/1471-2474-14-223
    1. Lee KS, Cha SH, Kang HW, Song JY, Lee KW, Ko KB, et al. Effects of serial passage on the characteristics and chondrogenic differentiation of canine umbilical cord matrix derived mesenchymal stem cells asian-australasian J Anim Sci. (2013) 26:588–95. 10.5713/ajas.2012.12488
    1. Elahi KC, Klein G, Avci-Adali M, Sievert KD, MacNeil S, Aicher WK. Human mesenchymal stromal cells from different sources diverge in their expression of cell surface proteins and display distinct differentiation patterns. Stem Cells Int. (2016) 2016:5646384. 10.1155/2016/5646384
    1. Heathman TRJ, Rafiq QA, Chan AKC, Coopman K, Nienow AW, Kara B, et al. Characterization of human mesenchymal stem cells from multiple donors and the implications for large scale bioprocess development. Biochem Eng J. (2016) 108:14–23. 10.1016/j.bej.2015.06.018
    1. Hu X, Xu Y, Zhong Z, Wu Y, Zhao J, Wang Y, et al. . A large-scale investigation of hypoxia-preconditioned allogeneic mesenchymal stem cells for myocardial repair in nonhuman primates: paracrine activity without remuscularization. Circ Res. (2016) 118:970–83. 10.1161/CIRCRESAHA.115.307516
    1. Bartosh TJ, Ylöstalo JH, Mohammadipoor A, Bazhanov N, Coble K, Claypool K, et al. . Aggregation of human mesenchymal stromal cells (MSCs) into 3D spheroids enhances their antiinflammatory properties. Proc Natl Acad Sci USA. (2010) 107:13724–9. 10.1073/pnas.1008117107
    1. Suzuki S, Muneta T, Tsuji K, Ichinose S, Makino H, Umezawa A, et al. . Properties and usefulness of aggregates of synovial mesenchymal stem cells as a source for cartilage regeneration. Arthritis Res Ther. (2012) 14:R136. 10.1186/ar3869
    1. Xu Y, Shi T, Xu A, Zhang L. 3D spheroid culture enhances survival and therapeutic capacities of MSCs injected into ischemic kidney. J Cell Mol Med. (2016) 20:203–13. 10.1111/jcmm.12651
    1. Cui X, Wang H, Guo H, Wang C, Ao H, Liu X, et al. . Transplantation of mesenchymal stem cells preconditioned with diazoxide, a mitochondrial ATP-sensitive potassium channel opener, promotes repair of myocardial infarction in rats. Tohoku J Exp Med. (2010) 220:139–47. 10.1620/tjem.220.139
    1. Pessina A, Cocce V, Pascucci L, Bonomi A, Cavicchini L, Sisto F, et al. . Mesenchymal stromal cells primed with paclitaxel attract and kill leukaemia cells, inhibit angiogenesis and improve survival of leukaemia-bearing mice. Br J Haematol. (2013) 160:766–78. 10.1111/bjh.12196
    1. Kang H, Kim KH, Lim J, Kim YS, Heo J, Choi J, et al. . The therapeutic effects of human mesenchymal stem cells primed with sphingosine-1 phosphate on pulmonary artery hypertension. Stem Cells Dev. (2015) 24:1658–71. 10.1089/scd.2014.0496
    1. Pasha Z, Wang Y, Sheikh R, Zhang D, Zhao T, Ashraf M. Preconditioning enhances cell survival and differentiation of stem cells during transplantation in infarcted myocardium. Cardiovasc Res. (2008) 77:134–42. 10.1093/cvr/cvm025
    1. Herrmann JL, Wang Y, Abarbanell AM, Weil BR, Tan J, Meldrum DR. Preconditioning mesenchymal stem cells with transforming growth factor-alpha improves mesenchymal stem cell-mediated cardioprotection. Shock (2010) 33:24–30. 10.1097/SHK.0b013e3181b7d137
    1. Uemura R, Xu M, Ahmad N, Ashraf M. Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling. Circ Res. (2006) 98:1414–21. 10.1161/01.RES.0000225952.61196.39
    1. Leroux L, Descamps B, Tojais NF, Seguy B, Oses P, Moreau C, et al. . Hypoxia preconditioned mesenchymal stem cells improve vascular and skeletal muscle fiber regeneration after ischemia through a wnt4-dependent pathway. Mol Ther. (2010) 18:1545–52. 10.1038/mt.2010.108
