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Cardiac mesenchymal cells from diabetic mice are ineffective for cell therapy-mediated myocardial repair

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Abstract

Although cell therapy improves cardiac function after myocardial infarction, highly variable results and limited understanding of the underlying mechanisms preclude its clinical translation. Because many heart failure patients are diabetic, we examined how diabetic conditions affect the characteristics of cardiac mesenchymal cells (CMC) and their ability to promote myocardial repair in mice. To examine how diabetes affects CMC function, we isolated CMCs from non-diabetic C57BL/6J (CMCWT) or diabetic B6.BKS(D)-Leprdb/J (CMCdb/db) mice. When CMCs were grown in 17.5 mM glucose, CMCdb/db cells showed > twofold higher glycolytic activity and a threefold higher expression of Pfkfb3 compared with CMCWT cells; however, culture of CMCdb/db cells in 5.5 mM glucose led to metabolic remodeling characterized by normalization of metabolism, a higher NAD+/NADH ratio, and a sixfold upregulation of Sirt1. These changes were associated with altered extracellular vesicle miRNA content as well as proliferation and cytotoxicity parameters comparable to CMCWT cells. To test whether this metabolic improvement of CMCdb/db cells renders them suitable for cell therapy, we cultured CMCWT or CMCdb/db cells in 5.5 mM glucose and then injected them into infarcted hearts of non-diabetic mice (CMCWT, n = 17; CMCdb/db, n = 13; Veh, n = 14). Hemodynamic measurements performed 35 days after transplantation showed that, despite normalization of their properties in vitro, and unlike CMCWT cells, CMCdb/db cells did not improve load-dependent and -independent parameters of left ventricular function. These results suggest that diabetes adversely affects the reparative capacity of CMCs and that modulating CMC characteristics via culture in lower glucose does not render them efficacious for cell therapy.

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References

  1. Action to Control Cardiovascular Risk in Diabetes Study G, Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT, Action to Control Cardiovascular Risk in Diabetes Study G (2008) Effects of intensive glucose lowering in type 2 diabetes. The N Engl J Med 358:2545–2559. https://doi.org/10.1056/nejmoa0802743

    Article  Google Scholar 

  2. Aguiari P, Leo S, Zavan B, Vindigni V, Rimessi A, Bianchi K, Franzin C, Cortivo R, Rossato M, Vettor R, Abatangelo G, Pozzan T, Pinton P, Rizzuto R (2008) High glucose induces adipogenic differentiation of muscle-derived stem cells. Proc Natl Acad Sci USA 105:1226–1231. https://doi.org/10.1073/pnas.0711402105

    Article  PubMed  PubMed Central  Google Scholar 

  3. Albiero M, Poncina N, Tjwa M, Ciciliot S, Menegazzo L, Ceolotto G, Vigili de Kreutzenberg S, Moura R, Giorgio M, Pelicci P, Avogaro A, Fadini GP (2014) Diabetes causes bone marrow autonomic neuropathy and impairs stem cell mobilization via dysregulated p66Shc and Sirt1. Diabetes 63:1353–1365. https://doi.org/10.2337/db13-0894

    Article  CAS  PubMed  Google Scholar 

  4. Bartunek J, Behfar A, Dolatabadi D, Vanderheyden M, Ostojic M, Dens J, El Nakadi B, Banovic M, Beleslin B, Vrolix M, Legrand V, Vrints C, Vanoverschelde JL, Crespo-Diaz R, Homsy C, Tendera M, Waldman S, Wijns W, Terzic A (2013) Cardiopoietic stem cell therapy in heart failure: the C-CURE (Cardiopoietic stem Cell therapy in heart failURE) multicenter randomized trial with lineage-specified biologics. J Am Coll Cardiol 61:2329–2338. https://doi.org/10.1016/j.jacc.2013.02.071

    Article  PubMed  Google Scholar 

  5. Bolli R, Chugh AR, D’Amario D, Loughran JH, Stoddard MF, Ikram S, Beache GM, Wagner SG, Leri A, Hosoda T, Sanada F, Elmore JB, Goichberg P, Cappetta D, Solankhi NK, Fahsah I, Rokosh DG, Slaughter MS, Kajstura J, Anversa P (2011) Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet 378:1847–1857. https://doi.org/10.1016/S0140-6736(11)61590-0

