Functional Effects of Delivering Human Mesenchymal Stem Cell-Seeded Biological Sutures to an Infarcted Heart

Abstract Stem cell therapy has the potential to improve cardiac function after myocardial infarction (MI); however, existing methods to deliver cells to the myocardium, including intramyocardial injection, suffer from low engraftment rates. In this study, we used a rat model of acute MI to assess the effects of human mesenchymal stem cell (hMSC)-seeded fibrin biological sutures on cardiac function at 1 week after implant. Biological sutures were seeded with quantum dot (Qdot)-loaded hMSCs for 24 h before implantation. At 1 week postinfarct, the heart was imaged to assess mechanical function in the infarct region. Regional parameters assessed were regional stroke work (RSW) and systolic area of contraction (SAC) and global parameters derived from the pressure waveform. MI (n = 6) significantly decreased RSW (0.026 ± 0.011) and SAC (0.022 ± 0.015) when compared with sham operation (RSW: 0.141 ± 0.009; SAC: 0.166 ± 0.005, n = 6) (p < 0.05). The delivery of unseeded biological sutures to the infarcted hearts did not change regional mechanical function compared with the infarcted hearts (RSW: 0.032 ± 0.004, SAC: 0.037 ± 0.008, n = 6). The delivery of hMSC-seeded sutures exerted a trend toward increase of regional mechanical function compared with the infarcted heart (RSW: 0.057 ± 0.011; SAC: 0.051 ± 0.014, n = 6). Global function showed no significant differences between any group (p > 0.05); however, there was a trend toward improved function with the addition of either unseeded or seeded biological suture. Histology demonstrated that Qdot-loaded hMSCs remained present in the infarcted myocardium after 1 week. Analysis of serial sections of Masson's trichrome staining revealed that the greatest infarct size was in the infarct group (7.0% ± 2.2%), where unseeded (3.8% ± 0.6%) and hMSC-seeded (3.7% ± 0.8%) suture groups maintained similar infarct sizes. Furthermore, the remaining suture area was significantly decreased in the unseeded group compared with that in the hMSC-seeded group (p < 0.05). This study demonstrated that hMSC-seeded biological sutures are a method to deliver cells to the infarcted myocardium and have treatment potential.

[1]  Bernd Hertenstein,et al.  Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial , 2004, The Lancet.

[2]  A. Zeiher,et al.  Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. , 2006, The New England journal of medicine.

[3]  M. Simoons,et al.  Acute myocardial infarction , 2003, The Lancet.

[4]  Gregor Poglajen,et al.  Comparison of Transendocardial and Intracoronary CD34+ Cell Transplantation in Patients With Nonischemic Dilated Cardiomyopathy , 2013, Circulation.

[5]  Doris A Taylor,et al.  Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the TIME randomized trial. , 2012, JAMA.

[6]  Lila R Collins,et al.  Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts , 2007, Nature Biotechnology.

[7]  Randall J Lee,et al.  Injectable fibrin scaffold improves cell transplant survival, reduces infarct expansion, and induces neovasculature formation in ischemic myocardium. , 2004, Journal of the American College of Cardiology.

[8]  C. Murry,et al.  Heart regeneration , 2011, Nature.

[9]  Paul D. Kessler,et al.  Human Mesenchymal Stem Cells Differentiate to a Cardiomyocyte Phenotype in the Adult Murine Heart , 2002, Circulation.

[10]  Talicia Tarver,et al.  HEART DISEASE AND STROKE STATISTICS–2014 UPDATE: A REPORT FROM THE AMERICAN HEART ASSOCIATION , 2014 .

[11]  A. Terzic,et al.  Guided cardiopoiesis enhances therapeutic benefit of bone marrow human mesenchymal stem cells in chronic myocardial infarction. , 2010, Journal of the American College of Cardiology.

[12]  K. Christman,et al.  Biomaterials for the treatment of myocardial infarction: a 5-year update. , 2011, Journal of the American College of Cardiology.

[13]  M. Rosen,et al.  Finding Fluorescent Needles in the Cardiac Haystack: Tracking Human Mesenchymal Stem Cells Labeled with Quantum Dots for Quantitative In Vivo Three‐Dimensional Fluorescence Analysis , 2007, Stem cells.

[14]  C. Murry,et al.  Regenerating the heart , 2005, Nature Biotechnology.