    1. Wei L, Fraser JL, Lu ZY, Hu X, Yu SP. Transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells enhances angiogenesis and neurogenesis after cerebral ischemia in rats. Neurobiol Dis. (2012) 46:635–45. 10.1016/j.nbd.2012.03.002
    1. Kong P, Xie X, Li F, Liu Y, Lu Y. Placenta mesenchymal stem cell accelerates wound healing by enhancing angiogenesis in diabetic Goto-Kakizaki (GK) rats. Biochem Biophys Res Commun. (2013) 438:410–9. 10.1016/j.bbrc.2013.07.088
    1. Yu J, Yin S, Zhang W, Gao F, Liu Y, Chen Z. Hypoxia preconditioned bone marrow mesenchymal stem cells promote liver regeneration in a rat massive hepatectomy model. Stem Cell Res Ther. (2013) 4:83. 10.1186/scrt234
    1. Zhang W, Liu L, Huo Y, Yang Y, Wang Y. Hypoxia-pretreated human MSCs attenuate acute kidney injury through enhanced angiogenic and antioxidative capacities. Biomed Res Int. (2014) 2014:462472. 10.1155/2014/462472
    1. Jiang CM, Liu J, Zhao JY, Xiao L, An S, Gou YC, et al. . Effects of hypoxia on the immunomodulatory properties of human gingiva-derived mesenchymal stem cells J Dent Res. (2015) 94:69–77. 10.1177/0022034514557671
    1. Lan YW, Choo KB, Chen CM, Hung TH, Chen YB, Hsieh CH, et al. . Hypoxia-preconditioned mesenchymal stem cells attenuate bleomycin-induced pulmonary fibrosis. Stem Cell Res Ther. (2015) 6:97. 10.1186/s13287-015-0081-6
    1. Mias C, Trouche E, Seguelas MH, Calcagno F, Dignat-George F, Sabatier F, et al. . Ex vivo pretreatment with melatonin improves survival, proangiogenic/mitogenic activity, and efficiency of mesenchymal stem cells injected into ischemic kidney. Stem Cells (2008) 26:1749–57. 10.1634/stemcells.2007-1000
    1. Tang Y, Cai B, Yuan F, He X, Lin X, Wang J, et al. . Melatonin pretreatment improves the survival and function of transplanted mesenchymal stem cells after focal cerebral ischemia. Cell Trans. (2014) 23:1279–91. 10.3727/096368913X667510
    1. Liu C, Fan Y, Zhou L, Zhu HY, Song YC, Hu L, et al. . Pretreatment of mesenchymal stem cells with angiotensin II enhances paracrine effects, angiogenesis, gap junction formation and therapeutic efficacy for myocardial infarction. Int J Cardiol. (2015) 188:22–32. 10.1016/j.ijcard.2015.03.425
    1. Wang CC, Chen CH, Hwang SM, Lin WW, Huang CH, Lee WY, et al. . Spherically symmetric mesenchymal stromal cell bodies inherent with endogenous extracellular matrices for cellular cardiomyoplasty. Stem Cells (2009) 27:724–32. 10.1634/stemcells.2008-0944
    1. Suenaga H, Furukawa KS, Suzuki Y, Takato T, Ushida T. Bone regeneration in calvarial defects in a rat model by implantation of human bone marrow-derived mesenchymal stromal cell spheroids. J Mater Sci Mater Med. (2015) 26:254. 10.1007/s10856-015-5591-3
    1. Zhang X, Hu M-G, Pan K, Li C-H, Liu R. 3D spheroid culture enhances the expression of antifibrotic factors in human adipose-derived mscs and improves their therapeutic effects on hepatic fibrosis. Stem Cells Int. (2016) 2016:4626073. 10.1155/2016/4626073
    1. Yao Y, Zhang F, Wang L, Zhang G, Wang Z, Chen J, et al. . Lipopolysaccharide preconditioning enhances the efficacy of mesenchymal stem cells transplantation in a rat model of acute myocardial infarction. J Biomed Sci. (2009) 16:74. 10.1186/1423-0127-16-74
    1. Tsai LK, Wang Z, Munasinghe J, Leng Y, Leeds P, Chuang DM. Mesenchymal stem cells primed with valproate and lithium robustly migrate to infarcted regions and facilitate recovery in a stroke model. Stroke (2011) 42:2932–9. 10.1161/STROKEAHA.110.612788
    1. Li N, Yang YJ, Qian HY, Li Q, Zhang Q, Li XD, et al. Intravenous administration of atorvastatin-pretreated mesenchymal stem cells improves cardiac performance after acute myocardial infarction: role of CXCR(2013) 4. Am J Trans Res. (2015) 7:1058–70.