    Article  PubMed  PubMed Central  Google Scholar 

  6. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820. https://doi.org/10.1038/414813a

    Article  CAS  PubMed  Google Scholar 

  7. Caballero S, Sengupta N, Afzal A, Chang KH, Li Calzi S, Guberski DL, Kern TS, Grant MB (2007) Ischemic vascular damage can be repaired by healthy, but not diabetic, endothelial progenitor cells. Diabetes 56:960–967. https://doi.org/10.2337/db06-1254

    Article  CAS  PubMed  Google Scholar 

  8. Ceriello A (2009) Hypothesis: the “metabolic memory”, the new challenge of diabetes. Diabetes Res Clin Pract 86(Suppl 1):S2–S6. https://doi.org/10.1016/S0168-8227(09)70002-6

    Article  CAS  PubMed  Google Scholar 

  9. Chalkiadaki A, Guarente L (2012) Sirtuins mediate mammalian metabolic responses to nutrient availability. Nature Rev Endocrinol 8:287–296. https://doi.org/10.1038/nrendo.2011.225

    Article  CAS  Google Scholar 

  10. Chen L, Wang Y, Pan Y, Zhang L, Shen C, Qin G, Ashraf M, Weintraub N, Ma G, Tang Y (2013) Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia/reperfusion injury. Biochem Biophys Res Comm 431:566–571. https://doi.org/10.1016/j.bbrc.2013.01.015

    Article  CAS  PubMed  Google Scholar 

  11. Choudhery MS, Khan M, Mahmood R, Mohsin S, Akhtar S, Ali F, Khan SN, Riazuddin S (2012) Mesenchymal stem cells conditioned with glucose depletion augments their ability to repair-infarcted myocardium. J Cell Mol Med 16:2518–2529. https://doi.org/10.1111/j.1582-4934.2012.01568.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chugh AR, Beache GM, Loughran JH, Mewton N, Elmore JB, Kajstura J, Pappas P, Tatooles A, Stoddard MF, Lima JA, Slaughter MS, Anversa P, Bolli R (2012) Administration of cardiac stem cells in patients with ischemic cardiomyopathy: the SCIPIO trial: surgical aspects and interim analysis of myocardial function and viability by magnetic resonance. Circulation 126:S54–S64. https://doi.org/10.1161/CIRCULATIONAHA.112.092627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. De Angelis A, Piegari E, Cappetta D, Russo R, Esposito G, Ciuffreda LP, Ferraiolo FA, Frati C, Fagnoni F, Berrino L, Quaini F, Rossi F, Urbanek K (2015) SIRT1 activation rescues doxorubicin-induced loss of functional competence of human cardiac progenitor cells. Int J Cardiol 189:30–44. https://doi.org/10.1016/j.ijcard.2015.03.438

    Article  PubMed  Google Scholar 

  14. Dei Cas A, Khan SS, Butler J, Mentz RJ, Bonow RO, Avogaro A, Tschoepe D, Doehner W, Greene SJ, Senni M, Gheorghiade M, Fonarow GC (2015) Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure. JACC Heart Fail 3:136–145. https://doi.org/10.1016/j.jchf.2014.08.004

    Article  PubMed  Google Scholar 

  15. Fadini GP, Albiero M, Vigili de Kreutzenberg S, Boscaro E, Cappellari R, Marescotti M, Poncina N, Agostini C, Avogaro A (2013) Diabetes impairs stem cell and proangiogenic cell mobilization in humans. Diabetes Care 36:943–949. https://doi.org/10.2337/dc12-1084

    Article  PubMed  PubMed Central  Google Scholar 

  16. Fadini GP, Boscaro E, de Kreutzenberg S, Agostini C, Seeger F, Dimmeler S, Zeiher A, Tiengo A, Avogaro A (2010) Time course and mechanisms of circulating progenitor cell reduction in the natural history of type 2 diabetes. Diabetes Care 33:1097–1102. https://doi.org/10.2337/dc09-1999

