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Edited by Stanislav Y. Shvartsman, Princeton University, Princeton, NJ, and accepted by Editorial Board Member James J. Collins June 5, 2019 (received for review February 13, 2019)
Significance
Intercellular communication between cells in tissues is frequently mediated by secreted factors, with rates of secretion frequently varying over time. Stem cells can be recruited and contribute to the reparative process in diverse tissues. How this versatile cytoprotective effect is achieved is not well understood. Here we describe a simple-to-use platform to estimate the dynamics of cellular paracrine signaling in response to a wide range of physiologically relevant perturbations. When injured cardiomyocytes were presented with a cocktail matching the dynamics and dosage of stromal cell-derived secreted factors, we found an improved survival response, suggesting that secretory dynamics can be a key component of therapeutic recombinant cocktails for tissue repair.
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.
Footnotes
↵1K., D.D.E., and Y.S. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: kshitiz{at}uchc.edu or andre.levchenko{at}yale.edu.
Author contributions: K., D.D.E., and A.L. designed research; K. and D.D.E. performed research; K., Y.S., J.A., and O.K. contributed new reagents/analytic tools; K., D.D.E., Y.S., L.W., and J.S. analyzed data; K. and A.L. wrote the paper; and K., Y.S., O.K., and A.L. helped with edits and images.
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.
This article is a PNAS Direct Submission. S.Y.S. is a guest editor invited by the Editorial Board.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1902598116/-/DCSupplemental.
Published under the PNAS license.
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Dynamic secretome of bone marrow-derived stromal cells reveals a cardioprotective biochemical cocktail
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