    1. Ejtehadifar M, Shamsasenjan K, Movassaghpour A, Akbarzadehlaleh P, Dehdilani N, Abbasi P, et al. . The effect of hypoxia on mesenchymal stem cell biology. Adv Pharmaceut Bull. (2015) 5:141–9. 10.15171/apb.2015.021
    1. Das R, Jahr H, van Osch GJ, Farrell E. The role of hypoxia in bone marrow-derived mesenchymal stem cells: considerations for regenerative medicine approaches. Tissue Eng Part B Rev. (2010) 16:159–68. 10.1089/ten.teb.2009.0296
    1. Hawkins KE, Sharp TV, McKay TR. The role of hypoxia in stem cell potency and differentiation. Regenet Med. (2013) 8:771–82. 10.2217/rme.13.71
    1. Berniakovich I, Giorgio M. Low oxygen tension maintains multipotency, whereas normoxia increases differentiation of mouse bone marrow stromal cells. Int J Mol Sci. (2013) 14:2119–34. 10.3390/ijms14012119
    1. Carrero R, Cerrada I, Lledo E, Dopazo J, Garcia-Garcia F, Rubio MP, et al. . IL1beta induces mesenchymal stem cells migration and leucocyte chemotaxis through NF-kappaB. Stem Cell Rev. (2012) 8:905–16. 10.1007/s12015-012-9364-9
    1. Gnecchi M, He H, Noiseux N, Liang OD, Zhang L, Morello F, et al. . Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J. (2006) 20:661–9. 10.1096/fj.05-5211com
    1. Xie L, Mao M, Zhou L, Zhang L, Jiang B. Signal factors secreted by 2D and spheroid mesenchymal stem cells and by cocultures of mesenchymal stem cells derived microvesicles and retinal photoreceptor neurons. Stem Cells Int. (2017) 2017:2730472. 10.1155/2017/2730472
    1. Lee MJ, Kim J, Kim MY, Bae YS, Ryu SH, Lee TG, et al. . Proteomic analysis of tumor necrosis factor-alpha-induced secretome of human adipose tissue-derived mesenchymal stem cells. J Proteome Res. (2010) 9:1754–62. 10.1021/pr900898n
    1. Heo SC, Jeon ES, Lee IH, Kim HS, Kim MB, Kim JH. Tumor necrosis factor-alpha-activated human adipose tissue-derived mesenchymal stem cells accelerate cutaneous wound healing through paracrine mechanisms. J Invest Dermatol. (2011) 131:1559–67. 10.1038/jid.2011.64
    1. Jin P, Zhao Y, Liu H, Chen J, Ren J, Jin J, et al. . Interferon-γ and tumor necrosis factor-α polarize bone marrow stromal cells uniformly to a Th1 phenotype. Sci Rep. (2016) 6:26345. 10.1038/srep26345
    1. Liu H, Xue W, Ge G, Luo X, Li Y, Xiang H, et al. . Hypoxic preconditioning advances CXCR4 and CXCR7 expression by activating HIF-1α in MSCs. Biochem Biophys Res Commun. (2010) 401:509–15. 10.1016/j.bbrc.2010.09.076
    1. Fan H, Zhao G, Liu L, Liu F, Gong W, Liu X, et al. . Pre-treatment with IL-1β enhances the efficacy of MSC transplantation in DSS-induced colitis. Cell Mol Immunol. (2012) 9:473–81. 10.1038/cmi.2012.40
    1. Kim YS, Noh MY, Cho KA, Kim H, Kwon MS, Kim KS, et al. . Hypoxia/reoxygenation-preconditioned human bone marrow-derived mesenchymal stromal cells rescue ischemic rat cortical neurons by enhancing trophic factor release Mol Neurobiol. (2015) 52:792–803. 10.1007/s12035-014-8912-5
    1. Jun EK, Zhang Q, Yoon BS, Moon J, Lee G, Park G. Hypoxic conditioned medium from human amniotic fluid-derived mesenchymal stem cells accelerates skin wound healing through TGF-β/SMAD2 and PI3K/Akt pathways. Int J Mol Sci. (2014) 15:605–28. 10.3390/ijms15010605
    1. Francois M, Romieu-Mourez R, Li M, Galipeau J. Human MSC suppression correlates with cytokine induction of indoleamine 2,3-dioxygenase and bystander M2 macrophage differentiation. Mol Ther. (2012) 20:187–95. 10.1038/mt.2011.189