    Article  PubMed  PubMed Central  Google Scholar 

  17. Fadini GP, Pucci L, Vanacore R, Baesso I, Penno G, Balbarini A, Di Stefano R, Miccoli R, de Kreutzenberg S, Coracina A, Tiengo A, Agostini C, Del Prato S, Avogaro A (2007) Glucose tolerance is negatively associated with circulating progenitor cell levels. Diabetologia 50:2156–2163. https://doi.org/10.1007/s00125-007-0732-y

    Article  CAS  PubMed  Google Scholar 

  18. Ferraro F, Lymperi S, Mendez-Ferrer S, Saez B, Spencer JA, Yeap BY, Masselli E, Graiani G, Prezioso L, Rizzini EL, Mangoni M, Rizzoli V, Sykes SM, Lin CP, Frenette PS, Quaini F, Scadden DT (2011) Diabetes impairs hematopoietic stem cell mobilization by altering niche function. Sci Transl Med 3:1041ra01. https://doi.org/10.1126/scitranslmed.3002191

    Article  CAS  Google Scholar 

  19. Gibb AA, Lorkiewicz PK, Zheng YT, Zhang X, Bhatnagar A, Jones SP, Hill BG (2017) Integration of flux measurements to resolve changes in anabolic and catabolic metabolism in cardiac myocytes. Biochem J 474:2785–2801. https://doi.org/10.1042/BCJ20170474

    Article  CAS  PubMed  Google Scholar 

  20. Group AC, Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F, Group AC (2008) Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 358:2560–2572. https://doi.org/10.1056/nejmoa0802987

    Article  Google Scholar 

  21. Guo Y, Wysoczynski M, Nong Y, Tomlin A, Zhu X, Gumpert AM, Nasr M, Muthusamy S, Li H, Book M, Khan A, Hong KU, Li Q, Bolli R (2017) Repeated doses of cardiac mesenchymal cells are therapeutically superior to a single dose in mice with old myocardial infarction. Basic Res Cardiol 112:18. https://doi.org/10.1007/s00395-017-0606-5

    Article  PubMed  PubMed Central  Google Scholar 

  22. Haigis MC, Guarente LP (2006) Mammalian sirtuins–emerging roles in physiology, aging, and calorie restriction. Genes Dev 20:2913–2921. https://doi.org/10.1101/gad.1467506

    Article  CAS  PubMed  Google Scholar 

  23. Hallows WC, Yu W, Denu JM (2012) Regulation of glycolytic enzyme phosphoglycerate mutase-1 by Sirt1 protein-mediated deacetylation. J Biol Chem 287:3850–3858. https://doi.org/10.1074/jbc.M111.317404

    Article  CAS  PubMed  Google Scholar 

  24. 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. https://doi.org/10.1001/jama.2012.25321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hare JM, Traverse JH, Henry TD, Dib N, Strumpf RK, Schulman SP, Gerstenblith G, DeMaria AN, Denktas AE, Gammon RS, Hermiller JB Jr, Reisman MA, Schaer GL, Sherman W (2009) A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol 54:2277–2286. https://doi.org/10.1016/j.jacc.2009.06.055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hayashida S, Arimoto A, Kuramoto Y, Kozako T, Honda S, Shimeno H, Soeda S (2010) Fasting promotes the expression of SIRT1, an NAD+-dependent protein deacetylase, via activation of PPARalpha in mice. Mol Cell Biochem 339:285–292. https://doi.org/10.1007/s11010-010-0391-z

    Article  CAS  PubMed  Google Scholar 

  27. Hill BG, Dranka BP, Zou L, Chatham JC, Darley-Usmar VM (2009) Importance of the bioenergetic reserve capacity in response to cardiomyocyte stress induced by 4-hydroxynonenal. Biochem J 424:99–107. https://doi.org/10.1042/BJ20090934

    Article  CAS  PubMed  Google Scholar 

  28. Hsu CP, Odewale I, Alcendor RR, Sadoshima J (2008) Sirt1 protects the heart from aging and stress. Biol Chem 389:221–231. https://doi.org/10.1515/BC.2008.032

