Abstract
Stem cells provide a new strategy for the treatment of cardiac diseases; however, their effectiveness in dilated cardiomyopathy (DCM) has not been investigated. In this study, cardiosphere-derived cells (CDCs) were isolated from infants (≤ 24 months) and identified by the cell surface markers CD105, CD90, CD117 and CD45, which is consistent with a previous report, although increased CD34 expression was observed. The molecular expression profile of CDCs from infants was determined by RNA sequencing and compared with adult CDCs, showing that infant CDCs have almost completely altered gene expression patterns compared with adult CDCs. The upregulated genes in infant CDCs are mainly related to the biological processes of cell morphogenesis and differentiation. The molecular profile of infant CDCs was characterized by lower expression of inflammatory cytokines and higher expression of stem cell markers and growth factors compared to adult CDCs. After intramyocardial administration of infant CDCs in the heart of DCM rats, we found that infant CDCs remained in the heart of DCM rats for at least 7 days, improved DCM-induced cardiac function impairment and protected the myocardium by elevating the left ventricular ejection fraction and fraction shortening. However, the effectiveness of transplanted CDCs was reversed later, as increased fibrosis formation instead of angiogenesis was observed. We concluded that infant CDCs, with higher expression of stem cell markers and growth factors, exhibit non-durable heart protection due to limited residence time in the heart of DCM animals, suggesting that multiple administrations of the CDCs or post-regulation after transplantation may be the key for cell therapy in the future.
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Abbreviations
- CDCs:
-
Cardiosphere-derived cells
- DCM:
-
Dilated cardiomyopathy
- GEO:
-
Gene expression omnibus
- CSps:
-
Explant-derived cardiospheres
- LVEF:
-
Left ventricular ejection fraction
- LVFS:
-
Left ventricular fractional shortening
- LVEDD:
-
Left ventricular end-diastolic diameter
- LVESD:
-
Left ventricular end-systolic diameter
- LVEDV:
-
Left ventricular end-diastolic volume
- LVESV:
-
Left ventricular end-systolic volume
- TOF:
-
Tetralogy of Fallot
- PA:
-
Pulmonary atresia
- PS:
-
Pulmonary stenosis
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Acknowledgements
We sincerely thank the Heart Center, Guangzhou Women and Children’s Medical Center for the surgical assistance. We also thank the Nature Science Foundation of China (No. 81670262), the Guangzhou Lingnan Yingjie Project and start-up funding from Guangzhou Women and Children’s Medical Center.
Funding
This work was funded by the Nature Science Foundation of China (No. 81670262), the Guangzhou Lingnan Yingjie Project and the start-up funding from Guangzhou Women and Children’s Medical Center.
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SW, WC, LM and MZ performed this experiment. XC and JD designed the study and wrote the main manuscript. WD and HY collected the data and analysed the results. LS reviewed the data and prepared the pictures. All authors read and approved the final manuscript.
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The study was approved by the Animal Ethics Committee of Guangzhou Medical University (G2017-080).
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Supplement Table 1
Detailed clinical information of the infant donors for CDCs isolation (data from the Heart Center of Guangzhou Women and Children Medical Center). (PDF 575 kb)
Supplement Table 2
Reported expression of cell surface markers on CDCs isolated from patients of different ages and the effect of CDCs in vivo after transplantation. References are listed in the last column. (PDF 196 kb)
Supplement Figure 3
(a-b) Expression of cell surface markers of infant CDCs by flow cytometry (a) after multiple generation culture and (b) after cryopreservation. (All graphs show the mean±S.E.M. *p<0.05, n=3). (PDF 164 kb)
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Wang, S., Chen, W., Ma, L. et al. Infant cardiosphere-derived cells exhibit non-durable heart protection in dilated cardiomyopathy rats. Cytotechnology 71, 1043–1052 (2019). https://doi.org/10.1007/s10616-019-00328-z
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DOI: https://doi.org/10.1007/s10616-019-00328-z