Targeting survival pathways to create infarct-spanning bridges of human embryonic stem cell–derived cardiomyocytes Jun Luo, MD, PhD, Matthew S. Weaver,

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Presentation transcript:

Targeting survival pathways to create infarct-spanning bridges of human embryonic stem cell–derived cardiomyocytes Jun Luo, MD, PhD, Matthew S. Weaver, PhD, James E. Dennis, PhD, Elizabeth Whalen, PhD, Michael A. Laflamme, MD, PhD, Margaret D. Allen, MD The Journal of Thoracic and Cardiovascular Surgery Volume 148, Issue 6, Pages 3180-3188.e1 (December 2014) DOI: 10.1016/j.jtcvs.2014.06.087 Copyright © 2014 The American Association for Thoracic Surgery Terms and Conditions

Figure 1 Microsphere biodistribution after intrainfarct injection. Representative example of an infarcted heart 15 minutes after intramyocardial injection of yellow fluorescent microspheres. A-C, Gross specimen showing the anterior left ventricle with infarct (circled). Black triangles mark ligation sites on the left anterior descending and diagonal coronary arteries. White arrows indicate the direction of transinfarct needle injection. C, Blue arrows point to the majority of the microspheres, which remain within the infarct along the injection tract, effectively spanning the infarct. D-F, Consecutive cross-sections through the same heart illustrating the microspheres within the mid-level sections. A and D, Dark field epi-illumination images; B and E, fluorescence imaging to visualize microspheres; C and F, merged images. Scale bar = 5 mm. G, Relative microsphere retention in heart, lung, and spleen as quantified by flow cytometry (n = 5). ***P < .0001 versus lung or spleen. The Journal of Thoracic and Cardiovascular Surgery 2014 148, 3180-3188.e1DOI: (10.1016/j.jtcvs.2014.06.087) Copyright © 2014 The American Association for Thoracic Surgery Terms and Conditions

Figure 2 Histology of human embryonic stem cell–derived cardiomyocyte (hESC-CM) grafts at 8 weeks after transinfarct implantation. A, Sectioning diagram for fixed hearts to survey the infarct for the presence of human grafts along the diagonally oriented injection tract. Further serial sectioning was performed within each region to determine the extent of human cell engraftment in the infarct center (eg, levels 1 and 2). Hematoxylin and eosin staining of representative hearts from (B-D) the group that received phosphate-buffered saline (PBS)–pretreated hESC-CMs [PBS (g)] and (E-G) the group that received cobalt protoporphyrin (CoPP)-pretreated hESC-CMs plus recipient treatment with systemic CoPP [CoPP (g+r)]. B and E, In basal regions, hESC-CM grafts in both treatment groups are seen extending into noninfarcted host myocardium. Note the lack of fibrotic encapsulation around the grafts. C and F, In the mid-infarct region, grafts are found at the lateral infarct margins, near the infarct border zone, under both experimental conditions (level 1). However, grafts are present in the infarct center only in (F) the CoPP-treated group, where the potential for infarct replacement by graft and the creation of infarct-spanning bridges is evident. D and G, In deeper levels of the infarct (level 2), grafts are seen only in the CoPP-treated heart, with no graft present in the heart that received PBS-treated cells. Grafts were confirmed to be of human origin by immunostaining with (H) β-myosin heavy chain (dark brown) and (I) human lamin A/C (green). J, Dual immunostaining demonstrating gap junction proteins (connexin 43, red) on graft cells (human lamin A/C, green), with yellow indicating color convergence. Scale bars = 500 μm, 50 μm, 25 μm, and 5 μm, for B-G, H, I, and J, respectively. LAD, Left anterior descending coronary artery. The Journal of Thoracic and Cardiovascular Surgery 2014 148, 3180-3188.e1DOI: (10.1016/j.jtcvs.2014.06.087) Copyright © 2014 The American Association for Thoracic Surgery Terms and Conditions

Figure 3 Left ventricular morphometry at 8 weeks after acute infarction and cell therapy. A, Percentage of the total graft area located within the infarct. B, Mean graft areas cumulative over all surveyed sections/heart. C, Extent of total infarct area replaced by cellular graft. A-C, *P < .01; **P < .001; ***P < .0001 between indicated groups. D, Infarct size quantified as a percentage of the total left ventricular circumference. *P < .02 versus SFM and CoPP(r); ***P ≤ .0001 versus SFM, CoPP(r), and PBS(g). E, Mean wall thickness in the infarct area as a percentage of the wall thickness in the adjacent, noninfarcted left ventricle. *P < .002 versus SFM and CoPP(r); ***P < .0001 versus SFM, CoPP(r), and PBS(g). Data represent mean values ± standard deviations; n = 8/group. Treatment groups—postinfarct cell therapies: PBS(g), Graft human embryonic stem cell–derived cardiomyocytes (hESC-CMs) pretreated with phosphate-buffered saline; CoPP(g), graft hESC-CMs pretreated with cobalt protoporphyrin (CoPP); CoPP(g+r), graft hESC-CMs pretreated with CoPP plus recipient treatment with systemic CoPP. Control groups without cell therapy: SFM, Infarct injections with serum-free media (vehicle-only control); CoPP(r), infarct recipients treated with systemic CoPP. The Journal of Thoracic and Cardiovascular Surgery 2014 148, 3180-3188.e1DOI: (10.1016/j.jtcvs.2014.06.087) Copyright © 2014 The American Association for Thoracic Surgery Terms and Conditions

Figure 4 Echocardiographic assessment of functional parameters at baseline, 48 hours, and 4 and 8 weeks after infarction. A, Fractional shortening (%). Data represent mean values ± standard deviations. *P < .01; **P ≤ .001; ***P ≤ .0001 versus SFM. B, LVESD. Points indicate mean values. Error bars showing standard deviations are limited to the 2 outermost groups so that trends in the mean values can be more easily visualized. SFM, Infarct injections with serum-free media (vehicle-only control); LVESD, left ventricular end-systolic diameter; CoPP(r), infarct recipients treated with systemic cobalt protoporphyrin (CoPP); PBS(g), graft human embryonic stem cell–derived cardiomyocytes (hESC-CMs) pretreated with phosphate-buffered saline; CoPP(g), graft hESC-CMs pretreated with CoPP; CoPP(g+r), graft hESC-CMs pretreated with CoPP plus recipient treatment with systemic CoPP. The Journal of Thoracic and Cardiovascular Surgery 2014 148, 3180-3188.e1DOI: (10.1016/j.jtcvs.2014.06.087) Copyright © 2014 The American Association for Thoracic Surgery Terms and Conditions

Figure E1 Characterization of cell injectates prior to implantation. Aliquots of differentiated human embryonic stem cell–derived cardiomyocyte (hESC-CM) injectates were stained with antibodies to (A) cardiac troponin I, denoting cardiomyocytes (green fluorescence); B, Nkx2.5, an early cardiomyocyte-specific transcription factor (red); or C, Ki67, indicating mitotic cells (red). The nuclei in all panels were counterstained with Hoechst dye (blue). Scale bars = 50 μm. The Journal of Thoracic and Cardiovascular Surgery 2014 148, 3180-3188.e1DOI: (10.1016/j.jtcvs.2014.06.087) Copyright © 2014 The American Association for Thoracic Surgery Terms and Conditions