Recruitment and retention of human autologous CD34+ CD117+ CD133+ bone marrow stem cells to infarcted myocardium followed by directed vasculogenesis: Novel strategy for cardiac regeneration
Abstract
Ongoing clinical trials, in regenerative therapy of patients suffering from myocardial infarctions, rely primarily upon administration of bone marrow stem cells to the infarcted zones. Unfortunately, low retention of these cells, to the therapeutic delivery sites, reduces effectiveness of this strategy; thus it has been identified as the most critical problem for advancement of cardiac regenerative medicine.
Figure 1 Concept of novel strategy for cardiac regeneration with human autologous bone marrow cells. (A) Heterospecific, tetravalent antibodies (htAbs) contain binding domains for four different antigens: CD34, CD117, CD133, and myosin. They are injected into the solution flowing over the sarcomeres of the infarcted myocardium. (B) The htAbs dock onto myosins of the sarcomeres. Excess of the htAbs is cleared from the circulation. (C) Human, autologous, bone marrow stem cells (haBMSCs) are spiked into the solution. (D) The cells displaying on their surfaces CD34, CD117, CD133 are recruited and retained to the infarcted myocardium sarcomeres with the aid of the htAbs (only CD117 cell is shown here for clarity). The retained haBMSCs are directed to differentiate into endothelium with the defined factors (not shown).
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Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD: Joint ESC/ACCF/AHA/WHF task force for universal definition of myocardial infarction. Third universal definition of myocardial infarction. Circulation. 2012, 126: 2020-2035. 10.1161/CIR.0b013e31826e1058.
CrossRefPubMedGoogle Scholar
Hare JM, Bolli R, Cooke JP, Gordon DJ, Henry TD, Perin EC, March KL, Murphy MP, Pepine CJ, Simari RD, Skarlatos SI, Traverse JH, Willerson JT, Szady AD, Taylor DA, Vojvodic RW, Yang PC, Moyé LA: Cardiovascular cell therapy research network. Phase II clinical research design in cardiology: learning the right lessons too well: observations and recommendations from the cardiovascular cell therapy research network (CCTRN). Circulation. 2013, 127: 1630-1635. 10.1161/CIRCULATIONAHA.112.000779.
PubMedCentralCrossRefPubMedGoogle Scholar
Libby P: Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med. 2013, 368: 2004-2013. 10.1056/NEJMra1216063.
CrossRefPubMedGoogle Scholar
Brehm M, Ebner P, Picard F, Urbien R, Turan G, Strauer BE: Enhanced mobilization of CD34(+) progenitor cells expressing cell adhesion molecules in patients with STEMI. Clin Res Cardiol. 2009, 98: 477-486. 10.1007/s00392-009-0021-5.
CrossRefPubMedGoogle Scholar
Suresh R, Chiriac A, Goel K, Villarraga HR, Lopez-Jimenez F, Thomas RJ, Terzic A, Nelson TJ, Perez-Terzic C: CXCR4+ And FLK-1+ identify circulating cells associated with improved cardiac function in patients following myocardial infarction. J Cardiovasc Transl Res. 2013, doi:10.1007/s12265-013-9502-z
Google Scholar
Musialek P, Tekieli L, Kostkiewicz M, Miszalski-Jamka T, Klimeczek P, Mazur W, Szot W, Majka M, Banys RP, Jarocha D, Walter Z, Krupinski M, Pieniazek P, Olszowska M, Zmudka K, Pasowicz M, Kereiakes DJ, Tracz W, Podolec P, Wojakowski W: Infarct size determines myocardial uptake of CD34+ cells in the peri-infarct zone: results from a study of (99m)Tc-extametazime-labeled cell visualization integrated with cardiac magnetic resonance infarct imaging. Circ Cardiovasc Imaging. 2013, 6: 320-328. 10.1161/CIRCIMAGING.112.979633.
CrossRefPubMedGoogle Scholar
Leri A, Kajstura J, Anversa P: Role of cardiac stem cells in cardiac pathophysiology: a paradigm shift in human myocardial biology. Circ Res. 2011, 109: 941-961. 10.1161/CIRCRESAHA.111.243154.