    1. Liang C, Chen SL, Wang M, Zhai WJ, Zhou Z, Pang AM, et al. Synergistic immunomodulatory effects of interferon-gamma and bone marrow mesenchymal stem cell]. Zhonghua xueyexue zazhi. (2013) 34:213–6. 10.3760/cma.j.issn.0253-2727.2013.03.007
    1. Noone C, Kihm A, English K, O'Dea S, Mahon BP. IFN-γ stimulated human umbilical-tissue derived cells potently suppress NK activation and resist NK mediated cytotoxicity in vitro. Stem Cells Dev. (2013) 15, 3003–3014. 10.1089/scd.2013.0028
    1. Tu Z, Li Q, Bu H, Lin F. Mesenchymal stem cells inhibit complement activation by secreting factor H. Stem Cells Dev. (2010) 19:1803–9. 10.1089/scd.2009.0418
    1. Du L, Lv R, Yang X, Cheng S, Ma T, Xu J. Hypoxic conditioned medium of placenta-derived mesenchymal stem cells protects against scar formation. Life Sci. (2016) 149:51–7. 10.1016/j.lfs.2016.02.050
    1. Lotfinia M, Lak S, Mohammadi Ghahhari N, Johari B, Maghsood F, Parsania S, et al. . Hypoxia pre-conditioned embryonic mesenchymal stem cell secretome reduces il-10 production by peripheral blood mononuclear cells. Iran Biomed J. (2016) 21:24–31. 10.6091/.21.1.24
    1. Ivanova-Todorova E, Bochev I, Dimitrov R, Belemezova K, Mourdjeva M, Kyurkchiev S, et al. . Conditioned medium from adipose tissue-derived mesenchymal stem cells induces CD4+FOXP3+ cells and increases IL-10 secretion. J Biomed Biotechnol. (2012) 2012:295167. 10.1155/2012/295167
    1. Potapova IA, Gaudette GR, Brink PR, Robinson RB, Rosen MR, Cohen IS, et al. . Mesenchymal stem cells support migration, extracellular matrix invasion, proliferation, and survival of endothelial cells in vitro Stem Cells (2007) 25:1761–8. 10.1634/stemcells.2007-0022
    1. Overath JM, Gauer S, Obermuller N, Schubert R, Schafer R, Geiger H, et al. . Short-term preconditioning enhances the therapeutic potential of adipose-derived stromal/stem cell-conditioned medium in cisplatin-induced acute kidney injury. Exp Cell Res. (2016) 342:175–83. 10.1016/j.yexcr.2016.03.002
    1. Ma T, Grayson WL, Frohlich M, Vunjak-Novakovic G. Hypoxia and stem cell-based engineering of mesenchymal tissues. Biotechnol Prog. (2009) 25:32–42. 10.1002/btpr.128
    1. Kiani AA, Kazemi A, Halabian R, Mohammadipour M, Jahanian-Najafabadi A, Roudkenar MH. HIF-1α confers resistance to induced stress in bone marrow-derived mesenchymal stem cells. Arch Med Res. (2013) 44:185–93. 10.1016/j.arcmed.2013.03.006
    1. Deschepper M, Oudina K, David B, Myrtil V, Collet C, Bensidhoum M, et al. . Survival and function of mesenchymal stem cells (MSCs) depend on glucose to overcome exposure to long-term, severe and continuous hypoxia. J Cellu Mol Med. (2011) 15:1505–14. 10.1111/j.1582-4934.2010.01138.x
    1. Cicione C, Muinos-Lopez E, Hermida-Gomez T, Fuentes-Boquete I, Diaz-Prado S, Blanco FJ. Effects of severe hypoxia on bone marrow mesenchymal stem cells differentiation potential. Stem Cells Int. (2013) 2013:232896. 10.1155/2013/232896
    1. Gnecchi M, He H, Liang OD, Melo LG, Morello F, Mu H, et al. . Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells Nat Med. (2005) 11:367–8. 10.1038/nm0405-367
    1. Imtiyaz HZ, Simon MC. Hypoxia-inducible factors as essential regulators of inflammation. Curr Top Microbiol Immunol. (2010) 345:105–20. 10.1007/82_2010_74
    1. Ahluwalia A, Tarnawski AS. Critical role of hypoxia sensor - HIF-1α in VEGF gene activation. Implications for angiogenesis and tissue injury healing. Curr Med Chem. (2005) 19:90–7. 10.2174/092986712803413944