    Article  CAS  PubMed  Google Scholar 

  29. Jarajapu YP, Hazra S, Segal M, LiCalzi S, Jhadao C, Qian K, Mitter SK, Raizada MK, Boulton ME, Grant MB (2014) Vasoreparative dysfunction of CD34+ cells in diabetic individuals involves hypoxic desensitization and impaired autocrine/paracrine mechanisms. PLoS ONE 9:e93965. https://doi.org/10.1371/journal.pone.0093965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Jialal I, Devaraj S, Singh U, Huet BA (2010) Decreased number and impaired functionality of endothelial progenitor cells in subjects with metabolic syndrome: implications for increased cardiovascular risk. Atherosclerosis 211:297–302. https://doi.org/10.1016/j.atherosclerosis.2010.01.036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jung C, Rafnsson A, Shemyakin A, Bohm F, Pernow J (2010) Different subpopulations of endothelial progenitor cells and circulating apoptotic progenitor cells in patients with vascular disease and diabetes. Int J Cardiol 143:368–372. https://doi.org/10.1016/j.ijcard.2009.03.075

    Article  PubMed  Google Scholar 

  32. Kanfi Y, Peshti V, Gozlan YM, Rathaus M, Gil R, Cohen HY (2008) Regulation of SIRT1 protein levels by nutrient availability. FEBS Lett 582:2417–2423. https://doi.org/10.1016/j.febslet.2008.06.005

    Article  CAS  PubMed  Google Scholar 

  33. Kang L, Chen Q, Wang L, Gao L, Meng K, Chen J, Ferro A, Xu B (2009) Decreased mobilization of endothelial progenitor cells contributes to impaired neovascularization in diabetes. Clin Exp Pharmacol Physiol 36:e47–e56. https://doi.org/10.1111/j.1440-1681.2009.05219.x

    Article  CAS  PubMed  Google Scholar 

  34. Lee C, Mitsialis SA, Aslam M, Vitali SH, Vergadi E, Konstantinou G, Sdrimas K, Fernandez-Gonzalez A, Kourembanas S (2012) Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation 126:2601–2611. https://doi.org/10.1161/CIRCULATIONAHA.112.114173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Li RC, Ping P, Zhang J, Wead WB, Cao X, Gao J, Zheng Y, Huang S, Han J, Bolli R (2000) PKCepsilon modulates NF-kappaB and AP-1 via mitogen-activated protein kinases in adult rabbit cardiomyocytes. Am J Physiol Heart Circ Physiol 279:H1679–H1689. https://doi.org/10.1152/ajpheart.2000.279.4.H1679

    Article  CAS  PubMed  Google Scholar 

  36. Liao YF, Chen LL, Zeng TS, Li YM, Fan Y, Hu LJ, Ling Y (2010) Number of circulating endothelial progenitor cells as a marker of vascular endothelial function for type 2 diabetes. Vasc Med 15:279–285. https://doi.org/10.1177/1358863X10367537

    Article  PubMed  Google Scholar 

  37. Liu HL, Zhu JG, Liu YQ, Fan ZG, Zhu C, Qian LM (2014) Identification of the microRNA expression profile in the regenerative neonatal mouse heart by deep sequencing. Cell Biochem Biophys 70:635–642. https://doi.org/10.1007/s12013-014-9967-7

    Article  CAS  PubMed  Google Scholar 

  38. Liu Y, Li Z, Liu T, Xue X, Jiang H, Huang J, Wang H (2013) Impaired cardioprotective function of transplantation of mesenchymal stem cells from patients with diabetes mellitus to rats with experimentally induced myocardial infarction. Cardiovasc Diabetol 12:40. https://doi.org/10.1186/1475-2840-12-40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lombardi R, Marian AJ (2011) Molecular genetics and pathogenesis of arrhythmogenic right ventricular cardiomyopathy: a disease of cardiac stem cells. Pediatr Cardiol 32:360–365. https://doi.org/10.1007/s00246-011-9890-2

    Article  PubMed  Google Scholar 

  40. Lopez-Otin C, Galluzzi L, Freije JM, Madeo F, Kroemer G (2016) Metabolic control of longevity. Cell 166:802–821. https://doi.org/10.1016/j.cell.2016.07.031

