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Fibrin, Bone Marrow Cells and macrophages interactively modulate cardiomyoblast fate

Inês Borrego, Aurélien Frobert, Guillaume Ajalbert, Jérémy Valentin, Cyrielle Kaltenrieder, Benoît Fellay, Michael Stumpe, Stéphane Cook, Joern Dengjel, View ORCID ProfileMarie-Noelle Giraud
doi: https://doi.org/10.1101/2022.01.06.475189
Inês Borrego
1Department of EMC, Faculty of Sciences and Medicine, University of Fribourg, 1700 Fribourg, Switzerland
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Aurélien Frobert
1Department of EMC, Faculty of Sciences and Medicine, University of Fribourg, 1700 Fribourg, Switzerland
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Guillaume Ajalbert
1Department of EMC, Faculty of Sciences and Medicine, University of Fribourg, 1700 Fribourg, Switzerland
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Jérémy Valentin
1Department of EMC, Faculty of Sciences and Medicine, University of Fribourg, 1700 Fribourg, Switzerland
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Cyrielle Kaltenrieder
1Department of EMC, Faculty of Sciences and Medicine, University of Fribourg, 1700 Fribourg, Switzerland
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Benoît Fellay
3Fribourg Cantonal Hospital, 1700 Fribourg, Switzerland
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Michael Stumpe
2Department of Biology, University of Fribourg, 1700 Fribourg, Switzerland
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Stéphane Cook
1Department of EMC, Faculty of Sciences and Medicine, University of Fribourg, 1700 Fribourg, Switzerland
3Fribourg Cantonal Hospital, 1700 Fribourg, Switzerland
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Joern Dengjel
2Department of Biology, University of Fribourg, 1700 Fribourg, Switzerland
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Marie-Noelle Giraud
1Department of EMC, Faculty of Sciences and Medicine, University of Fribourg, 1700 Fribourg, Switzerland
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  • ORCID record for Marie-Noelle Giraud
  • For correspondence: marie-noelle.giraud@unifr.ch
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ABSTRACT

Interactions between macrophages, cardiac cells and the extracellular matrix are crucial for cardiac repair following myocardial infarction (MI). The paracrine effects of cell-based treatments of MI might modulate these interactions and impact cardiac repair. The immunomodulatory capacity of the therapeutic cells is therefore of interest and could be modulated by the use of biomaterials. We first showed that bone marrow cells (BMC) associated with fibrin could treat MI. Then, we interrogated the influence of fibrin, as a biologically active scaffold, on the secretome of BMC and the impact of their association on macrophage fate and cardiomyoblast proliferation.

Methods In vivo, two weeks post-MI, rats were treated with epicardial implantation of BMC and fibrin or sham-operated. High-resolution echocardiography was performed to evaluate the heart function and structure changes after 4 weeeks. Histology and immunostaining were performed on harvested hearts. In vitro, BMC were first primed with fibrin. Second, non-polarized macrophages were differentiated toward either pro-inflammatory or anti-inflammatory phenotypes and stimulated with the conditioned medium of fibrin-primed BMC (F-BMC). Proteomic, cytokine levels quantification, and RT-PCR were performed. EdU incorporation and real-time cell analysis assessed cell proliferation.

Results The epicardial implantation of fibrin and BMC reduced the loss of cardiac function induced by MI, increased wall thickness and prevented the fibrotic scar expansion. After 4 and 12 weeks, the infarct content of CD68+ and CD206+ was similar in control and treated animals. In vitro, we showed that fibrin profoundly influenced the gene expression and the secretome of BMC, simultaneously upregulating both pro- and anti-inflammatory mediators. Furthermore, the conditioned medium from F-BMC significantly increased the proliferation of macrophages in a subsets dependent manner and modulated their gene expression and cytokines secretion. For instance, F-BMC significantly downregulated the expression of Nos2, Il6 and Ccl2/Mcp1 while Arg1, Tgfb and IL10 were upregulated. Interestingly, macrophages educated by F-BMC increased cardiomyoblast proliferation.

In conclusion, our study provides evidence that BMC/fibrin-based treatment lowered the infarct extent and improved cardiac function. The macrophage content was unmodified when measured at a chronic stage. Nevertheless, acutely and in vitro, the F-BMC secretome promotes an anti-inflammatory response that stimulates cardiac cell growth. Finally, our study emphases the acute impact of F-BMC educated macrophages on cardiac cell fate.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 06, 2022.
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Fibrin, Bone Marrow Cells and macrophages interactively modulate cardiomyoblast fate
Inês Borrego, Aurélien Frobert, Guillaume Ajalbert, Jérémy Valentin, Cyrielle Kaltenrieder, Benoît Fellay, Michael Stumpe, Stéphane Cook, Joern Dengjel, Marie-Noelle Giraud
bioRxiv 2022.01.06.475189; doi: https://doi.org/10.1101/2022.01.06.475189
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Fibrin, Bone Marrow Cells and macrophages interactively modulate cardiomyoblast fate
Inês Borrego, Aurélien Frobert, Guillaume Ajalbert, Jérémy Valentin, Cyrielle Kaltenrieder, Benoît Fellay, Michael Stumpe, Stéphane Cook, Joern Dengjel, Marie-Noelle Giraud
bioRxiv 2022.01.06.475189; doi: https://doi.org/10.1101/2022.01.06.475189

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