    1. Bader AM, Klose K, Bieback K, Korinth D, Schneider M, Seifert M, et al. . Hypoxic preconditioning increases survival and pro-angiogenic capacity of human cord blood mesenchymal stromal cells in vitro. PLoS ONE (2015) 10:e0138477. 10.1371/journal.pone.0138477
    1. Liu J, Hao H, Xia L, Ti D, Huang H, Dong L, et al. . Hypoxia pretreatment of bone marrow mesenchymal stem cells facilitates angiogenesis by improving the function of endothelial cells in diabetic rats with lower ischemia. PLoS ONE (2015) 10:e0126715. 10.1371/journal.pone.0126715
    1. Bian S, Zhang L, Duan L, Wang X, Min Y, Yu H. Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. J Mol Med. (2014) 92:387–97. 10.1007/s00109-013-1110-5
    1. Anderson JD, Johansson HJ, Graham CS, Vesterlund M, Pham MT, Bramlett CS, et al. . Comprehensive proteomic analysis of mesenchymal stem cell exosomes reveals modulation of angiogenesis via nuclear factor-kappab signaling. Stem Cells (2016) 34:601–13. 10.1002/stem.2298
    1. Park H, Park H, Mun D, Kang J, Kim H, Kim M, et al. . Extracellular vesicles derived from hypoxic human mesenchymal stem cells attenuate GSK3beta expression via mirna-26a in an ischemia-reperfusion injury model. Yonsei Med J. (2018) 59:736–45. 10.3349/ymj.2018.59.6.736
    1. Han YD, Bai Y, Yan XL, Ren J, Zeng Q, Li XD, et al. . Co-transplantation of exosomes derived from hypoxia-preconditioned adipose mesenchymal stem cells promotes neovascularization and graft survival in fat grafting Biochem Biophys Res Commun. (2018) 497:305–12. 10.1016/j.bbrc.2018.02.076
    1. Feng Y, Huang W, Wani M, Yu X, Ashraf M. Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22. PLoS ONE (2014) 9:e88685. 10.1371/journal.pone.0088685
    1. Kilpinen L, Impola U, Sankkila L, Ritamo I, Aatonen M, Kilpinen S, et al. . Extracellular membrane vesicles from umbilical cord blood-derived MSC protect against ischemic acute kidney injury, a feature that is lost after inflammatory conditioning. J Extracell Vesicles (2013) 2, 1–15. 10.3402/jev.v2i0.21927
    1. Yang J, Gao F, Zhang Y, Liu Y, Zhang D. Buyang huanwu decoction (BYHWD) enhances angiogenic effect of mesenchymal stem cell by upregulating vegf expression after focal cerebral ischemia. J Mol Neurosci. (2015) 56:898–906. 10.1007/s12031-015-0539-0
    1. Crisostomo PR, Wang Y, Markel TA, Wang M, Lahm T, Meldrum DR. Human mesenchymal stem cells stimulated by TNF-α, LPS, or hypoxia produce growth factors by an NFκB- but not JNK-dependent mechanism. Am J Physiol Cell Physiol. (2008) 294:C675–82. 10.1152/ajpcell.00437.2007
    1. Beegle J, Lakatos K, Kalomoiris S, Stewart H, Isseroff R, Nolta RJA, et al. . Hypoxic preconditioning of mesenchymal stromal cells induces metabolic changes, enhances survival, and promotes cell retention in vivo. Stem Cells (2015) 33:1818–28. 10.1002/stem.1976
    1. Saparov A, Ogay V, Nurgozhin T, Jumabay M, Chen WCW. Preconditioning of human mesenchymal stem cells to enhance their regulation of the immune response. Stem Cells Int. (2016) 2016:3924858. 10.1155/2016/3924858
    1. Wang Y, Chen X, Cao W, Shi Y. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat Immunol. (2014) 15:1009–16. 10.1038/ni.3002
    1. Park CW, Kim KS, Bae S, Son HK, Myung PK, Hong HJ, et al. Cytokine secretion profiling of human mesenchymal stem cells by antibody array international J Stem Cells (2009) 2:59–68.
