Decline in cellular function of aged mouse c-kit cardiac progenitor cells.
Authors:
Journal: The Journal of physiology
Publication Type: Journal Article
Date: 2017
DOI: PMC5621489
ID: 28737214
Abstract
While autologous stem cell-based therapies are currently being tested on elderly patients, there are limited data on the function of aged stem cells and in particular c-kit cardiac progenitor cells (CPCs). We isolated c-kit cells from young (3 months) and aged (24 months) C57BL/6 mice to compare their biological properties. Aged CPCs have increased senescence, decreased stemness and reduced capacity to proliferate or to differentiate following dexamethasone (Dex) treatment in vitro, as evidenced by lack of cardiac lineage gene upregulation. Aged CPCs fail to activate mitochondrial biogenesis and increase proteins involved in mitochondrial oxidative phosphorylation in response to Dex. Aged CPCs fail to upregulate paracrine factors that are potentially important for proliferation, survival and angiogenesis in response to Dex. The results highlight marked differences between young and aged CPCs, which may impact future design of autologous stem cell-based therapies.
Chemical List
- Electron Transport Chain Complex Proteins|||GATA Transcription Factors|||Lin-28 protein, mouse|||MEF2 Transcription Factors|||Mef2c protein, mouse|||Platelet Endothelial Cell Adhesion Molecule-1|||RNA, Messenger|||RNA-Binding Proteins|||Dexamethasone|||Proto-Oncogene Proteins c-kit
Reference List
- Abbott JD, Huang Y, Liu D, Hickey R, Krause DS & Giordano FJ (2004). Stromal cell‐derived factor‐1α plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury. Circulation 110, 3300–3305.|||Baxter MA, Wynn RF, Jowitt SN, Wraith JE, Fairbairn LJ & Bellantuono I (2004). Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion. Stem Cells 22, 675–682.|||Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, Kasahara H, Rota M, Musso E, Urbanek K, Leri A, Kajstura J, Nadal‐Ginard B & Anversa P (2003). Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114, 763–776.|||Bergmann O, Zdunek S, Felker A, Salehpour M, Alkass K, Bernard S, Sjostrom SL, Szewczykowska M, Jackowska T, Dos Remedios C, Malm T, Andra M, Jashari R, Nyengaard JR, Possnert G, Jovinge S, Druid H & Frisen J (2015). Dynamics of cell generation and turnover in the human heart. Cell 161, 1566–1575.|||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.|||Bolli R, Tang XL, Sanganalmath SK, Rimoldi O, Mosna F, Abdel‐Latif A, Jneid H, Rota M, Leri A & Kajstura J (2013). Intracoronary delivery of autologous cardiac stem cells improves cardiac function in a porcine model of chronic ischemic cardiomyopathy. Circulation 128, 122–131.|||Brodsky SV, Gealekman O, Chen J, Zhang F, Togashi N, Crabtree M, Gross SS, Nasjletti A & Goligorsky MS (2004). Prevention and reversal of premature endothelial cell senescence and vasculopathy in obesity‐induced diabetes by ebselen. Circ Res 94, 377–384.|||Bromage DI, Davidson SM & Yellon DM (2014). Stromal derived factor 1α: a chemokine that delivers a two‐pronged defence of the myocardium. Pharmacol Ther 143, 305–315.|||Cai CL & Molkentin JD (2017). The elusive progenitor cell in cardiac regeneration: slip slidin’ away. Circ Res 120, 400–406.|||Castaldi A, Chesini GP, Taylor AE, Sussman MA, Brown JH & Purcell NH (2016). Sphingosine 1‐phosphate elicits RhoA‐dependent proliferation and MRTF‐A mediated gene induction in CPCs. Cell Signal 28, 871–879.|||Cheng K, Malliaras K, Smith RR, Shen D, Sun B, Blusztajn A, Xie Y, Ibrahim A, Aminzadeh MA, Liu W, Li TS, De Robertis MA, Marban L, Czer LS, Trento A & Marban E (2014). Human cardiosphere‐derived cells from advanced heart failure patients exhibit augmented functional potency in myocardial repair. JACC Heart Fail 2, 49–61.