    Article  CAS  PubMed  Google Scholar 

  41. Makkar RR, Smith RR, Cheng K, Malliaras K, Thomson LE, Berman D, Czer LS, Marban L, Mendizabal A, Johnston PV, Russell SD, Schuleri KH, Lardo AC, Gerstenblith G, Marban E (2012) Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet 379:895–904. https://doi.org/10.1016/S0140-6736(12)60195-0

    Article  PubMed  PubMed Central  Google Scholar 

  42. Marrotte EJ, Chen DD, Hakim JS, Chen AF (2010) Manganese superoxide dismutase expression in endothelial progenitor cells accelerates wound healing in diabetic mice. J Clin Invest 120:4207–4219. https://doi.org/10.1172/JCI36858

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Matsushima S, Sadoshima J (2015) The role of sirtuins in cardiac disease. Am J Physiol Heart Circ Physiol 309:H1375–H1389. https://doi.org/10.1152/ajpheart.00053.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Molgat AS, Tilokee EL, Rafatian G, Vulesevic B, Ruel M, Milne R, Suuronen EJ, Davis DR (2014) Hyperglycemia inhibits cardiac stem cell-mediated cardiac repair and angiogenic capacity. Circulation 130:S70–S76. https://doi.org/10.1161/CIRCULATIONAHA.113.007908

    Article  CAS  PubMed  Google Scholar 

  45. Mor I, Cheung EC, Vousden KH (2011) Control of glycolysis through regulation of PFK1: old friends and recent additions. Cold Spring Harb Symp Quant Biol 76:211–216. https://doi.org/10.1101/sqb.2011.76.010868

    Article  CAS  PubMed  Google Scholar 

  46. Nadtochiy SM, Redman E, Rahman I, Brookes PS (2011) Lysine deacetylation in ischaemic preconditioning: the role of SIRT1. Cardiovasc Res 89:643–649. https://doi.org/10.1093/cvr/cvq287

    Article  CAS  PubMed  Google Scholar 

  47. Nadtochiy SM, Yao H, McBurney MW, Gu W, Guarente L, Rahman I, Brookes PS (2011) SIRT1-mediated acute cardioprotection. Am J Physiol Heart Circ Physiol 301:H1506–H1512. https://doi.org/10.1152/ajpheart.00587.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404:787–790. https://doi.org/10.1038/35008121

    Article  CAS  PubMed  Google Scholar 

  49. Perin EC, Sanz-Ruiz R, Sanchez PL, Lasso J, Perez-Cano R, Alonso-Farto JC, Perez-David E, Fernandez-Santos ME, Serruys PW, Duckers HJ, Kastrup J, Chamuleau S, Zheng Y, Silva GV, Willerson JT, Fernandez-Aviles F (2014) Adipose-derived regenerative cells in patients with ischemic cardiomyopathy: The PRECISE Trial. Am Heart J 168(88–95):e82. https://doi.org/10.1016/j.ahj.2014.03.022

    Article  CAS  Google Scholar 

  50. Quyyumi AA, Waller EK, Murrow J, Esteves F, Galt J, Oshinski J, Lerakis S, Sher S, Vaughan D, Perin E, Willerson J, Kereiakes D, Gersh BJ, Gregory D, Werner A, Moss T, Chan WS, Preti R, Pecora AL (2011) CD34+ cell infusion after ST elevation myocardial infarction is associated with improved perfusion and is dose dependent. Am Heart J 161:98–105. https://doi.org/10.1016/j.ahj.2010.09.025

    Article  PubMed  Google Scholar 

  51. Rawal S, Munasinghe PE, Nagesh PT, Lew JKS, Jones GT, Williams MJA, Davis P, Bunton D, Galvin IF, Manning P, Lamberts RR, Katare R (2017) Down-regulation of miR-15a/b accelerates fibrotic remodelling in the Type 2 diabetic human and mouse heart. Clin Sci 131:847–863. https://doi.org/10.1042/CS20160916

    Article  CAS  Google Scholar 

  52. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P (2005) Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434:113–118. https://doi.org/10.1038/nature03354