    1. Hsu WT, Lin CH, Chiang BL, Jui HY, Wu KK, Lee CM. Prostaglandin E2 potentiates mesenchymal stem cell-induced IL-10+IFN-γ+CD4+ regulatory T cells to control transplant arteriosclerosis. J Immunol. (2013) 190:2372–80. 10.4049/jimmunol.1202996
    1. Németh K, Leelahavanichkul A, Yuen PST, Mayer B, Parmelee A, Doi K, et al. . Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med. (2009) 15:42–9. 10.1038/nm.1905
    1. Chen K, Wang D, Du WT, Han ZB, Ren H, Chi Y, et al. . Human umbilical cord mesenchymal stem cells hUC-MSCs exert immunosuppressive activities through a PGE2-dependent mechanism. Clin Immunol. (2010) 135:448–58. 10.1016/j.clim.2010.01.015
    1. Maffioli E, Nonnis S, Angioni R, Santagata F, Cali B, Zanotti L, et al. . Proteomic analysis of the secretome of human bone marrow-derived mesenchymal stem cells primed by pro-inflammatory cytokines. J Proteomics (2017) 166:115–26. 10.1016/j.jprot.2017.07.012
    1. Augello A, Tasso R, Negrini SM, Amateis A, Indiveri F, Cancedda R, et al. . Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur J Immunol. (2005) 35:1482–90. 10.1002/eji.200425405
    1. Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, et al. . Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell (2008) 2:141–50. 10.1016/j.stem.2007.11.014
    1. Akiyama K, Chen C, Wang D, Xu X, Qu C, Yamaza T, et al. . Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis. Cell Stem Cell (2012) 10:544–55. 10.1016/j.stem.2012.03.007
    1. Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni P, Matteucci DP, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood (2002) 99:3838–43. 10.1182/blood.V99.10.3838
    1. Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J, Larson BL, et al. . Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell. (2009) 5:54–63. 10.1016/j.stem.2009.05.003
    1. Roddy GW, Oh JY, Lee RH, Bartosh TJ, Ylostalo J, Coble K, et al. . Action at a distance: systemically administered adult stem/progenitor cells (MSCs) reduce inflammatory damage to the cornea without engraftment and primarily by secretion of TNF-α stimulated gene/protein 6. Stem Cells (2011) 29:1572–9. 10.1002/stem.708
    1. Ryan JM, Barry F, Murphy JM, Mahon BP. Interferon-γ does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin Exp Immunol. (2007) 149:353–63. 10.1111/j.1365-2249.2007.03422.x
    1. Polchert D, Sobinsky J, Douglas GW, Kidd M, Moadsiri A, Reina E, et al. . IFN-γ activation of mesenchymal stem cells for treatment and prevention of graft versus host disease Eur J Immunol. (2008) 38:1745–55.
    1. English K. Mechanisms of mesenchymal stromal cell immunomodulation. Immunol Cell Biol. (2013) 91:19–26. 10.1038/icb.2012.56
    1. Kim DS, Jang IK, Lee MW, Ko YJ, Lee D-H, Lee JW, et al. . Enhanced immunosuppressive properties of human mesenchymal stem cells primed by interferon-γ. EBio Med. (2018) 28:261–73. 10.1016/j.ebiom.2018.01.002
    1. Krampera M, Cosmi L, Angeli R, Pasini A, Liotta F, Andreini A, et al. . Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells (2006) 24:386–98. 10.1634/stemcells.2005-0008
    1. Ren G, Su J, Zhang L, Zhao X, Ling W, L'Huillie A, et al. . Species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression. Stem Cells (2009) 27:1954–62. 10.1002/stem.118
    1. Lu Z, Chen Y, Dunstan C, Roohani-Esfahani S, Zreiqat H. Priming adipose stem cells with tumor necrosis factor-α preconditioning potentiates their exosome efficacy for bone regeneration. Tissue Eng Part A (2017) 23:1212–20. 10.1089/ten.tea.2016.0548
    1. Cosenza S, Toupet K, Maumus M, Luz-Crawford P, Blanc-Brude O, Jorgensen C, et al. . Mesenchymal stem cells-derived exosomes are more immunosuppressive than microparticles in inflammatory arthritis. Theranostics (2018) 8:1399–410. 10.7150/thno.21072