|||Chimenti I, Smith RR, Li TS, Gerstenblith G, Messina E, Giacomello A & Marban E (2010). Relative roles of direct regeneration versus paracrine effects of human cardiosphere‐derived cells transplanted into infarcted mice. Circ Res 106, 971–980.|||Cohen ED, Tian Y & Morrisey EE (2008). Wnt signaling: an essential regulator of cardiovascular differentiation, morphogenesis and progenitor self‐renewal. Development 135, 789–798.|||Cottage CT, Bailey B, Fischer KM, Avitabile D, Collins B, Tuck S, Quijada P, Gude N, Alvarez R, Muraski J & Sussman MA (2010). Cardiac progenitor cell cycling stimulated by pim‐1 kinase. Circ Res 106, 891–901.|||Dawn B, Stein AB, Urbanek K, Rota M, Whang B, Rastaldo R, Torella D, Tang XL, Rezazadeh A, Kajstura J, Leri A, Hunt G, Varma J, Prabhu SD, Anversa P & Bolli R (2005). Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function. Proc Natl Acad Sci USA 102, 3766–3771.|||Der Sarkissian S, Levesque T & Noiseux N (2017). Optimizing stem cells for cardiac repair: current status and new frontiers in regenerative cardiology. World J Stem Cells 9, 9–25.|||Ellison GM, Vicinanza C, Smith AJ, Aquila I, Leone A, Waring CD, Henning BJ, Stirparo GG, Papait R, Scarfo M, Agosti V, Viglietto G, Condorelli G, Indolfi C, Ottolenghi S, Torella D & Nadal‐Ginard B (2013). Adult c‐kit(pos) cardiac stem cells are necessary and sufficient for functional cardiac regeneration and repair. Cell 154, 827–842.|||Feng Z, Hanson RW, Berger NA & Trubitsyn A (2016). Reprogramming of energy metabolism as a driver of aging. Oncotarget 7, 15410–15420.|||Ferando I, Faas GC & Mody I (2016). Diminished KCC2 confounds synapse specificity of LTP during senescence. Nat Neurosci 19, 1197–1200.|||Fischer KM, Cottage CT, Konstandin MH, Volkers M, Khan M & Sussman MA (2011). Pim‐1 kinase inhibits pathological injury by promoting cardioprotective signaling. J Mol Cell Cardiol 51, 554–558.|||Fontana L, Vinciguerra M & Longo VD (2012). Growth factors, nutrient signaling, and cardiovascular aging. Circ Res 110, 1139–1150.|||Goichberg P, Bai Y, D'Amario D, Ferreira‐Martins J, Fiorini C, Zheng H, Signore S, del Monte F, Ottolenghi S, D'Alessandro DA, Michler RE, Hosoda T, Anversa P, Kajstura J, Rota M & Leri A (2011). The ephrin A1‐EphA2 system promotes cardiac stem cell migration after infarction. Circ Res 108, 1071–1083.|||Goichberg P, Kannappan R, Cimini M, Bai Y, Sanada F, Sorrentino A, Signore S, Kajstura J, Rota M, Anversa P & Leri A (2013). Age‐associated defects in EphA2 signaling impair the migration of human cardiac progenitor cells. Circulation 128, 2211–2223.|||Goumans MJ, de Boer TP, Smits AM, van Laake LW, van Vliet P, Metz CH, Korfage TH, Kats KP, Hochstenbach R, Pasterkamp G, Verhaar MC, van der Heyden MA, de Kleijn D, Mummery CL, van Veen TA, Sluijter JP & Doevendans PA (2007). TGF‐β1 induces efficient differentiation of human cardiomyocyte progenitor cells into functional cardiomyocytes in vitro . Stem Cell Res 1, 138–149.|||Hariharan N, Quijada P, Mohsin S, Joyo A, Samse K, Monsanto M, De La Torre A, Avitabile D, Ormachea L, McGregor MJ, Tsai EJ & Sussman MA (2015). Nucleostemin rejuvenates cardiac progenitor cells and antagonizes myocardial aging. J Am Coll Cardiol 65, 133–147.|||Hariharan N & Sussman MA (2015). Cardiac aging – Getting to the stem of the problem. J Mol Cell Cardiol 83, 32–36.|||Hong KU & Bolli R (2014). Cardiac stem cell therapy for cardiac repair. Curr Treat Options Cardiovasc Med 16, 324.|||Hsieh PC, Segers VF, Davis ME, MacGillivray C, Gannon J, Molkentin JD, Robbins J & Lee RT (2007). Evidence from a genetic fate‐mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nat Med 13, 970–974.|||Ito K & Suda T (2014). Metabolic requirements for the maintenance of self‐renewing stem cells. Nat Rev Mol Cell Biol 15, 243–256.