PubMedCentralCrossRefPubMedGoogle Scholar
Gill M, Dias S, Hattori K, Rivera ML, Hicklin D, Witte L, Girardi L, Yurt R, Himel H, Rafii S: Vascular trauma induces rapid but transient mobilization of VEGFR2(+)AC133(+) endothelial precursor cells. Circ Res. 2001, 88 (2): 167-174. 10.1161/01.RES.88.2.167.
CrossRefPubMedGoogle Scholar
Kanashiro-Takeuchi RM, Takeuchi LM, Hatzistergos K, Quevedo H, Selem SM, Treuer AV, Premer C, Balkan W, Margitich I, Song Y, Hu Q, Hare JM: Effects of combination of proliferative agents and erythropoietin on left ventricular remodeling post-myocardial infarction. Clin Transl Sci. 2011, 4: 168-174. 10.1111/j.1752-8062.2011.00278.x.
PubMedCentralCrossRefPubMedGoogle Scholar
Suzuki G, Iyer V, Cimato T, Canty JM: Pravastatin improves function in hibernating myocardium by mobilizing CD133+ and cKit + bone marrow progenitor cells and promoting myocytes to reenter the growth phase of the cardiac cell cycle. Circ Res. 2009, 104: 255-264. 10.1161/CIRCRESAHA.108.188730.
PubMedCentralCrossRefPubMedGoogle Scholar
Li Q, Guo Y, Wu WJ, Ou Q, Zhu X, Tan W, Yuan F, Chen N, Dawn B, Luo L, O’Brien E, Bolli R: Gene transfer as a strategy to achieve permanent cardioprotection I: rAAV-mediated gene therapy with inducible nitric oxide synthase limits infarct size 1 year later without adverse functional consequences. Basic Res Cardiol. 2011, 106: 1355-1366. 10.1007/s00395-011-0207-7.
PubMedCentralCrossRefPubMedGoogle Scholar
Bolli R, Dawn B: The cornucopia of “pleiotropic” actions of statins: myogenesis as a new mechanism for statin-induced benefits?. Circ Res. 2009, 104: 144-146. 10.1161/CIRCRESAHA.108.192500.
PubMedCentralCrossRefPubMedGoogle Scholar
Sanganalmath SK, Bolli R: Cell therapy for heart failure: a comprehensive overview of experimental and clinical studies, current challenges, and future directions. Circ Res. 2013, 113 (6): 810-834. 10.1161/CIRCRESAHA.113.300219. doi:10.1161/CIRCRESAHA.113.300219
PubMedCentralCrossRefPubMedGoogle Scholar
Schulman IH, Hare JM: Key developments in stem cell therapy in cardiology. Regen Med. 2012, 7 (6 Suppl): 17-24.
PubMedCentralCrossRefPubMedGoogle Scholar
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: 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. 2012, 126: S54-S6414. 10.1161/CIRCULATIONAHA.112.092627.
PubMedCentralCrossRefPubMedGoogle Scholar
Oskouei BN, Lamirault G, Joseph C, Treuer AV, Landa S, Da Silva J, Hatzistergos K, Dauer M, Balkan W, McNiece I, Hare JM: Increased potency of cardiac stem cells compared with bone marrow mesenchymal stem cells in cardiac repair. Stem Cells Transl Med. 2012, 1: 116-124. 10.5966/sctm.2011-0015.
PubMedCentralCrossRefPubMedGoogle Scholar
Hatzistergos KE, Quevedo H, Oskouei BN, Hu Q, Feigenbaum GS, Margitich IS, Mazhari R, Boyle AJ, Zambrano JP, Rodriguez JE, Dulce R, Pattany PM, Valdes D, Revilla C, Heldman AW, McNiece I, Hare JM: Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ Res. 2010, 107 (7): 913-922. 10.1161/CIRCRESAHA.110.222703. doi:10.1161/CIRCRESAHA.110.222703
PubMedCentralCrossRefPubMedGoogle Scholar
Leri A, Anversa P: Stem cells and myocardial regeneration: cooperation wins over competition. Circulation. 2013, 127: 165-168. 10.1161/CIRCULATIONAHA.112.153973.
