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The Myocardial Microenvironment Modulates the Biology of Transplanted Mesenchymal Stem Cells

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Abstract

Purpose

The maximal efficacy of cell therapy depends on the survival of stem cells, as well as on the phenotypic and biologic changes that may occur on these cells after transplantation. It has been hypothesized that the post-ischemic myocardial microenvironment can play a critical role in these changes, potentially affecting the survival and reparative potential of mesenchymal stem cells (MSCs). Here, we use a dual reporter gene sensor for the in vivo monitoring of the phenotype of MSCs and study their therapeutic effect on cardiac function.

Procedures

The mitochondrial sensor was tested in cell culture in response to different mitochondrial stressors. For in vivo testing, MSCs (3 × 105) were delivered in a murine ischemia-reperfusion (IR) model. Bioluminescence imaging was used to assess the mitochondrial biology and the viability of transplanted MSCs, while high-resolution ultrasound provided a non-invasive analysis of cardiac contractility and dyssynchrony.

Results

The mitochondrial sensor showed increased activity in response to mitochondrial stressors. Furthermore, when tested in the living subject, it showed a significant increase in mitochondrial dysfunction in MSCs delivered in IR, compared with those delivered under sham conditions. Importantly, MSCs delivered to ischemic hearts, despite their mitochondrial stress and poor survival, were able to induce a significant improvement in cardiac function, through decreased collagen deposition and resynchronization/contractility of left ventricular wall motion.

Conclusions

The ischemic myocardium induces changes in the phenotype of transplanted MSCs. Despite their limited survival, MSCs still elicit a certain therapeutic response, as evidenced by improvement in myocardial remodeling and cardiac function. Maximization of the survival and reparative efficacy of stem cells remains a key for the success of stem cell therapies.

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Funding

This study was supported financially by National Institutes of Health awards RO1HL119795 (MR-P) and RO1CA161091 (RP).

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Authors and Affiliations

  1. Department of Cardiovascular Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA

    Federico Franchi, Vidhya Ramaswamy, Michaela Olthoff, Karen M. Peterson & Martin Rodriguez-Porcel

  2. Department of Radiology and Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, Stanford, CA, USA

    Ramasamy Paulmurugan

Authors
  1. Federico Franchi
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  2. Vidhya Ramaswamy
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  3. Michaela Olthoff
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  4. Karen M. Peterson
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  5. Ramasamy Paulmurugan
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  6. Martin Rodriguez-Porcel
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Corresponding author

Correspondence to Federico Franchi.

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All applicable institutional and/or national guidelines for the care and use of animals were followed.

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Franchi, F., Ramaswamy, V., Olthoff, M. et al. The Myocardial Microenvironment Modulates the Biology of Transplanted Mesenchymal Stem Cells. Mol Imaging Biol 22, 948–957 (2020). https://doi.org/10.1007/s11307-019-01470-y

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