Research article

Therapeutic effects of paracrine factors secreted by human umbilical cord blood mononuclear cells in myocardial infarctions
Paracrine effects of cord blood cells

  • Stem cell paracrine factors are beneficial in myocardial infarction (MI) treatment. However, specific stem cell factor effects on myocardial cytokines and their molecular pathways have not been precisely identified. We treated 44 rats with MIs with intramyocardial Isolyte or 4 × 106 human umbilical cord blood mononuclear cells (hUCBC) without immune suppression. We measured infarct sizes and myocardial cytokines. We then stressed isolated myocytes with H2O2 to simulate MIs in the absence and presence of paracrine factors from hypoxic hUCBC. We measured myocyte Akt protein kinase, which causes survival, and JNK and p38 protein kinases, which cause myocyte death. In Isolyte treated MIs, TNF-α increased from 6.1% to 51.3%, MCP increased from 5.6% to 39.8%, MIP increased from 8.1% to 25.9%, and IL-1 increased from 7.1% to 20.0%. In hUCBC treated MIs, inflammatory cytokines did not change and there was no hUCBC rejection. MI sizes averaged 30% in Isolyte treated rats and 10% in hUCBC treated rats (p < 0.01). Hypoxic hUCBC increased secretion of HGF by 338%, IGF by 200%, VEGF by 192%, PGF by 150%, IL-10 by 150%, and SCF and TIMP by 100% in comparison with non-stressed hUCBC (p < 0.001). H2O2 increased myocyte activation of JNK by 297% and p38 by 83% and increased myocyte necrosis by >60% (all p < 0.01 vs. normal myocytes). In myocytes treated with H2O2 and hUCBC paracrine factors, JNK and p38 activation decreased by ≥ 40%, while Akt activation and myocyte viability increased by >100% (all p < 0.01 vs. myocytes with H2O2) The Akt inhibitor API prevented hUCBC paracrine factor effects on myocytes. Addition of the JNK inhibitor SP600125 or p38 inhibitor SB203580 to myocytes with H2O2 plus hUCBC factors increased myocyte viability. We conclude that hUCBC secrete growth factors and anti-inflammatory cytokines that increase myocyte Akt activation and myocyte survival and decrease myocyte JNK, p38 and myocyte death in MIs.

    Citation: Robert J. Henning, Qing Zhu, Xiao Wang. Therapeutic effects of paracrine factors secreted by human umbilical cord blood mononuclear cells in myocardial infarctionsParacrine effects of cord blood cells[J]. AIMS Cell and Tissue Engineering, 2018, 2(4): 220-237. doi: 10.3934/celltissue.2018.4.220

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  • Stem cell paracrine factors are beneficial in myocardial infarction (MI) treatment. However, specific stem cell factor effects on myocardial cytokines and their molecular pathways have not been precisely identified. We treated 44 rats with MIs with intramyocardial Isolyte or 4 × 106 human umbilical cord blood mononuclear cells (hUCBC) without immune suppression. We measured infarct sizes and myocardial cytokines. We then stressed isolated myocytes with H2O2 to simulate MIs in the absence and presence of paracrine factors from hypoxic hUCBC. We measured myocyte Akt protein kinase, which causes survival, and JNK and p38 protein kinases, which cause myocyte death. In Isolyte treated MIs, TNF-α increased from 6.1% to 51.3%, MCP increased from 5.6% to 39.8%, MIP increased from 8.1% to 25.9%, and IL-1 increased from 7.1% to 20.0%. In hUCBC treated MIs, inflammatory cytokines did not change and there was no hUCBC rejection. MI sizes averaged 30% in Isolyte treated rats and 10% in hUCBC treated rats (p < 0.01). Hypoxic hUCBC increased secretion of HGF by 338%, IGF by 200%, VEGF by 192%, PGF by 150%, IL-10 by 150%, and SCF and TIMP by 100% in comparison with non-stressed hUCBC (p < 0.001). H2O2 increased myocyte activation of JNK by 297% and p38 by 83% and increased myocyte necrosis by >60% (all p < 0.01 vs. normal myocytes). In myocytes treated with H2O2 and hUCBC paracrine factors, JNK and p38 activation decreased by ≥ 40%, while Akt activation and myocyte viability increased by >100% (all p < 0.01 vs. myocytes with H2O2) The Akt inhibitor API prevented hUCBC paracrine factor effects on myocytes. Addition of the JNK inhibitor SP600125 or p38 inhibitor SB203580 to myocytes with H2O2 plus hUCBC factors increased myocyte viability. We conclude that hUCBC secrete growth factors and anti-inflammatory cytokines that increase myocyte Akt activation and myocyte survival and decrease myocyte JNK, p38 and myocyte death in MIs.