    1. Opitz CA, Litzenburger UM, Lutz C, Lanz TV, Tritschler I, Koppel A, et al. . Toll-like receptor engagement enhances the immunosuppressive properties of human bone marrow-derived mesenchymal stem cells by inducing indoleamine-2,3-dioxygenase-1 via interferon-beta and protein kinase R. Stem Cells (2009) 27:909–19. 10.1002/stem.7
    1. Sioud M, Mobergslien A, Boudabous A, Floisand Y. Evidence for the involvement of galectin-3 in mesenchymal stem cell suppression of allogeneic T-cell proliferation. Scand J Immunol. (2010) 71:267–74. 10.1111/j.1365-3083.2010.02378.x
    1. Liotta F, Angeli R, Cosmi L, Fili L, Manuelli C, Frosali F, et al. . Toll-like receptors 3 and 4 are expressed by human bone marrow-derived mesenchymal stem cells and can inhibit their T-cell modulatory activity by impairing Notch signaling. Stem Cells (2008) 26:279–89. 10.1634/stemcells.2007-0454
    1. Hahn JY, Cho HJ, Kang HJ, Kim TS, Kim MH, Chung JH, et al. . Pre-treatment of mesenchymal stem cells with a combination of growth factors enhances gap junction formation, cytoprotective effect on cardiomyocytes, and therapeutic efficacy for myocardial infarction. J Am Coll Cardiol. (2008) 51:933–43. 10.1016/j.jacc.2007.11.040
    1. Bai Y, Han YD, Yan XL, Ren J, Zeng Q, Li XD, et al. . Adipose mesenchymal stem cell-derived exosomes stimulated by hydrogen peroxide enhanced skin flap recovery in ischemia-reperfusion injury. Biochem Biophys Res Commun. (2018) 500:310–7. 10.1016/j.bbrc.2018.04.065
    1. Potapova IA, Brink PR, Cohen IS, Doronin SV. Culturing of human mesenchymal stem cells as three-dimensional aggregates induces functional expression of CXCR4 that regulates adhesion to endothelial cells. J Biol Chem. (2008) 283:13100–7. 10.1074/jbc.M800184200
    1. Petrenko Y, Syková E, Kubinová Š. The therapeutic potential of three-dimensional multipotent mesenchymal stromal cell spheroids. Stem Cell Res Ther. (2017) 8:94. 10.1186/s13287-017-0558-6
    1. Cesarz Z, Tamama K. Spheroid culture of mesenchymal stem cells. Stem Cells Int. (2016) 2016:9176357. 10.1155/2016/9176357
    1. Lee EJ, Park SJ, Kang SK, Kim GH, Kang HJ, Lee SW, et al. . Spherical bullet formation via E-cadherin promotes therapeutic potency of mesenchymal stem cells derived from human umbilical cord blood for myocardial infarction Mol Ther. (2012) 20:1424–33. 10.1038/mt.2012.58
    1. Kim YS, Ahn Y, Kwon JS, Cho YK, Jeong MH, Cho JG, et al. . Priming of mesenchymal stem cells with oxytocin enhances the cardiac repair in ischemia/reperfusion injury. Cells Tissues Organs (2012) 195:428–42. 10.1159/000329234
    1. Liu J, Zhu P, Song P, Xiong W, Chen H, Peng W, et al. . Pretreatment of adipose derived stem cells with curcumin facilitates myocardial recovery via antiapoptosis and angiogenesis. Stem Cells Int. (2015) 2015:638153. 10.1155/2015/638153
    1. Phan J, Kumar P, Hao D, Gao K, Farmer D, Wang A. Engineering mesenchymal stem cells to improve their exosome efficacy and yield for cell-free therapy. J Extracell Vesicles (2018) 7:1522236. 10.1080/20013078.2018.1522236
    1. Phelps J, Sanati-Nezhad A, Ungrin M, Duncan NA, Sen A. bioprocessing of mesenchymal stem cells and their derivatives: toward cell-free therapeutics. Stem Cells Int. (2018) 2018:9415367. 10.1155/2018/9415367
    1. Tolar J, Le Blanc K, Keating A, Blazar BR. Hitting the right spot with mesenchymal stromal cells (MSCs). Stem Cells (2010) 28:1446–55. 10.1002/stem.459
    1. Zhang J, Huang X, Wang H, Liu X, Zhang T, Wang Y, et al. . The challenges and promises of allogeneic mesenchymal stem cells for use as a cell-based therapy. Stem Cell Res Ther. (2015) 6:234. 10.1186/s13287-015-0240-9

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться