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. 2018 Oct;11(5):420-428.
doi: 10.1007/s12265-018-9822-0. Epub 2018 Sep 19.

Transplantation of Cardiac Mesenchymal Stem Cell-Derived Exosomes Promotes Repair in Ischemic Myocardium

Chengwei Ju  1 , Yan Shen  2 , Gengshan Ma  1 , Yutao Liu  2 , Jingwen Cai  2 , Il-Man Kim  2 , Neal L Weintraub  2 , Naifeng Liu  3 , Yaoliang Tang  4
Affiliations

Transplantation of Cardiac Mesenchymal Stem Cell-Derived Exosomes Promotes Repair in Ischemic Myocardium

Chengwei Ju et al. J Cardiovasc Transl Res. 2018 Oct.

Abstract

Our previous study demonstrated the beneficial effects of exosomes secreted by cardiac mesenchymal stem cells (C-MSC-Exo) in protecting acute ischemic myocardium from reperfusion injury. Here, we investigated the effect of exosomes from C-MSC on angiogenesis in ischemic myocardium. We intramyocardially injected C-MSC-Exo or PBS into the infarct border zone after induction of acute mouse myocardial infarction (MI). We observed that hearts treated with C-MSC-Exo exhibit improved cardiac function compared to control hearts treated with PBS at one month after MI. Capillary density and Ki67-postive cells were significantly higher following treatment with C-MSC-Exo as compared with PBS. Moreover, C-MSC-Exo treatment increased cardiomyocyte proliferation in infarcted hearts. In conclusion, intramyocardial delivery of C-MSC-Exo after myocardial infarction enhances cardiac angiogenesis, promotes cardiomyocyte proliferation, and preserves heart function. C-MSC-Exo constitute a novel form of cell-free therapy for cardiac repair.

Keywords: Angiogenesis; Cardiac mesenchymal stem cells; Exosomes; Myocardial infarction.

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Conflict of interest statement

Conflict of Interest: All authors declares that he/she has no conflict of interest.

Figures

Figure 1:
Figure 1:
Phenotypic characterization of C-MSC cells. A, Immunofluorescent staining of C-MSC cells for expression of the cardiac transcription factors GATA4 (red); cell nuclei were counterstained with DAPI (blue). B. Flow cytometric analyses of C-MSC cells for expression of the mesenchymal cell surface markers CD105, CD44 and CD140.
Figure 2:
Figure 2:
Characterization of C-MSC derived exosomes. (A) Transmission Electron micrograph image of C-MSC-derived exosomes after immunoelectron labeling with anti-CD63 antibody. Scale bar = 200 nm. (B) Western blot results demonstrate the expression of Tsg101, CD81 and CD63 in exosomes derived from C-MSC. (C) Particle size distribution in purified pellets consistent with size range of exosomes (average size 120 nm), measured by ZetaView® Particle Tracking Analyzer.
Figure 3:
Figure 3:
Effects of C-MSC-Exo on capillary tube formation by HUVEC. (A) Culturing HUVEC were seeded on Matrigel-coated wells in medium containing PBS or C-MSC-Exo; (B) The total tube length per field of view was quantified after 20hrs. Values are expressed as mean ± SEM, * P<0.05, n = 6.
Figure 4:
Figure 4:
Echocardiographic measurements of cardiac function at baseline, 1 day and 1 month after PBS or C-MSC-Exo treatment. (A) M-mode images of mice treated with PBS or C-MSC-Exo at 1 month post MI; (B-C) Average LVEF and FS at baseline, 1d and 1 month after PBS and C-MSC-Exo treatment in infarcted hearts (*, P<0.05, n = 7 for PBS group, n=8 for Exo group).
Figure 5:
Figure 5:
C-MSC-Exo treatment preserves wall thickness in myocardium post-MI. (A) Representative Masson’s trichrome images of LV sections show thicker scar with increased numbers of viable myocardium (red cells) in the infarcted hearts treated with C-MSC-Exo in comparison with PBS. (B) Scar thickness measurement in both PBS and C-MSC-Exo treated MI mice revealed significantly thicker scar in 1-month post-MI CMSC-Exo treated mice’s hearts (*, P<0.05, n = 4 for PBS and C-MSC-Exo treated mice).
Figure 6:
Figure 6:
Stimulation of cardiac angiogenesis in C-MSC-Exo treated hearts. (A) Immunofluorescent staining of CD31 and Ki67 was performed to detect vessel density and cell proliferation in infarcted hearts 1 month post-MI; (B) The comparison of CD31+ cells per area (10,000μm2) between PBS and C-MSC-Exo treated infarcted hearts (*, P<0.05, n=6); (D) the comparison of percentage of Ki67-positive cells between PBS and C-MSC-Exo treated infarcted hearts (*, P<0.05, n=6).
Figure 7:
Figure 7:
C-MSC-Exo treatment activates proliferation of cardiomyocytes in infarcted hearts. (A) Immunofluorescent staining of Ki67 and cTnI was performed to detect proliferation of cardiomyocytes one month after treatment; (B) The comparison of Ki67+ cTnI+ cells per field between PBS and C-MSC-Exo treated infarcted hearts (*, P<0.05, n=6).
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