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Therapeutic effect of allogeneic bone marrow–derived mesenchymal stromal cells on aortic aneurysms

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Abstract

We previously reported the effectiveness of autologous mesenchymal stromal cells (MSCs) for the treatment of aortic aneurysm (AA), mediated mainly by these cells’ anti-inflammatory properties. In this study, we investigate whether the therapeutic effects of allogeneic MSCs on AA are the same as those of autologous MSCs. To examine the immune response to allogeneic MSCs, C57BL/6 lymphocytes were co-cultured with BALB/c MSCs for 5 days in vitro. Apolipoprotein E-deficient C57BL/6 mice with AA induced by angiotensin II were randomly divided into three groups defined by the following intravenous injections: (i) 0.2 ml of saline (n = 10, group S) as a control, (ii) 1 × 106 autologous MSCs (isolated from C57BL/6, n = 10, group Au) and (iii) 1 × 106 allogeneic MSCs (isolated from BALB/c, n = 10, group Al). Two weeks after injection, aortic diameters were measured, along with enzymatic activities of MMP-2 and MMP-9 and cytokine concentrations in AAs. Neither allogenic (BALB/c) MSCs nor autologous (C57BL/6) MSCs accelerated the proliferation of lymphocytes obtained from C57BL/6. Compared with group S, groups Au and Al had significantly shorter aortic diameters (group S vs Au vs Al; 2.29 vs 1.40 vs 1.36 mm, respectively, p < 0.01), reduced MMP-2 and MMP-9 activities, downregulated IL-6 and MCP-1 and upregulated expression of IGF-1 and TIMP-2. There were no differences in these results between groups Au and Al. Thus, our study suggests that treatment with allogeneic MSCs improves chronic inflammation and reduced aortic dilatation. These effects were equivalent to those of autologous MSCs in established mouse models of AA.

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Abbreviations

AA:

Aortic aneurysm

ANOVA:

Analysis of variance

ATII:

Angiotensin II

apoE−/−:

Apolipoprotein E-deficient

BM-MSCs:

Bone marrow mesenchymal stromal cells

ECM:

Extracellular matrix

ELISA:

Enzyme-linked immunosorbent assay

EVG:

Elastica van Gieson

IGF:

Insulin-like growth factor

IL:

Interleukin

iNOS:

Inducible nitric oxide synthase

MCP-1:

Monocyte chemoattractant protein-1

MHC:

Major histocompatibility complex

MMP:

Matrix metalloproteinase

MSCs:

Mesenchymal stromal cells

ROS:

Reactive oxygen species

TIMP:

Tissue inhibitor of metalloproteinase

TGF-β1:

Transforming growth factor-β1

TNF-α:

Tumor necrosis factor-α

References

  • Aggarwal S, Pittenger MF (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105:1815–1822

    CAS  PubMed  Google Scholar 

  • Bernardo ME, Locatelli F, Fibbe WE (2009) Mesenchymal stromal cells. Ann N Y Acad Sci 1176:101–117

    CAS  PubMed  Google Scholar 

  • Cooper MA, Upchurch GR Jr (2019) The society of vascular surgery practice guidelines on the care of patients with abdominal aortic aneurysms. JAMA Surg 154:553–554

    PubMed  Google Scholar 

  • Curci JA, Thompson RW (2004) Adaptive cellular immunity in aortic aneurysms: cause, consequence, or context? J Clin Invest 114:168–171

    CAS  PubMed  PubMed Central  Google Scholar 

  • Daugherty A, Manning MW, Cassis LA (2000) Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. J Clin Invest 105:1605–1612

    CAS  PubMed  PubMed Central  Google Scholar 

  • Efimenko A, Dzhoyashvili N, Kalinina N, Kochegura T, Akchurin R, Tkachuk V, Parfyonova Y (2014) Adipose-derived mesenchymal stromal cells from aged patients with coronary artery disease keep mesenchymal stromal cell properties but exhibit characteristics of aging and have impaired angiogenic potential. Stem Cells Transl Med 3:32–41