    Article  CAS  PubMed  Google Scholar 

  53. Rodriguez P, Sassi Y, Troncone L, Benard L, Ishikawa K, Gordon RE, Lamas S, Laborda J, Hajjar RJ (2018) Deletion of delta-like 1 homologue accelerates fibroblast-myofibroblast differentiation and induces myocardial fibrosis. Eur Heart J. https://doi.org/10.1093/eurheartj/ehy188

    Article  PubMed  PubMed Central  Google Scholar 

  54. Rota M, LeCapitaine N, Hosoda T, Boni A, De Angelis A, Padin-Iruegas ME, Esposito G, Vitale S, Urbanek K, Casarsa C, Giorgio M, Luscher TF, Pelicci PG, Anversa P, Leri A, Kajstura J (2006) Diabetes promotes cardiac stem cell aging and heart failure, which are prevented by deletion of the p66shc gene. Circ Res 99:42–52. https://doi.org/10.1161/01.RES.0000231289.63468.08

    Article  CAS  PubMed  Google Scholar 

  55. Saito H, Yamamoto Y, Yamamoto H (2012) Diabetes alters subsets of endothelial progenitor cells that reside in blood, bone marrow, and spleen. Am J Physiol Cell Physiol 302:C892–C901. https://doi.org/10.1152/ajpcell.00380.2011

    Article  CAS  PubMed  Google Scholar 

  56. Salabei JK, Lorkiewicz PK, Holden CR, Li Q, Hong KU, Bolli R, Bhatnagar A, Hill BG (2015) Glutamine regulates cardiac progenitor cell metabolism and proliferation. Stem Cells 33:2613–2627

    Article  PubMed  PubMed Central  Google Scholar 

  57. Salabei JK, Lorkiewicz PK, Mehra P, Gibb AA, Haberzettl P, Hong KU, Wei X, Zhang X, Li Q, Wysoczynski M (2016) Type 2 diabetes dysregulates glucose metabolism in cardiac progenitor cells. J Biol Chem 291:13634–13648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sarma S, Mentz RJ, Kwasny MJ, Fought AJ, Huffman M, Subacius H, Nodari S, Konstam M, Swedberg K, Maggioni AP, Zannad F, Bonow RO, Gheorghiade M, Investigators E (2013) Association between diabetes mellitus and post-discharge outcomes in patients hospitalized with heart failure: findings from the EVEREST trial. Eur J Heart Fail 15:194–202. https://doi.org/10.1093/eurjhf/hfs153

    Article  CAS  PubMed  Google Scholar 

  59. Schachinger V, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Holschermann H, Yu J, Corti R, Mathey DG, Hamm CW, Suselbeck T, Assmus B, Tonn T, Dimmeler S, Zeiher AM, Investigators R-A (2006) Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 355:1210–1221. https://doi.org/10.1056/NEJMoa060186

    Article  CAS  PubMed  Google Scholar 

  60. Schachinger V, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Holschermann H, Yu J, Corti R, Mathey DG, Hamm CW, Suselbeck T, Werner N, Haase J, Neuzner J, Germing A, Mark B, Assmus B, Tonn T, Dimmeler S, Zeiher AM, Investigators R-A (2006) Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial. Eur Heart J 27:2775–2783. https://doi.org/10.1093/eurheartj/ehl388

    Article  PubMed  Google Scholar 

  61. Singh H, Gordon HS, Deswal A (2005) Variation by race in factors contributing to heart failure hospitalizations. J Cardiac Fail 11:23–29

    Article  Google Scholar 

  62. Sundaresan NR, Pillai VB, Gupta MP (2011) Emerging roles of SIRT1 deacetylase in regulating cardiomyocyte survival and hypertrophy. J Mol Cell Cardiol 51:614–618. https://doi.org/10.1016/j.yjmcc.2011.01.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Tepper OM, Galiano RD, Capla JM, Kalka C, Gagne PJ, Jacobowitz GR, Levine JP, Gurtner GC (2002) Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation 106:2781–2786

    Article  PubMed  Google Scholar 

  64. Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, Zeiher AM, Dimmeler S (2001) Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 89:E1–E7

