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Proc Natl Acad Sci U S A. 2019 Jul 9;116(28):14374-14383. doi: 10.1073/pnas.1902598116. Epub 2019 Jun 25.

Dynamic secretome of bone marrow-derived stromal cells reveals a cardioprotective biochemical cocktail.

Author information

1
Yale Institute of Systems Biology, Yale University, West Haven, CT 06516; kshitiz@uchc.edu andre.levchenko@yale.edu.
2
Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, CT 06030.
3
Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, MD 21205.
4
Department of Cardiology, University of California, San Francisco, CA 94115.
5
Yale Institute of Systems Biology, Yale University, West Haven, CT 06516.
6
Department of Cellular Molecular and Biomedical Sciences, University of Vermont, Burlington, VT 05405.

Abstract

Transplanted stromal cells have demonstrated considerable promise as therapeutic agents in diverse disease settings. Paracrine signaling can be an important mediator of these therapeutic effects at the sites of acute or persistent injury and inflammation. As many stromal cell types, including bone marrow-derived stromal cells (BMSCs), display tissue-specific responses, there is a need to explore their secretory dynamics in the context of tissue and injury type. Paracrine signals are not static, and could encode contextual dynamics in the kinetic changes of the concentrations of the secreted ligands. However, precise measurement of dynamic and context-specific cellular secretory signatures, particularly in adherent cells, remains challenging. Here, by creating an experimental and computational analysis platform, we reconstructed dynamic secretory signatures of cells based on a very limited number of time points. By using this approach, we demonstrate that the secretory signatures of CD133-positive BMSCs are uniquely defined by distinct biological contexts, including signals from injured cardiac cells undergoing oxidative stress, characteristic of cardiac infarction. Furthermore, we show that the mixture of recombinant factors reproducing the dynamics of BMSC-generated secretion can mediate a highly effective rescue of cells injured by oxidative stress and an improved cardiac output. These results support the importance of the dynamic multifactorial paracrine signals in mediating remedial effects of stromal stem cells, and pave the way for stem cell-inspired cell-free treatments of cardiac and other injuries.

KEYWORDS:

cell–cell communication; paracrine dynamics; paracrine signaling; secretion dynamics; secretome

PMID:
31239339
PMCID:
PMC6628676
[Available on 2019-12-25]
DOI:
10.1073/pnas.1902598116

Conflict of interest statement

Conflict of interest statement: A.L., K., D.D.E, Y.S., and J.A. have filed a patent describing the device mentioned in the manuscript. The application number of the patent filing is 15/525328.

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