    CAS  PubMed  Google Scholar 

  • Efimenko AY, Kochegura TN, Akopyan ZA, Parfyonova YV (2015) Autologous stem cell therapy: how aging and chronic diseases affect stem and progenitor cells. Biores Open Access 4:26–38

    CAS  PubMed  PubMed Central  Google Scholar 

  • Elliot LC, Ronald LD, Mark KE, Benjamin MJ, Anthony Lee W, Ashraf Mansour M, Tara MM, Matthew M, Hassan Murad M, Louis LN, Gustavo SO, Madhukar SP, Marc LS, Benjamin WS (2018) The society for vascular surgery practice guidelines on the care of patients with an abdominal aortic aneurysm. J Vasc Surg 67:2–77

    Google Scholar 

  • Fan M, Chen W, Liu W, Du GQ, Jiang SL, Tian WC, Sun L, Li RK, Tian H (2010) The effect of age on the efficacy of human mesenchymal stem cell transplantation after a myocardial infarction. Rejuvenation Res 13:429–438

    PubMed  Google Scholar 

  • Fehrer C, Lepperdinger G (2005) Mesenchymal stem cell aging. Exp Gerontol 40:926–930

    CAS  PubMed  Google Scholar 

  • Fu XM, Yamawaki-Ogata A, Oshima H, Ueda Y, Usui A, Narita Y (2013) Intravenous administration of mesenchymal stem cells prevents angiotensin II-induced aortic aneurysm formation in apolipoprotein E-deficient mouse. J Transl Med 11:175

    CAS  PubMed  PubMed Central  Google Scholar 

  • Griffin MD, Ryan AE, Alagesan S, Lohan P, Treacy O, Ritter T (2013) Anti-donor immune responses elicited by allogeneic mesenchymal stem cells: what have we learned so far? Immunol Cell Biol 91:40–51

    CAS  PubMed  Google Scholar 

  • Hare JM, Fishman JE, Gerstenblith G, DiFede Velazquez DL, Zambrano JP, Suncion VY, Tracy M, Ghersin E, Johnston PV, Brinker JA, Breton E, Davis-Sproul J, Schulman IH, Byrnes J, Mendizabal AM, Lowery MH, Rouy D, Altman P, Wong Po Foo C, Ruiz P, Amador A, Da Silva J, McNiece IK, Heldman AW, George R, Lardo A (2012) Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA 308:2369–2379

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hashizume R, Yamawaki-Ogata A, Ueda Y, Wagner WR, Narita Y (2011) Mesenchymal stem cells attenuate angiotensin II-induced aortic aneurysm growth in apolipoprotein E-deficient mice. J Vasc Surg 54:1743–1752

    PubMed  Google Scholar 

  • Hoogduijn MJ, Lombardo E (2019) Concise review: Mesenchymal stromal cells anno 2019: aawn of the therapeutic era? Stem Cells Transl Med 8:1126–1134

    PubMed  PubMed Central  Google Scholar 

  • Ishikane S, Ohnishi S, Yamahara K, Sada M, Harada K, Mishima K, Iwasaki K, Fujiwara M, Kitamura S, Nagaya N, Ikeda T (2008) Allogeneic injection of fetal membrane-derived mesenchymal stem cells induces therapeutic angiogenesis in a rat model of hind limb ischemia. Stem cells 26:2625–2633

    CAS  PubMed  Google Scholar 

  • Jackson L, Jones DR, Scotting P, Sottile V (2007) Adult mesenchymal stem cells: differentiation potential and therapeutic applications. J Postgrad Med 53:121–127

    CAS  PubMed  Google Scholar 

  • Jacomelli J, Summers L, Stevenson A, Lees T, Earnshaw JJ (2016) Impact of the first 5 years of a national abdominal aortic aneurysm screening programme. Br J Surg 103:1125–1131

    CAS  PubMed  Google Scholar 

  • Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM (2002) Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418:41–49

