Dataset Information

Expandable human cardiovascular progenitors from stem cells for regenerating mouse heart after myocardial infarction.

ABSTRACT:

Aims

Cardiovascular diseases caused by loss of functional cardiomyocytes (CMs) are a major cause of mortality and morbidity worldwide due in part to the low regenerative capacity of the adult human heart. Human pluripotent stem cell (hPSC)-derived cardiovascular progenitor cells (CPCs) are a potential cell source for cardiac repair. The aim of this study was to examine the impact of extensive remuscularization and coincident revascularization on cardiac remodelling and function in a mouse model of myocardial infarction (MI) by transplanting doxycycline (DOX)-inducible (Tet-On-MYC) hPSC-derived CPCs in vivo and inducing proliferation and cardiovascular differentiation in a drug-regulated manner.

Methods and results

CPCs were injected firstly at a non-cardiac site in Matrigel suspension under the skin of immunocompromised mice to assess their commitment to the cardiovascular lineage and ability to self-renew or differentiate in vivo when instructed by systemically delivered factors including DOX and basic fibroblast growth factor (bFGF). CPCs in Matrigel were then injected intra-myocardially in mice subjected to MI to assess whether expandable CPCs could mediate cardiac repair. Transplanted CPCs expanded robustly both subcutis and in the myocardium using the same DOX/growth factor inducing regime. Upon withdrawal of these cell-renewal factors, CPCs differentiated with high efficiency at both sites into the major cardiac lineages including CMs, endothelial cells, and smooth muscle cells. After MI, engraftment of CPCs in the heart significantly reduced fibrosis in the infarcted area and prevented left ventricular remodelling, although cardiac function determined by magnetic resonance imaging was unaltered.

Conclusion

Replacement of large areas of muscle may be required to regenerate the heart of patients following MI. Our human/mouse model demonstrated that proliferating hPSC-CPCs could reduce infarct size and fibrosis resulting in formation of large grafts. Importantly, the results suggested that expanding transplanted cells in situ at the progenitor stage maybe be an effective alternative causing less tissue damage than injection of very large numbers of CMs.

SUBMITTER: Schwach V

PROVIDER: S-EPMC7252440 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

Expandable human cardiovascular progenitors from stem cells for regenerating mouse heart after myocardial infarction.

Schwach Verena V Gomes Fernandes Maria M Maas Saskia S Gerhardt Sophie S Tsonaka Roula R van der Weerd Louise L Passier Robert R Mummery Christine L CL Birket Matthew J MJ Salvatori Daniela C F DCF

Cardiovascular research 20200301 3

<h4>Aims</h4>Cardiovascular diseases caused by loss of functional cardiomyocytes (CMs) are a major cause of mortality and morbidity worldwide due in part to the low regenerative capacity of the adult human heart. Human pluripotent stem cell (hPSC)-derived cardiovascular progenitor cells (CPCs) are a potential cell source for cardiac repair. The aim of this study was to examine the impact of extensive remuscularization and coincident revascularization on cardiac remodelling and function in a mous ...[more]

PMID: 31287499

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Project description:AAR measurement is useful when assessing the efficacy of reperfusion therapy and novel cardioprotective agents after myocardial infarction. Multi-slice (Typically 10-12) T2-STIR has been used widely for its measurement, typically with a short axis stack (SAX) covering the entire left ventricle, which can result in long acquisition times and multiple breath holds. This study sought to compare 3-slice T2-short-tau inversion recovery (T2- STIR) technique against conventional multi-slice T2-STIR technique for the assessment of area at risk (AAR).CMR imaging was performed on 167 patients after successful primary percutaneous coronary intervention. 82 patients underwent a novel 3-slice SAX protocol and 85 patients underwent standard 10-slice SAX protocol. AAR was obtained by manual endocardial and epicardial contour mapping followed by a semi- automated selection of normal myocardium; the volume was expressed as mass (%) by two independent observers.85 patients underwent both 10-slice and 3-slice imaging assessment showing a significant and strong correlation (intraclass correlation coefficient?=?0.92;p?<?0.0001) and a low Bland-Altman limit (mean difference -0.03?±?3.21%, 95% limit of agreement,- 6.3 to 6.3) between the 2 analysis techniques. A further 82 patients underwent 3-slice imaging alone, both the 3-slice and the 10-slice techniques showed statistically significant correlations with angiographic risk scores (3-slice to BARI r?=?0.36, 3-slice to APPROACH r?=?0.42, 10-slice to BARI r?=?0.27, 10-slice to APPROACH r?=?0.46). There was low inter-observer variability demonstrated in the 3-slice technique, which was comparable to the 10-slice method (z?=?1.035, p?=?0.15). Acquisition and analysis times were quicker in the 3-slice compared to the 10-slice method (3-slice median time: 100 seconds (IQR: 65-171 s) vs. (10-slice time: 355 seconds (IQR: 275-603 s); p?<?0.0001.AAR measured using 3-slice T2-STIR technique correlates well with standard 10-slice techniques, with no significant bias demonstrated in assessing the AAR. The 3-slice technique requires less time to perform and analyse and is therefore advantageous for both patients and clinicians.

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Dataset Information

Expandable human cardiovascular progenitors from stem cells for regenerating mouse heart after myocardial infarction.

Aims

Methods and results

Conclusion

Publications

Expandable human cardiovascular progenitors from stem cells for regenerating mouse heart after myocardial infarction.

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