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    [1] Klug M, Soonpaa M, Koh G, et al. (1996) Genetically selected cardiomyocytes from differentiating embryonic stem cells form stable intracardiac grafts. J Clin Invest 98: 216–224. doi: 10.1172/JCI118769
    [2] Mummery C, Ward‐van Oostwaard D, Doevendans P, et al. (2003) Differentiation of human embryonic stem cells to cardiomyocytes: Role of coculture with visceral endoderm-like cells. Circulation 107: 2733–2740. doi: 10.1161/01.CIR.0000068356.38592.68
    [3] Kehat I, Kenyagin-Karsenti D, Snir M, et al. (2011) Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest 108: 407–414.
    [4] Kinnaird T, Stabile E, Burnett MS, et al. (2004) Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in-vitro and in-vivo angiogenesis through paracrine mechanisms. Circ Res 94: 678–685. doi: 10.1161/01.RES.0000118601.37875.AC
    [5] Gnecchi M, He H, Liang OD, et al. (2005) Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med 11: 367–368. doi: 10.1038/nm0405-367
    [6] Gnecchi M, He H, Noiseux N, et al. (2006). Evidence supporting the paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J 20: 661–669. doi: 10.1096/fj.05-5211com
    [7] Broxmeyer HE (2010) Cord blood hematopoietic stem cell transplantation. In: Broxmeyer HE, StemBook, Cambridge (MA), Harvard Stem Cell Institute, USA.
    [8] Margossian T, Reppel L, Makdissy N, et al. (2012) Mesenchymal stem cells derived from Wharton's jelly: comparative phenotype analysis between tissue and in-vitro expansion. Biomed Mater Eng 22: 243–254.
    [9] Gluckman E (2009) History of cord blood transplantation. Bone Marrow Transpl 44: 621–626. doi: 10.1038/bmt.2009.280
    [10] Zhang J, Chen GH, Wang YW, et al. (2012) Hydrogen peroxide preconditioning enhances the therapeutic efficacy of Wharton's Jelly mesenchymal stem cells after myocardial infarction. Chin Med J 125: 3472–3478.
    [11] Morgan E, Faullx M, McElfresh T, et al. (2004) Validation of echocardiographic methods for assessing left ventricular dysfunction in rats with myocardial infarction. Am J Physiol Heart Circ Physiol 287:2049–2053. doi: 10.1152/ajpheart.00393.2004
    [12] Adegboyega P, Adesokan A, Haque AK, et al. (1997) Sensitivity and specificity of triphenyl tetrazolium chloride in the gross diagnosis of acute myocardial infarcts. Arch Pathol Lab Med 121: 1063–1068.
    [13] Deten, A, Volz H, Briest W, et al. (2002) Cardiac cytokine expression is unregulated in infarction. Cardiovasc Res 55: 329–340. doi: 10.1016/S0008-6363(02)00413-3
    [14] Lin Y, Huang R, Chen L, et al. (2003) Profiling of cytokine expression by biotin-labeled-based protein arrays. Proteom 3:1750–1757. doi: 10.1002/pmic.200300530
    [15] Hescheler J, Meyer R, Plant S, et al. (1991). Morphological, biochemical and electrophysiological characterization of a clonal cell (H9c2) line from rat heart. Circ Res 61: 1476–1486.
