Mammalian Cardiac Regeneration After Fetal Myocardial Infarction Requires Cardiac Progenitor Cell Recruitment Myron Allukian, MD, Junwang Xu, PhD, Michael.

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Mammalian Cardiac Regeneration After Fetal Myocardial Infarction Requires Cardiac Progenitor Cell Recruitment Myron Allukian, MD, Junwang Xu, PhD, Michael Morris, MD, Robert Caskey, MD, Wanda Dorsett-Martin, DVM, Theodore Plappert, CVT, Michael Griswold, PhD, Joseph H. Gorman, MD, Robert C. Gorman, MD, Kenneth W. Liechty, MD The Annals of Thoracic Surgery Volume 96, Issue 1, Pages 163-170 (July 2013) DOI: 10.1016/j.athoracsur.2013.04.005 Copyright © 2013 The Society of Thoracic Surgeons Terms and Conditions

Fig 1 Fetal cardiac function is restored at 1 month after myocardial infarction (MI). Inhibiting stromal-derived factor-1α (SDF-1α) in fetal MI resulted in decreased cardiac function at 1 month after MI similar to the adult. Quantitative echocardiography measurements were obtained at baseline, post-MI, 3 days, and 1 month after MI. Selected individual animal trajectories are displayed in the background (light lines, open circles) with means (95% confidence intervals) in the foreground (heavy lines). (A) Fetal and adult infarct length (IL): average fetal IL decreased by 0.94 cm (p = 0.001) at 1 month, whereas adult IL increased by 0.84 cm (p < 0.001). (B) Fetal and adult ejection fraction (EF): fetal EF returned to near-baseline levels at 1 month (difference of –1.98%, p = 0.548), whereas adult EF was decreased by 12.7% (p < 0.001). (C) Mean IL after empty or mutant SDF-1α transgene (SDFi) treatment was 1.13 cm at 3 days but returned to 0 at 1 month in the empty vector (p < 0.001) but increased by +0.49 cm (p < 0.001) for the SDFi vector. (D) EF in empty or SDFi lentiviral vector–treated fetal infarcts: EF returned to near baseline levels at 1 month for the empty vector (difference of –3.85%, p = 0.555), whereas EF in the SDFi vector was decreased by –12.6% (p = 0.053). The Annals of Thoracic Surgery 2013 96, 163-170DOI: (10.1016/j.athoracsur.2013.04.005) Copyright © 2013 The Society of Thoracic Surgeons Terms and Conditions

Fig 2 Restoration of fetal myocardial architecture after myocardial infarction (MI) does not occur with stromal-derived factor-1α (SDF-1α) inhibition is shown in representative images. (A) Gross appearance of the fetal heart 3 days and 1 month after MI (scale bar = 3 mm). (B) Hematoxylin and eosin staining of fetal infarct 3 days after MI. Remote (RM), borderzone (BZ), and infarct (INF) regions are shown (left panel; scale bar = 200 μm). (C) Trichrome staining of the apex of the fetal infarct at 1 month (right panel; scale bar = 200 μm). (D) Gross appearance of empty and mutant SDF-1α transgene (SDFi) lentiviral vector–treated fetal hearts 1 month post-MI (scale bar = 3 mm). Trichrome staining of fetal hearts treated with (E) empty vector and (F) and SDFi at 1 month (scale bars = 200 μm). The Annals of Thoracic Surgery 2013 96, 163-170DOI: (10.1016/j.athoracsur.2013.04.005) Copyright © 2013 The Society of Thoracic Surgeons Terms and Conditions

Fig 3 Fetal cardiac cell repopulation after myocardial infarction (MI) is blocked by stromal-derived factor-1α (SDF-1α) inhibition. Representative images show (A) staining with 4',6-diamidino-2-phenylindole (DAPI; blue), immunohistochemistry for nkx2.5 (red), and merged DAPI and nkx2.5 in the fetal infarct. Representative images (scale bars = 50 μm) are shown of the apex of fetal sham operation and fetal infarct at 3 day and of untreated fetal infarct and fetal infarct treated with mutant SDF-1α transgene (SDFi) at 1 month. (B) Mean cellularity (DAPI) at the apex 3 days after fetal MI was decreased by 158.8 cells/high-powered field (hpf; *p < 0.001). At 1 month, untreated fetal infarct cellularity increased by 108.1cells/hpf (**p < 0.001), comparable with empty treated infarcts (p = 0.909), and had increased compared with SDFi infarcts (++p = 0.005). (C) Mean cardiac progenitor cell counts at the apex (nkx2.5) 3 days post-MI were decreased by 112.7cells/hpf (*p < 0.001). At 1 month, the apical nkx2.5 cell population had increased by 58.7cells/hpf (**p < 0.001), was comparable to empty vector–treated infarcts, and had increased compared with SDFi infarcts, which had 120.1 fewer cells/hpf (++p < 0.001). (D) Images show double immunohistochemistry for nkx2.5 (green) and heavy chain myosin (red), with DAPI counterstaining (blue) in untreated and (E) SDFi treated (right panel) fetal infarcts 1 month after MI (scale bars = 200 μm). Error bars correspond to mean value ± standard error of the mean. The Annals of Thoracic Surgery 2013 96, 163-170DOI: (10.1016/j.athoracsur.2013.04.005) Copyright © 2013 The Society of Thoracic Surgeons Terms and Conditions

Fig 4 Early fetal cardiac cell proliferation is not affected by stromal-derived factor-1α (SDF1a) inhibition (SDFi). (A) Representative immunohistochemistry for 5-bromo-2-deoxyuridine (BrdU; red) and nkx2.5 (green) 3 days after myocardial infarction (MI). Representative images of the borderzone region of sham (top row), untreated (middle row), and mutant SDF-1α transgene SDFi-treated (bottom row) fetal infarcts are shown. (B) Comparable populations of proliferating cardiac progenitor cells (BrdU+ and nkx2.5+) were observed in the apex and remote regions. Mean population of cardiac progenitor cells in the borderzone in untreated fetal hearts increased by 24.8 cells/high-powered field (hpf; *p < 0.001) and 15.7cells/hpf in SDFi treated hearts (**p < 0.001). Error bars correspond to the 95% confidence interval. The Annals of Thoracic Surgery 2013 96, 163-170DOI: (10.1016/j.athoracsur.2013.04.005) Copyright © 2013 The Society of Thoracic Surgeons Terms and Conditions