    CAS  PubMed  Google Scholar 

  • Johnston KW, Rutherford RB, Tilson MD, Shah DM, Hollier L, Stanley JC (1991) Suggested standards for reporting on arterial aneurysms. Subcommittee on reporting standards for arterial aneurysms, Ad Hoc committee on reporting standards, society for vascular surgery and North American chapter, international society for cardiovascular surgery. J Vasc Surg 13:452–458

    CAS  PubMed  Google Scholar 

  • Jones JA, Beck C, Barbour JR, Zavadzkas JA, Mukherjee R, Spinale FG, et al. (2009) Alterations in aortic cellular constituents during thoracic aortic aneurysm development. Myofibroblast-mediated vascular remodeling, Am J Pathol 175:1746-5

    CAS  PubMed  Google Scholar 

  • Jung H-G, Ahn E-K, Lee J-H, Kim Y-H, Leem S-H, Heo J, Kim H (2014) Effects of harvesting sites and ages on adipose tissue-derived stem cells in rat. Tissue Eng Regen Med 11:137–142

    CAS  Google Scholar 

  • Karthikesalingam A, Nicoli TK, Holt PJ, Hinchliffe RJ, Pasha N, Loftus IM, Thompson MM (2011) The fate of patients referred to a specialist vascular unit with large infra-renal abdominal aortic aneurysms over a two-year period. European journal of vascular and endovascular surgery : Eur J Vasc Endovasc Surg 42:295–301

    CAS  PubMed  Google Scholar 

  • Kassem M (2004) Mesenchymal stem cells: biological characteristics and potential clinical applications. Cloning Stem Cells 6:369–374

    CAS  PubMed  Google Scholar 

  • Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler RM, Bacigalupo A, Fibbe W, Ringden O (2008) Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371:1579–1586

    PubMed  Google Scholar 

  • Mendez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, Macarthur BD, Lira SA, Scadden DT, Ma’ayan A, Enikolopov GN, Frenette PS (2010) Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466:829–834

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mueller SM, Glowacki J (2001) Age-related decline in the osteogenic potential of human bone marrow cells cultured in three-dimensional collagen sponges. J Cell Biochem 82:583–590

    CAS  PubMed  Google Scholar 

  • Mukonoweshuro B, Brown CJ, Fisher J, Ingham E (2014) Immunogenicity of undifferentiated and differentiated allogeneic mouse mesenchymal stem cells. J Tissue Eng 5:2041731414534255

    PubMed  PubMed Central  Google Scholar 

  • Ryan JM, Barry FP, Murphy JM, Mahon BP (2005) Mesenchymal stem cells avoid allogeneic rejection. J Inflamm 2:8

    Google Scholar 

  • Sasaki M, Abe R, Fujita Y, Ando S, Inokuma D, Shimizu H (2008) Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. J Immunol 180:2581–2587

    CAS  PubMed  Google Scholar 

  • Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC, Moretta L (2008) Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 111:1327–1333

    CAS  PubMed  Google Scholar 

  • Squillaro T, Peluso G, Galderisi U (2016) Clinical trials with mesenchymal stem cells: an update. Cell Transplant 25:829–848

    PubMed  Google Scholar 

  • Sudres M, Norol F, Trenado A, Gregoire S, Charlotte F, Levacher B, Lataillade JJ, Bourin P, Holy X, Vernant JP, Klatzmann D, Cohen JL (2006) Bone marrow mesenchymal stem cells suppress lymphocyte proliferation in vitro but fail to prevent graft-versus-host disease in mice. J Immunol 176:7761–7767

    CAS  PubMed  Google Scholar 

  • Sweeting MJ, Thompson SG, Brown LC, Powell JT (2012) Meta-analysis of individual patient data to examine factors affecting growth and rupture of small abdominal aortic aneurysms. Br J Surg 99:655–665

    CAS  PubMed  Google Scholar 

  • Thompson RW, Geraghty PJ, Lee JK (2002) Abdominal aortic aneurysms: basic mechanisms and clinical implications. Curr Probl Surg 39:110–230