    Article  CAS  PubMed  Google Scholar 

  65. Wang Y, Zhang L, Li Y, Chen L, Wang X, Guo W, Zhang X, Qin G, He SH, Zimmerman A, Liu Y, Kim IM, Weintraub NL, Tang Y (2015) Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium. Int J Cardiol 192:61–69. https://doi.org/10.1016/j.ijcard.2015.05.020

    Article  PubMed  PubMed Central  Google Scholar 

  66. Wang Y, Zhao X, Wu X, Dai Y, Chen P, Xie L (2016) microRNA-182 Mediates Sirt1-induced diabetic corneal nerve regeneration. Diabetes 65:2020–2031. https://doi.org/10.2337/db15-1283

    Article  CAS  PubMed  Google Scholar 

  67. Wei X, Lorkiewicz PK, Shi B, Salabei JK, Hill BG, Kim S, McClain CJ, Zhang X (2017) Analysis of stable isotope assisted metabolomics data acquired by high resolution mass spectrometry. Anal Methods 9:2275–2283. https://doi.org/10.1039/C7AY00291B

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Westerweel PE, Teraa M, Rafii S, Jaspers JE, White IA, Hooper AT, Doevendans PA, Verhaar MC (2013) Impaired endothelial progenitor cell mobilization and dysfunctional bone marrow stroma in diabetes mellitus. PLoS ONE 8:e60357. https://doi.org/10.1371/journal.pone.0060357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Williams AR, Trachtenberg B, Velazquez DL, McNiece I, Altman P, Rouy D, Mendizabal AM, Pattany PM, Lopera GA, Fishman J, Zambrano JP, Heldman AW, Hare JM (2011) Intramyocardial stem cell injection in patients with ischemic cardiomyopathy: functional recovery and reverse remodeling. Circ Res 108:792–796. https://doi.org/10.1161/CIRCRESAHA.111.242610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Winnik S, Auwerx J, Sinclair DA, Matter CM (2015) Protective effects of sirtuins in cardiovascular diseases: from bench to bedside. Eur Heart J 36:3404–3412. https://doi.org/10.1093/eurheartj/ehv290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Wollert KC, Meyer GP, Lotz J, Ringes-Lichtenberg S, Lippolt P, Breidenbach C, Fichtner S, Korte T, Hornig B, Messinger D, Arseniev L, Hertenstein B, Ganser A, Drexler H (2004) Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 364:141–148. https://doi.org/10.1016/S0140-6736(04)16626-9

    Article  PubMed  Google Scholar 

  72. Wysoczynski M, Dassanayaka S, Zafir A, Ghafghazi S, Long BW, Noble C, DeMartino AM, Brittian KR, Bolli R, Jones SP (2016) A new method to stabilize c-kit expression in reparative cardiac mesenchymal cells. Front Cell Dev Biol 4:78. https://doi.org/10.3389/fcell.2016.00078

    Article  PubMed  PubMed Central  Google Scholar 

  73. Wysoczynski M, Guo Y, Moore JBT, Muthusamy S, Li Q, Nasr M, Li H, Nong Y, Wu W, Tomlin AA, Zhu X, Hunt G, Gumpert AM, Book MJ, Khan A, Tang XL, Bolli R (2017) Myocardial reparative properties of cardiac mesenchymal cells isolated on the basis of adherence. J Am Coll Cardiol 69:1824–1838. https://doi.org/10.1016/j.jacc.2017.01.048

    Article  PubMed  PubMed Central  Google Scholar 

  74. Xuan YT, Guo Y, Zhu Y, Wang OL, Rokosh G, Messing RO, Bolli R (2005) Role of the protein kinase C-epsilon-Raf-1-MEK-1/2-p44/42 MAPK signaling cascade in the activation of signal transducers and activators of transcription 1 and 3 and induction of cyclooxygenase-2 after ischemic preconditioning. Circulation 112:1971–1978. https://doi.org/10.1161/CIRCULATIONAHA.105.561522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Yalcin A, Telang S, Clem B, Chesney J (2009) Regulation of glucose metabolism by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases in cancer. Exp Mol Pathol 86:174–179. https://doi.org/10.1016/j.yexmp.2009.01.003