[15]  Arjun Deb,et al.  Secreted frizzled related protein 2 (Sfrp2) is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair , 2007, Proceedings of the National Academy of Sciences.

[16]  Loren E Wold,et al.  Thickening of the infarcted wall by collagen injection improves left ventricular function in rats: a novel approach to preserve cardiac function after myocardial infarction. , 2005, Journal of the American College of Cardiology.

[17]  Gaurav Sharma,et al.  Accuracy and reproducibility of a subpixel extended phase correlation method to determine micron level displacements in the heart. , 2007, Medical engineering & physics.

[18]  J. Kastrup,et al.  Bone marrow-derived mesenchymal stromal cell treatment in patients with severe ischaemic heart failure: a randomized placebo-controlled trial (MSC-HF trial). , 2015, European heart journal.

[19]  M. Matsuzaki,et al.  Local implantation of autologous bone marrow cells for therapeutic angiogenesis in patients with ischemic heart disease: clinical trial and preliminary results. , 2001, Japanese circulation journal.

[20]  J. De Sutter,et al.  Diastolic filling and pressure imaging: taking advantage of the information in a colour M-mode Doppler image. , 2001, European journal of echocardiography : the journal of the Working Group on Echocardiography of the European Society of Cardiology.

[21]  Z. Popović,et al.  SDF‐1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[22]  J. Guyette,et al.  Delivering stem cells to the healthy heart on biological sutures: effects on regional mechanical function , 2017, Journal of tissue engineering and regenerative medicine.

[23]  A. Keating,et al.  Bone Marrow-derived Mesenchymal Stromal Cells Express Cardiac-specific Markers, Retain the Stromal Phenotype, and Do Not Become Functional Cardiomyocytes in Vitro Departments of a Physiology And , 2022 .

[24]  A. Ganser,et al.  Intracoronary Bone Marrow Cell Transfer After Myocardial Infarction: Eighteen Months’ Follow-Up Data From the Randomized, Controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) Trial , 2006, Circulation.

[25]  Dejian Lai,et al.  Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial. , 2012, JAMA.

[26]  A. Ibrahim,et al.  Acute myocardial infarction. , 2014, Critical care clinics.

[27]  William Wijns,et al.  Cardiopoietic stem cell therapy in heart failure: the C-CURE (Cardiopoietic stem Cell therapy in heart failURE) multicenter randomized trial with lineage-specified biologics. , 2013, Journal of the American College of Cardiology.

[28]  Ronald G. Tompkins,et al.  Mesenchymal Stem Cells: Mechanisms of Immunomodulation and Homing , 2010, Cell transplantation.

[29]  J. Guyette,et al.  A novel suture-based method for efficient transplantation of stem cells. , 2013, Journal of biomedical materials research. Part A.

[30]  J. Grzyb,et al.  Wide-spread myocardial remodeling after acute myocardial infarction in rat. Features for heart failure progression. , 2008, Vascular pharmacology.

[31]  Shawn P. Carey,et al.  Fibrin microthreads support mesenchymal stem cell growth while maintaining differentiation potential. , 2011, Journal of biomedical materials research. Part A.

[32]  K. Rufibach,et al.  Intracoronary Injection of Bone Marrow–Derived Mononuclear Cells Early or Late After Acute Myocardial Infarction: Effects on Global Left Ventricular Function , 2013, Circulation.

[33]  Ping Zhang,et al.  Radiolabeled Cell Distribution After Intramyocardial, Intracoronary, and Interstitial Retrograde Coronary Venous Delivery: Implications for Current Clinical Trials , 2005, Circulation.

[34]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[35]  Doris A Taylor,et al.  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. , 2011, JAMA.

[36]  Fei Ye,et al.  Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. , 2004, The American journal of cardiology.

[37]  Joshua M Hare,et al.  A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. , 2009, Journal of the American College of Cardiology.

[38]  R. Henning,et al.  Recent advances in the diagnosis and treatment of acute myocardial infarction. , 2015, World journal of cardiology.

[39]  Hassan Foroosh,et al.  Extension of phase correlation to subpixel registration , 2002, IEEE Trans. Image Process..

[40]  R. Bonow,et al.  Intracoronary cardiosphere-derived cells after myocardial infarction: evidence of therapeutic regeneration in the final 1-year results of the CADUCEUS trial (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction). , 2014, Journal of the American College of Cardiology.