    [16] Zordoky B, El-Kadi A (2007) H9c2 cell line is a valuable in-vitro model to study the drug metabolizing enzymes in the heart. J Pharmacol Toxicol Methods 56: 317–322. doi: 10.1016/j.vascn.2007.06.001
    [17] Yang L, Dan H, Sun M, et al. (2004). Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt. Cancer Res 64: 4394–4399. doi: 10.1158/0008-5472.CAN-04-0343
    [18] Bennett B, Sasaki D, Murray B, et al. (2001) SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci U S A 98: 13681–13686. doi: 10.1073/pnas.251194298
    [19] Remondino A, Kwon S, Communal C, et al. (2003) β-Adrenergic receptor-stimulated apoptosis in cardiac myocytes is mediated by reactive species/c-Jun NH2-terminal kinase-dependent activation of the mitochondrial pathway. Circ Res 92: 136–138. doi: 10.1161/01.RES.0000054624.03539.B4
    [20] Mackay K, Mochly-Rosen D (1999) An inhibitor of p38 mitogen-activated protein kinase protects neonatal cardiac myocytes from ischemia. J Biol Chem 274: 6272–6279. doi: 10.1074/jbc.274.10.6272
    [21] Liao P, Wang SQ, Wang S, et al. (2002) p38 mitogen-activated protein kinase mediates a negative inotropic effect in cardiac myocytes. Circ Res 90: 190–196. doi: 10.1161/hh0202.104220
    [22] Prabhu SD, Frangogiannis NG (2016) The Biological Basis for Cardiac Repair After Myocardial Infarction: From Inflammation to Fibrosis. Circ Res 119: 91–112. doi: 10.1161/CIRCRESAHA.116.303577
    [23] Kain V, Prabhu SD, Halade GV (2014) Inflammation revisited: inflammation versus resolution of inflammation following myocardial infarction. Basic Res Cardiol 109: 444. doi: 10.1007/s00395-014-0444-7
    [24] Tsai C, Wu C, Lee J, et al. (2015) NF-α down-regulates sarcoplasmic reticulum Ca²⁺ ATPase expression and leads to left ventricular diastolic dysfunction through binding of NF-κB to promoter response element. Cardiovasc Res 105: 318–329. doi: 10.1093/cvr/cvv008
    [25] Ridker P, Rifai N, Pfeffer M, et al. (2000) Elevation of tumor necrosis factor-a and increased risk of recurrent coronary events after myocardial infarction. Circulation 101: 2149–2153. doi: 10.1161/01.CIR.101.18.2149
    [26] Maekawa N, Wada H, Kanda T, et al. (2002) Improved myocardial ischemia/reperfusion injury in mice lacking tumor necrosis factor-alpha. J Am Coll Cardiol 39: 1229–1235. doi: 10.1016/S0735-1097(02)01738-2
    [27] Nian M, Lee P, Khaper N, et al. (2004) Inflammatory cytokines and postmyocardial infarction remodeling. Circ Res 94: 1543–1553. doi: 10.1161/01.RES.0000130526.20854.fa
    [28] Schiopu A, Bengtsson E, Gonçalves I, et al. (2016) Associations between macrophage colony-stimulating factor and monocyte chemotactic protein 1 in plasma and first-time coronary events: A nested case-control study. J Am Heart Assoc 5: e002851.