PubMedCentralCrossRefPubMedGoogle Scholar
Williams AR, Hatzistergos KE, Addicott B, McCall F, Carvalho D, Suncion V, Morales AR, Da Silva J, Sussman MA, Heldman AW, Hare JM: 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. 2013, 127: 213-223. 10.1161/CIRCULATIONAHA.112.131110.
PubMedCentralCrossRefPubMedGoogle Scholar
Donndorf P, Kaminski A, Tiedemann G, Kundt G, Steinhoff G: Validating intramyocardial bone marrow stem cell therapy in combination with coronary artery bypass grafting, the PERFECT Phase III randomized multicenter trial: study protocol for a randomized controlled trial. Trials. 2012, 13: 99-104. 10.1186/1745-6215-13-99.
PubMedCentralCrossRefPubMedGoogle Scholar
Traverse JH, Henry TD, Ellis SG, Pepine CJ, Willerson JT, Zhao DX, Forder JR, Byrne BJ, Hatzopoulos AK, Penn MS, Perin EC, Baran KW, Chambers J, Lambert C, Raveendran G, Simon DI, Vaughan DE, Simpson LM, Gee AP, Taylor DA, Cogle CR, Thomas JD, Silva GV, Jorgenson BC, Olson RE, Bowman S, Francescon J, Geither C, Handberg E, Smith DX: Cardiovascular cell therapy ResearchNetwork. Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function: the LateTIME randomized trial. JAMA. 2011, 306: 2110-2119. 10.1001/jama.2011.1670.
PubMedCentralCrossRefPubMedGoogle Scholar
Hirsch A, Nijveldt R, van der Vleuten PA, Tijssen JG, van der Giessen WJ, Tio RA, Waltenberger J, ten Berg JM, Doevendans PA, Aengevaeren WR, Zwaginga JJ, Biemond BJ, van Rossum AC, Piek JJ, Zijlstra F: HEBE investigators. Intracoronary infusion of mononuclear cells from bone marrow or peripheral blood compared with standard therapy in patients after acute myocardial infarction treated by primary percutaneous coronary intervention: results of the randomized controlled HEBE trial. Eur Heart J. 2011, 32: 1736-1747. 10.1093/eurheartj/ehq449.
CrossRefPubMedGoogle Scholar
Turan RG, Bozdag-T I, Turan CH, Ortak J, Akin I, Kische S, Schneider H, Rauchhaus M, Rehders TC, Kleinfeldt T, Belu C, Amen S, Hermann T, Yokus S, Brehm M, Steiner S, Chatterjee T, Sahin K, Nienaber CA, Ince H: Enhanced mobilization of the bone marrow-derived circulating progenitor cells by intracoronary freshly isolated bone marrow cells transplantation in patients with acute myocardial infarction. J Cell Mol Med. 2012, 16: 852-864. 10.1111/j.1582-4934.2011.01358.x.
PubMedCentralCrossRefPubMedGoogle Scholar
Povsic TJ, Junge C, Nada A, Schatz RA, Harrington RA, Davidson CJ, Fortuin FD, Kereiakes DJ, Mendelsohn FO, Sherman W, Schaer GL, White CJ, Stewart D, Story K, Losordo DW, Henry TD: A phase 3, randomized, double-blinded, active-controlled, unblinded standard of care study assessing the efficacy and safety of intramyocardial autologous CD34+ cell administration in patients with refractory angina: design of the RENEW study. Am Heart J. 2013, 165: 854-861. 10.1016/j.ahj.2013.03.003.
CrossRefPubMedGoogle Scholar
Poole JC, Quyyumi AA: Progenitor cell therapy to treat acute myocardial infarction: the promise of high-dose autologous CD34(+) bone marrow mononuclear cells. Stem Cells Int. 2013, 658480: 1-8.
CrossRefGoogle Scholar
Klein HM, Ghodsizad A, Marktanner R, Poll L, Voelkel T, Mohammad Hasani MR, Piechaczek C, Feifel N, Stockschlaeder M, Burchardt ER, Kar BJ, Gregoric I, Gams E: Intramyocardial implantation of CD133+ stem cells improved cardiac function without bypass surgery. Heart Surg Forum. 2007, 10: E66-E69. 10.1532/HSF98.20061054.