|||Janzen V, Forkert R, Fleming HE, Saito Y, Waring MT, Dombkowski DM, Cheng T, DePinho RA, Sharpless NE & Scadden DT (2006). Stem‐cell ageing modified by the cyclin‐dependent kinase inhibitor p16INK4a. Nature 443, 421–426.|||Kanasi E, Ayilavarapu S & Jones J (2016). The aging population: demographics and the biology of aging. Periodontol 2000 72, 13–18.|||Khanabdali R, Rosdah AA, Dusting GJ & Lim SY (2016). Harnessing the secretome of cardiac stem cells as therapy for ischemic heart disease. Biochem Pharmacol 113, 1–11.|||Kosugi R, Shioi T, Watanabe‐Maeda K, Yoshida Y, Takahashi K, Machida Y & Izumi T (2006). Angiotensin II receptor antagonist attenuates expression of aging markers in diabetic mouse heart. Circ J 70, 482–488.|||Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al‐Regaiey K, Su L & Sharpless NE (2004). Ink4a/Arf expression is a biomarker of aging. J Clin Invest 114, 1299–1307.|||Lakatta EG & Levy D (2003). Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease. Circulation 107, 346–354.|||Leifke E, Gorenoi V, Wichers C, Von Zur Muhlen A, Von Buren E & Brabant G (2000). Age‐related changes of serum sex hormones, insulin‐like growth factor‐1 and sex‐hormone binding globulin levels in men: cross‐sectional data from a healthy male cohort. Clin Endocrinol (Oxf) 53, 689–695.|||Li Q, Guo Y, Ou Q, Chen N, Wu WJ, Yuan F, O'Brien E, Wang T, Luo L, Hunt GN, Zhu X & Bolli R (2011). Intracoronary administration of cardiac stem cells in mice: a new, improved technique for cell therapy in murine models. Basic Res Cardiol 106, 849–864.|||Masters M & Riley PR (2014). The epicardium signals the way towards heart regeneration. Stem Cell Res 13, 683–692.|||McCall FC, Telukuntla KS, Karantalis V, Suncion VY, Heldman AW, Mushtaq M, Williams AR & Hare JM (2012). Myocardial infarction and intramyocardial injection models in swine. Nat Protoc 7, 1479–1496.|||Moc C, Taylor AE, Chesini GP, Zambrano CM, Barlow MS, Zhang X, Gustafsson AB & Purcell NH (2015). Physiological activation of Akt by PHLPP1 deletion protects against pathological hypertrophy. Cardiovasc Res 105, 160–170.|||Molofsky AV, Slutsky SG, Joseph NM, He S, Pardal R, Krishnamurthy J, Sharpless NE & Morrison SJ (2006). Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443, 448–452.|||Olson KA, Beatty AL, Heidecker B, Regan MC, Brody EN, Foreman T, Kato S, Mehler RE, Singer BS, Hveem K, Dalen H, Sterling DG, Lawn RM, Schiller NB, Williams SA, Whooley MA & Ganz P (2015). Association of growth differentiation factor 11/8, putative anti‐ageing factor, with cardiovascular outcomes and overall mortality in humans: analysis of the Heart and Soul and HUNT3 cohorts. Eur Heart J 36, 3426–3434.|||Orogo AM, Gonzalez ER, Kubli DA, Baptista IL, Ong SB, Prolla TA, Sussman MA, Murphy AN & Gustafsson AB (2015). Accumulation of mitochondrial DNA mutations disrupts cardiac progenitor cell function and reduces survival. J Biol Chem 290, 22061–22075.|||Oshima M, Hasegawa N, Mochizuki‐Kashio M, Muto T, Miyagi S, Koide S, Yabata S, Wendt GR, Saraya A, Wang C, Shimoda K, Suzuki Y & Iwama A (2016). Ezh2 regulates the Lin28/let‐7 pathway to restrict activation of fetal gene signature in adult hematopoietic stem cells. Exp Hematol 44, 282–296.e283.|||Quijada P, Salunga HT, Hariharan N, Cubillo JD, El‐Sayed FG, Moshref M, Bala KM, Emathinger JM, De La Torre A, Ormachea L, Alvarez R Jr, Gude NA & Sussman MA (2015). Cardiac stem cell hybrids enhance myocardial repair. Circ Res 117, 695–706.|||Rochette L, Zeller M, Cottin Y & Vergely C (2015). Growth and differentiation factor 11 (GDF11): functions in the regulation of erythropoiesis and cardiac regeneration. Pharmacol Ther 156, 26–33.|||Rota M, Goichberg P, Anversa P & Leri A (2015). Aging effects on cardiac progenitor cell physiology. Compr Physiol 5, 1775–1814.