    [29] Dewald O, Zymek P, Winkelmann K, et al. (2005) CCL2/monocyte chemoattractant protein-1 regulates inflammatory responses critical to healing myocardial infarcts. Circ Res 96: 881–889. doi: 10.1161/01.RES.0000163017.13772.3a
    [30] de Lemos JA, Morrow DA, Sabatine MS, et al. (2003) Association between plasma levels of monocyte chemoattractant protein-1 and long-term clinical outcomes in patients with acute coronary syndromes. Circulation 107: 690–695. doi: 10.1161/01.CIR.0000049742.68848.99
    [31] White D, Fang L, Chan W, et al. (2013) Pro-Inflammatory action of MIF in acute myocardial infarction via activation of peripheral blood mononuclear cells. PLoS One 8: e76206. doi: 10.1371/journal.pone.0076206
    [32] Parissis JT, Adamopoulos S, Venetsanou KF, et al. (2002) Serum profiles of C-C chemokines in acute myocardial infarction: possible implication in postinfarction left ventricular remodeling. J Interferon Cytokine Res 22: 223–229. doi: 10.1089/107999002753536194
    [33] Van Tassell BW, Toldo S, Mezzaroma E, et al. (2013) Targeting interleukin-1 in heart disease. Circulation 128: 1910–1923. doi: 10.1161/CIRCULATIONAHA.113.003199
    [34] Ridker PM, Everett BM, Thuren T, et al. (2017) Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 377:1119–1131. doi: 10.1056/NEJMoa1707914
    [35] Ishikawa K, Fish K, Aguero J, et al. (2015) Stem cell factor gene transfer improves cardiac function after myocardial infarction in swine. Circ Heart Fail 8: 167–174. doi: 10.1161/CIRCHEARTFAILURE.114.001711
    [36] Awada HK, Johnson NR, Wang Y (2015) Sequential delivery of angiogenic growth factors improves revascularization and heart function after myocardial infarction. J Control Release 207: 7–17. doi: 10.1016/j.jconrel.2015.03.034
    [37] Tao Z, Chen B, Tan X, et al. (2011) Coexpression of VEGF and angiopoietin-1 promotes angiogenesis and cardiomyocyte proliferation reduces apoptosis in porcine myocardial infarction (MI) heart. Proc Natl Acad Sci U S A 108: 2064–2069. doi: 10.1073/pnas.1018925108
    [38] Iwasaki H, Kawamoto A, Tjwa M, et al. (2011) Placental growth factor repairs myocardial ischemia through mechanisms of angiogenesis, cardioprotection and recruitment of myo-angiogenic competent marrow progenitors. PLoS One 6: e24872. doi: 10.1371/journal.pone.0024872
    [39] Koudstaal S, Bastings M, Feyen D, et al. (2014) Sustained delivery of insulin-like growth factor-1/hepatocyte growth factor stimulates endogenous cardiac repair in the chronic infarcted pig heart. J Cardiovasc Transl Res 7:232–241. doi: 10.1007/s12265-013-9518-4
    [40] Kandalam V, Basu R, Abraham T, et al. (2010). Early activation of matrix metalloproteinases underlies the exacerbated systolic and diastolic dysfunction in mice lacking TIMP3 following myocardial infarction. Am J Physiol Heart Circ Physiol 299: H1012–1023. doi: 10.1152/ajpheart.00246.2010
    [41] Rophael J, Craft R, Palmer J, et al. (2007) Angiogenic growth factor synergism in a murine tissue engineering model of angiogenesis and adipogenesis. Am J Pathol 171: 2048–2057. doi: 10.2353/ajpath.2007.070066
    [42] Cao R, Brakenhielm E, Pawliuk R, et al. (2003) Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2. Nat Med 9: 604–613. doi: 10.1038/nm848
    [43] Henning RJ (2016) Therapeutic angiogenesis: angiogenic growth factors for ischemic heart disease. Future Cardiol 12: 585–599. doi: 10.2217/fca-2016-0006
    [44] Jung M, Ma Y, Iyer R, et al. (2017) IL-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation. Basic Res Cardiol 112: 33–44. doi: 10.1007/s00395-017-0622-5
    [45] Jones S, Trocha S (2001) Cardioprotective actions of IL-10 are independent of iNOS. Am J Physiol Heart Circ Physiol 281: H48–52. doi: 10.1152/ajpheart.2001.281.1.H48
    [46] Frangogiannis N (2012) Regulation of the Inflammatory Response in Cardiac Repair. Circ Res 110: 159–173. doi: 10.1161/CIRCRESAHA.111.243162
    [47] Ito T, Ikeda U (2003) Inflammatory cytokines and cardiovascular disease. Curr Drug Targets Inflamm Allergy 2: 257–263. doi: 10.2174/1568010033484106
    [48] Sussman M, Volkers M, Fischer K, et al. (2011) Myocardial Akt: the omnipresent nexus. Physiol Rev 91: 1023–1070. doi: 10.1152/physrev.00024.2010
    [49] Oudit G, Penninger J (2009) Cardiac regulation by phosphoinositide 3-kinases and PTEN. Cardiovasc Res 82: 250–260.