    PubMed  Google Scholar 

  • Trounson A, McDonald C (2015) Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell 17:11–22

    CAS  PubMed  Google Scholar 

  • Ulug P, Sweeting MJ, von Allmen RS, Thompson SG, Powell JT (2017) Morphological suitability for endovascular repair, non-intervention rates, and operative mortality in women and men assessed for intact abdominal aortic aneurysm repair: systematic reviews with meta-analysis. Lancet 389:2482–2491

    PubMed  PubMed Central  Google Scholar 

  • van den Akker F, de Jager SC, Sluijter JP (2013) Mesenchymal stem cell therapy for cardiac inflammation: immunomodulatory properties and the influence of toll-like receptors. Mediators Inflamm 2013:181020

    PubMed  PubMed Central  Google Scholar 

  • Wang Z, Wang L, Su X, Pu J, Jiang M, He B (2017) Rational transplant timing and dose of mesenchymal stromal cells in patients with acute myocardial infarction: a meta-analysis of randomized controlled trials. Stem Cell Res Ther 8:21

    PubMed  PubMed Central  Google Scholar 

  • Wanhainen A, Verzini F, Van Herzeele I, Allaire E, Bown M, Cohnert T, Dick F, van Herwaarden J, Karkos C, Koelemay M, Kolbel T, Loftus I, Mani K, Melissano G, Powell J, Szeberin Z, Esvs Guidelines C, de Borst GJ, Chakfe N, Debus S, Hinchliffe R, Kakkos S, Koncar I, Kolh P, Lindholt JS, de Vega M, Vermassen F, Document R, Bjorck M, Cheng S, Dalman R, Davidovic L, Donas K, Earnshaw J, Eckstein HH, Golledge J, Haulon S, Mastracci T, Naylor R, Ricco JB, Verhagen H (2019) Editor’s Choice - European Society for Vascular Surgery (ESVS) 2019 clinical practice guidelines on the management of abdominal aorto-iliac artery aneurysms. European journal of vascular and endovascular surgery : Eur J Vasc Endovasc Surg 57:8–93

    PubMed  Google Scholar 

  • Wei X, Yang X, Han ZP, Qu FF, Shao L, Shi YF (2013) Mesenchymal stem cells: a new trend for cell therapy. Acta Pharmacol Sin 34:747–754

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yamawaki-Ogata A, Fu X, Hashizume R, Fujimoto KL, Araki Y, Oshima H, Narita Y, Usui A (2014) Therapeutic potential of bone marrow-derived mesenchymal stem cells in formed aortic aneurysms of a mouse model. European journal of cardio-thoracic surgery : Eur J Cardiothorac Surg 45:e156-165

    PubMed  Google Scholar 

  • Zhang W, Ge W, Li C, You S, Liao L, Han Q, Deng W, Zhao RC (2004) Effects of mesenchymal stem cells on differentiation, maturation, and function of human monocyte-derived dendritic cells. Stem Cells Dev 13:263–271

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors wish to acknowledge the Division for Medical Research Engineering, Nagoya University Graduate School of Medicine, for allowing the use of equipment, including a FACSCalibur and microtome cryostat (Leica Microsystems).

Funding

This study was supported in part by the Japan Society for the Promotion of Science (JSPS), KAKENHI Grant Number 26713043.

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Authors and Affiliations

  1. Division of Vascular Surgery, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Naohiro Akita & Kimihiro Komori

  2. Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan

    Yuji Narita, Aika Yamawaki-Ogata & Akihiko Usui

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  1. Naohiro Akita
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  2. Yuji Narita
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Correspondence to Yuji Narita.

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Akita, N., Narita, Y., Yamawaki-Ogata, A. et al. Therapeutic effect of allogeneic bone marrow–derived mesenchymal stromal cells on aortic aneurysms. Cell Tissue Res 383, 781–793 (2021). https://doi.org/10.1007/s00441-020-03295-6

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