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Basic Research in Cardiology

, 113:46 | Cite as

Cardiac mesenchymal cells from diabetic mice are ineffective for cell therapy-mediated myocardial repair

  • Parul Mehra
  • Yiru Guo
  • Yibing Nong
  • Pawel Lorkiewicz
  • Marjan Nasr
  • Qianhong Li
  • Senthilkumar Muthusamy
  • James A. Bradley
  • Aruni Bhatnagar
  • Marcin Wysoczynski
  • Roberto Bolli
  • Bradford G. Hill
Original Contribution

Abstract

Although cell therapy improves cardiac function after myocardial infarction, highly variable results and limited understanding of the underlying mechanisms preclude its clinical translation. Because many heart failure patients are diabetic, we examined how diabetic conditions affect the characteristics of cardiac mesenchymal cells (CMC) and their ability to promote myocardial repair in mice. To examine how diabetes affects CMC function, we isolated CMCs from non-diabetic C57BL/6J (CMCWT) or diabetic B6.BKS(D)-Leprdb/J (CMCdb/db) mice. When CMCs were grown in 17.5 mM glucose, CMCdb/db cells showed > twofold higher glycolytic activity and a threefold higher expression of Pfkfb3 compared with CMCWT cells; however, culture of CMCdb/db cells in 5.5 mM glucose led to metabolic remodeling characterized by normalization of metabolism, a higher NAD+/NADH ratio, and a sixfold upregulation of Sirt1. These changes were associated with altered extracellular vesicle miRNA content as well as proliferation and cytotoxicity parameters comparable to CMCWT cells. To test whether this metabolic improvement of CMCdb/db cells renders them suitable for cell therapy, we cultured CMCWT or CMCdb/db cells in 5.5 mM glucose and then injected them into infarcted hearts of non-diabetic mice (CMCWT, n = 17; CMCdb/db, n = 13; Veh, n = 14). Hemodynamic measurements performed 35 days after transplantation showed that, despite normalization of their properties in vitro, and unlike CMCWT cells, CMCdb/db cells did not improve load-dependent and -independent parameters of left ventricular function. These results suggest that diabetes adversely affects the reparative capacity of CMCs and that modulating CMC characteristics via culture in lower glucose does not render them efficacious for cell therapy.

Keywords

Cell therapy Heart failure Metabolism Glycolysis Mitochondria Extracellular vesicle 

Notes

Acknowledgements

The authors acknowledge funding support from the National Institutes of Health (NIH) [to BGH: HL122580, HL130174, ES028268; to RB: HL78825, HL113530; to AB: GM103492, HL55477) and the American Diabetes Association Pathway to Stop Diabetes Grant (BGH: ADA 1-16-JDF-041.)].

Author contributions

PM: experimental studies, assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; YG: in vivo experiments, data analysis and interpretation, final approval of manuscript; YN: experimental studies; PL: experimental studies, manuscript writing, final approval of manuscript; MN: experimental studies, final approval of manuscript; SM: experimental studies; JAB: experimental studies, final approval of manuscript; QL: experimental studies; AB, financial support, concept and design, final approval of manuscript; MW: concept and design, experimental studies, data analysis and interpretation, manuscript writing, final approval of manuscript; RB: concept and design, in vivo experimental studies, data analysis and interpretation, manuscript writing, final approval of manuscript; and BGH, financial support, concept and design, assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript.

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Supplementary material

395_2018_703_MOESM1_ESM.pdf (464 kb)
Supplementary material 1 (PDF 464 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Parul Mehra
    • 1
  • Yiru Guo
    • 1
  • Yibing Nong
    • 1
  • Pawel Lorkiewicz
    • 1
  • Marjan Nasr
    • 1
  • Qianhong Li
    • 1
  • Senthilkumar Muthusamy
    • 1
  • James A. Bradley
    • 1
  • Aruni Bhatnagar
    • 1
  • Marcin Wysoczynski
    • 1
  • Roberto Bolli
    • 1
  • Bradford G. Hill
    • 1
  1. 1.Division of Cardiovascular Medicine, Department of Medicine, Institute of Molecular Cardiology, Envirome Institute, Diabetes and Obesity CenterUniversity of Louisville School of MedicineLouisvilleUSA

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