    [50] Datta S, Dudek, H, Tao X, et al. (1997) Akt phosphorylation of BAD couples survival signals to cell intrinsic death machinery. Cell 91: 231–241. doi: 10.1016/S0092-8674(00)80405-5
    [51] Ronnebaum S, Patterson C (2010). The FoxO family in cardiac function and dysfunction. Annu Rev Physiol 72: 81–94. doi: 10.1146/annurev-physiol-021909-135931
    [52] Fulton D, Gratton JP, McCabe T (1999) Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nat 399: 597–601. doi: 10.1038/21218
    [53] Cittadini A, Monti M, Iaccarino G, et al. (2006) Adenoviral gene transfer of Akt enhances myocardial contractility and intracellular calcium handling. Gene Ther 3: 8–19.
    [54] Crackower M, Oudit G, Kozieradzki I, et al. (2002) Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell 110:737–749. doi: 10.1016/S0092-8674(02)00969-8
    [55] Tateishi K, Ashihara E, Honsho S, et al. (2007) Human cardiac stem cells exhibit mesenchymal features and are maintained through Akt/GSK-3beta signaling. Biochem Biophys Res Commun 352: 635–641. doi: 10.1016/j.bbrc.2006.11.096
    [56] Shi B, Wang Y, Zhao R, et al. (2018) Bone marrow mesenchymal stem cell-derived exosomal miR-21 protects C-kit+ cardiac stem cells from oxidative injury through the PTEN/PI3K/Akt axis. PLoS One 13: e0191616. doi: 10.1371/journal.pone.0191616
    [57] O'Neal W, Griffin WF, Kent SD, et al. (2012) Cellular Pathways of Death and Survival in Acute Myocardial Infarction. Clin Exp Cardiolog 6: 003.
    [58] Aoki H, Kang P, Hampe J, et al. (2002) Direct activation of mitochondrial apoptosis machinery by c-jun n-terminal kinase in adult cardiac myocytes. J Biol Chem 277: 10244-10250. doi: 10.1074/jbc.M112355200
    [59] Ferrandi C, Ballerio R, Gaillard P, et al. (2004) Inhibition of c-Jun N-terminal kinase decreases cardiomyocyte apoptosis and infarct size after myocardial ischemia and reperfusion in anaesthetized rats. Br J Pharmacol 142: 953–960. doi: 10.1038/sj.bjp.0705873
    [60] Kwon S, Pimentel D, Remondino A, et al. (2003) H2O2 regulates cardiac myocyte phenotype via concentration-dependent activation of distinct kinase pathways. J Mol Cell Cardiol 35: 615-621. doi: 10.1016/S0022-2828(03)00084-1
    [61] Singh M, Sharma H, Singh N (2007) Hydrogen peroxide induces apoptosis in HeLa cells through mitochondrial pathway. Mitochondria 7: 367–373. doi: 10.1016/j.mito.2007.07.003
    [62] Tournier C, Hess P, Yang DD, et al. (2000) Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Sci 288: 870–874. doi: 10.1126/science.288.5467.870
    [63] Levresse V, Butterfield L, Zentrich E, et al. (2000) Akt negatively regulates the cJun N-terminal kinase pathway in PC12 cells. J Neurosci Res 62: 799–808. doi: 10.1002/1097-4547(20001215)62:6<799::AID-JNR6>3.0.CO;2-1
    [64] Zhao HF, Wang J, Tony To SS (2015) The phosphatidylinositol 3-kinase/Akt and c-Jun N-terminal kinase signaling in cancer: Alliance or contradiction? Int J Oncol 47: 429–436. doi: 10.3892/ijo.2015.3052
    [65] Porras A, Zuluaga S, Black E, et al. (2004) Mitogen-activated protein kinase sensitizes cells to apoptosis induced by different stimuli. Mol Biol Cell 15: 922–933. doi: 10.1091/mbc.e03-08-0592
    [66] Scneider S, Chen W, Hou J, et al. (2001) Inhibition of p38 MAPK reduces ischemic injury and does not block the protective effect of preconditioning. Am J Physiol Heart Circ Physiol 280: H499–508. doi: 10.1152/ajpheart.2001.280.2.H499
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