    Article  CAS  PubMed  Google Scholar 

  76. Yamamoto T, Tamaki K, Shirakawa K, Ito K, Yan X, Katsumata Y, Anzai A, Matsuhashi T, Endo J, Inaba T, Tsubota K, Sano M, Fukuda K, Shinmura K (2016) Cardiac Sirt1 mediates the cardioprotective effect of caloric restriction by suppressing local complement system activation after ischemia-reperfusion. Am J Physiol Heart Circ Physiol 310:H1003–H1014. https://doi.org/10.1152/ajpheart.00676.2015

    Article  PubMed  Google Scholar 

  77. Yan J, Tie G, Wang S, Messina KE, DiDato S, Guo S, Messina LM (2012) Type 2 diabetes restricts multipotency of mesenchymal stem cells and impairs their capacity to augment postischemic neovascularization in db/db mice. J Am Heart Assoc 1:e002238. https://doi.org/10.1161/JAHA.112.002238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Yang NC, Song TY, Chang YZ, Chen MY, Hu ML (2015) Up-regulation of nicotinamide phosphoribosyltransferase and increase of NAD+ levels by glucose restriction extend replicative lifespan of human fibroblast Hs68 cells. Biogerontology 16:31–42. https://doi.org/10.1007/s10522-014-9528-x

    Article  CAS  PubMed  Google Scholar 

  79. Yang Y, Cheng HW, Qiu Y, Dupee D, Noonan M, Lin YD, Fisch S, Unno K, Sereti KI, Liao R (2015) MicroRNA-34a plays a key role in cardiac repair and regeneration following myocardial infarction. Circ Res 117:450–459. https://doi.org/10.1161/CIRCRESAHA.117.305962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Yiu KH, Tse HF (2014) Specific role of impaired glucose metabolism and diabetes mellitus in endothelial progenitor cell characteristics and function. Arterioscler Thromb Vasc Biol 34:1136–1143. https://doi.org/10.1161/ATVBAHA.114.302192

    Article  CAS  PubMed  Google Scholar 

  81. Zhong L, Mostoslavsky R (2010) SIRT6: a master epigenetic gatekeeper of glucose metabolism. Transcription 1:17–21. https://doi.org/10.4161/trns.1.1.12143

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors acknowledge funding support from the National Institutes of Health (NIH) [to BGH: HL122580, HL130174, ES028268; to RB: HL78825, HL113530; to AB: GM103492, HL55477) and the American Diabetes Association Pathway to Stop Diabetes Grant (BGH: ADA 1-16-JDF-041.)].

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  1. Division of Cardiovascular Medicine, Department of Medicine, Institute of Molecular Cardiology, Envirome Institute, Diabetes and Obesity Center, University of Louisville School of Medicine, 580 S. Preston St., Rm 321E, Louisville, KY, 40202, USA

    Parul Mehra, Yiru Guo, Yibing Nong, Pawel Lorkiewicz, Marjan Nasr, Qianhong Li, Senthilkumar Muthusamy, James A. Bradley, Aruni Bhatnagar, Marcin Wysoczynski, Roberto Bolli & Bradford G. Hill

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  1. Parul Mehra
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  2. Yiru Guo
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Contributions

PM: experimental studies, assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; YG: in vivo experiments, data analysis and interpretation, final approval of manuscript; YN: experimental studies; PL: experimental studies, manuscript writing, final approval of manuscript; MN: experimental studies, final approval of manuscript; SM: experimental studies; JAB: experimental studies, final approval of manuscript; QL: experimental studies; AB, financial support, concept and design, final approval of manuscript; MW: concept and design, experimental studies, data analysis and interpretation, manuscript writing, final approval of manuscript; RB: concept and design, in vivo experimental studies, data analysis and interpretation, manuscript writing, final approval of manuscript; and BGH, financial support, concept and design, assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript.

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Correspondence to Bradford G. Hill.

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Mehra, P., Guo, Y., Nong, Y. et al. Cardiac mesenchymal cells from diabetic mice are ineffective for cell therapy-mediated myocardial repair. Basic Res Cardiol 113, 46 (2018). https://doi.org/10.1007/s00395-018-0703-0

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