|||Samse K, Emathinger J, Hariharan N, Quijada P, Ilves K, Volkers M, Ormachea L, De La Torre A, Orogo AM, Alvarez R, Din S, Mohsin S, Monsanto M, Fischer KM, Dembitsky WP, Gustafsson AB & Sussman MA (2015). Functional effect of Pim1 depends upon intracellular localization in human cardiac progenitor cells. J Biol Chem 290, 13935–13947.|||Sharma S, Mishra R, Bigham GE, Wehman BP, Khan MM, Datla SR, Saha P, Goo YA, Chen L, Goodlett DR & Kaushal S (2017). Deep proteome analysis identified complete secretome as the functional unit of human cardiac progenitor cells. Circulation 120, 816–834.|||Sousa‐Victor P, Gutarra S, Garcia‐Prat L, Rodriguez‐Ubreva J, Ortet L, Ruiz‐Bonilla V, Jardi M, Ballestar E, Gonzalez S, Serrano AL, Perdiguero E & Munoz‐Canoves P (2014). Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316–321.|||Stastna M, Chimenti I, Marban E & Van Eyk JE (2010). Identification and functionality of proteomes secreted by rat cardiac stem cells and neonatal cardiomyocytes. Proteomics 10, 245–253.|||Tang XL, Rokosh G, Sanganalmath SK, Yuan F, Sato H, Mu J, Dai S, Li C, Chen N, Peng Y, Dawn B, Hunt G, Leri A, Kajstura J, Tiwari S, Shirk G, Anversa P & Bolli R (2010). Intracoronary administration of cardiac progenitor cells alleviates left ventricular dysfunction in rats with a 30‐day‐old infarction. Circulation 121, 293–305.|||Terzi MY, Izmirli M & Gogebakan B (2016). The cell fate: senescence or quiescence. Mol Biol Rep 43, 1213–1220.|||Toko H, Hariharan N, Konstandin MH, Ormachea L, McGregor M, Gude NA, Sundararaman B, Joyo E, Joyo AY, Collins B, Din S, Mohsin S, Uchida T & Sussman MA (2014). Differential regulation of cellular senescence and differentiation by prolyl isomerase Pin1 in cardiac progenitor cells. J Biol Chem 289, 5348–5356.|||Torella D, Rota M, Nurzynska D, Musso E, Monsen A, Shiraishi I, Zias E, Walsh K, Rosenzweig A, Sussman MA, Urbanek K, Nadal‐Ginard B, Kajstura J, Anversa P & Leri A (2004). Cardiac stem cell and myocyte aging, heart failure, and insulin‐like growth factor‐1 overexpression. Circ Res 94, 514–524.|||van Berlo JH, Kanisicak O, Maillet M, Vagnozzi RJ, Karch J, Lin SC, Middleton RC, Marban E & Molkentin JD (2014). c‐kit+ cells minimally contribute cardiomyocytes to the heart. Nature 509, 337–341.|||van Rooij E (2016). Cardiac repair after myocardial infarction. N Engl J Med 374, 85–87.|||Williams AR, Hatzistergos KE, Addicott B, McCall F, Carvalho D, Suncion V, Morales AR, Da Silva J, Sussman MA, Heldman AW & Hare JM (2013). Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and to restore cardiac function after myocardial infarction. Circulation 127, 213–223.|||Wong TY, Solis MA, Chen YH & Huang LL (2015). Molecular mechanism of extrinsic factors affecting anti‐aging of stem cells. World J Stem Cells 7, 512–520.|||Writing Group Members , Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jimenez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB, American Heart Association Statistics Committee & Stroke Statistics Subcommittee (2016). Heart disease and stroke statistics‐2016 update: a report from the American Heart Association. Circulation 133, e38–360.|||Xu X, Duan S, Yi F, Ocampo A, Liu GH & Izpisua Belmonte JC (2013). Mitochondrial regulation in pluripotent stem cells. Cell Metab 18, 325–332.|||Yellamilli A & van Berlo JH (2016). The role of cardiac side population cells in cardiac regeneration. Front Cell Dev Biol 4, 102.|||Zhang NK, Cao Y, Zhu ZM, Zheng N, Wang L, Xu XH & Gao LR (2016). Activation of endogenous cardiac stem cells by apelin‐13 in infarcted rat heart. Cell Transplant 25, 1645–1652.|||Zhong X, Li N, Liang S, Huang Q, Coukos G & Zhang L (2010). Identification of microRNAs regulating reprogramming factor LIN28 in embryonic stem cells and cancer cells. J Biol Chem 285, 41961–41971.