CrossRefPubMedGoogle Scholar
Ghodsizad A, Bordel V, Bruckner B, Loebe M, Fuerst G, Mirsaidi I, Sucker M, Ruhparwar A, Karck M, Klein HM: Clinical labeling and imaging of transplanted CD133+/CD34+ stem cells in patients with ischemic heart disease. Heart Surg Forum. 2012, 15: E116-E118. 10.1532/HSF98.20111138.
CrossRefPubMedGoogle Scholar
Peichev M, Naiyer AJ, Pereira D, Zhu Z, Lane WJ, Williams M: Expression of VEGFR-2 and AC133 by circulating humanCD34(+) cells identifies a population of functional endothelial precursors. Blood. 2000, 95: 952-958.
PubMedGoogle Scholar
Gehling UM, Ergun S, Schumacher U, Wagener C, Pantel K, Otte M: In vitro differentiation of endothelial cells from AC133-positive progenitor cells. Blood. 2000, 95: 3106-3112.
PubMedGoogle Scholar
Salven P, Mustjoki S, Alitalo R, Alitalo K, Rafii S: VEGFR-3 and CD133 identify a population of CD34+ lymphatic/vascular endothelial precursor cells. Blood. 2003, 101 (1): 168-172. 10.1182/blood-2002-03-0755. Epub 2002 Aug 15
CrossRefPubMedGoogle Scholar
Kubo H, Berretta RM, Jaleel N, Angert D, Houser SR: c-Kit + bone marrow stem cells differentiate into functional cardiac myocytes. Clin Transl Sci. 2009, 2 (1): 26-32. 10.1111/j.1752-8062.2008.00089.x. doi:10.1111/j.1752-8062.2008.00089.x
PubMedCentralCrossRefPubMedGoogle Scholar
Gambini E, Pompilio G, Biondi A, Alamanni F, Capogrossi MC, Agrifoglio M, Pesce M: C-kit + cardiac progenitors exhibit mesenchymal markers and preferential cardiovascular commitment. Cardiovasc Res. 2011, 89 (2): 362-373. 10.1093/cvr/cvq292. doi:10.1093/cvr/cvq292. Epub 2010 Sep 10
CrossRefPubMedGoogle Scholar
Sandstedt J, Jonsson M, Lindahl A, Jeppsson A, Asp J: C-kit + CD45- cells found in the adult human heart represent a population of endothelial progenitor cells. Basic Res Cardiol. 2010, 105 (4): 545-556. 10.1007/s00395-010-0088-1. doi:10.1007/s00395-010-0088-1. Epub 2010 Feb 2
CrossRefPubMedGoogle Scholar
Quirici N, Soligo D, Caneva L, Servida F, Bossolasco P, Deliliers GL: Differentiation and expansion of endothelial cells from human bone marrow CD133(+) cells. Br J Haematol. 2001, 115 (1): 186-194. 10.1046/j.1365-2141.2001.03077.x.
CrossRefPubMedGoogle Scholar
Duran JM, Makarewich CA, Sharp TE, Starosta T, Zhu F, Hoffman NE, Chiba Y, Madesh M, Berretta RM, Kubo H, Houser SR: Bone-derived stem cells repair the heart after myocardial infarction through transdifferentiation and paracrine signaling mechanisms. Circ Res. 2013, 113: 539-552. 10.1161/CIRCRESAHA.113.301202.
CrossRefPubMedGoogle Scholar
Li TS, Cheng K, Malliaras K, Smith RR, Zhang Y, Sun B, Matsushita N, Blusztajn A, Terrovitis J, Kusuoka H, Marbán L, Marbán E: Direct comparison of different stem cell types and subpopulations reveals superior paracrine potency and myocardial repair efficacy with cardiosphere-derived cells. J Am Coll Cardiol. 2012, 59: 942-953. 10.1016/j.jacc.2011.11.029.
PubMedCentralCrossRefPubMedGoogle Scholar
Shim W, Mehta A, Wong P, Chua T, Koh TH: Critical path in cardiac stem cell therapy: an update on cell delivery. Cytotherapy. 2013, 15: 399-415. 10.1016/j.jcyt.2012.11.003.
CrossRefPubMedGoogle Scholar
Malecki M: Improved targeting and enhanced retention of the human, autologous, fibroblast-derived, induced, pluripotent stem cells to the sarcomeres of the infarcted myocardium with the aid of the bioengineered, heterospecific, tetravalent antibodies. J Stem Cell Res Ther. 2013, 3: 138-156.
PubMedCentralPubMedGoogle Scholar
Assmus B, Tonn T, Seeger FH, Yoon CH, Leistner D, Klotsche J, Schächinger V, Seifried E, Zeiher AM, Dimmeler S: Red blood cell contamination of the final cell product impairs the efficacy of autologous bone marrow mononuclear cell therapy. J Am Coll Cardiol. 2010, 55: 1385-1394. 10.1016/j.jacc.2009.10.059.
CrossRefPubMedGoogle Scholar
Malecki M, Malecki R, Malecki B: Molecular death tags and methods of their use. WIPO Patent. 2011, 1-81.http://patentscope.wipo.int/search/en/WO2012048161,
Google Scholar
Prasher DC, Eckenrode VK, Ward WW, Prendergast FG, Cormier MJ: Primary structure of the Aequorea victoria green-fluorescent protein. Gene. 1992, 111 (2): 229-233. 10.1016/0378-1119(92)90691-H.
CrossRefPubMedGoogle Scholar
Chalfie M, Tu Y, Euskirchen G, Ward WW, Prasher DC: Green fluorescent protein as a marker for gene expression. Science. 1994, 263 (5148): 802-805. 10.1126/science.8303295.
CrossRefPubMedGoogle Scholar
Heim R, Prasher DC, Tsien RY: Wavelength mutations and posttranslational autoxidation of green fluorescent protein. Proc Natl Acad Sci USA. 1994, 91 (26): 12501-12504. 10.1073/pnas.91.26.12501.
PubMedCentralCrossRefPubMedGoogle Scholar
Haseloff J, Siemering KR, Prasher DC, Hodge S: Removal of a cryptic intron and subcellular localization of green fluorescent protein are required to mark transgenic Arabidopsis plants brightly. Proc Natl Acad Sci USA. 1997, 94 (6): 2122-2127. 10.1073/pnas.94.6.2122.
PubMedCentralCrossRefPubMedGoogle Scholar
Malecki M, Malecki B: Polyspecifc tetrabodies – biomolecular engineering of synthetic antibodies targeting four different epitopes. Proceedings of the 26th Annual Symposium of the American Protein Society, San Diego. 2012, 163: 278-
Google Scholar
Malecki M, Hsu L, Trung L, Sanchez S: Molecular immunolabeling with recombinant single-chain variable fragment (scFv) antibodies designed with metal-binding domains. Proc Natl Acad Sci USA. 2012, 99: 213-218.
CrossRefGoogle Scholar
Wobus AM: The Janus face of pluripotent stem cells--connection between pluripotency and tumourigenicity. Bioessays. 2010, 32 (11): 993-1002. 10.1002/bies.201000065.
CrossRefPubMedGoogle Scholar
Kooreman NG, Wu JC: Tumorigenicity of pluripotent stem cells: biological insights from molecular imaging. J R Soc Interface. 2010, 7 (Suppl 6): S753-S763. doi: 10.1098/rsif.2010.0353.focus. Epub 2010 Sep 29
PubMedCentralCrossRefPubMedGoogle Scholar
Ben-David U, Benvenisty N: The tumorigenicity of human embryonic and induced pluripotent stem cells. Nat Rev Cancer. 2011, 11 (4): 268-277. 10.1038/nrc3034. doi: 10.1038/nrc3034. Epub 2011 Mar 10
CrossRefPubMedGoogle Scholar
Zarogoulidis P, Darwiche K, Sakkas A, Varmus L, Huang H, Li Q, Freitag L, Zarogoulidis K, Malecki M: Suicide gene therapy for cancer – current strategies. J Gen Syndr Gene Ther. 2013, 4: 139-doi:10.4172/2157-7412.1000139
Google Scholar
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