Circulating exosomes derived from transplanted progenitor cells aid the functional recovery of ischemic myocardium

• Type of Material: Article
• Authors: Progyaparamita Saha, University of Maryland; Sudhish Sharma, University of Maryland; Laxminarayana Korutla, University of Pennsylvania; Srinivasa Raju Datla, University of Maryland; Farnaz Shoja-Taheri, Emory University; Rachana Mishra, University of Maryland; Grace E. Bigham, University of Maryland; Malini Sarkar, University of Maryland; David Morales, University of Maryland; Gregory Bittle, University of Maryland; Muthukumar Gunasekaran, University of Maryland; Chetan Ambastha, University of Maryland; Mir Yasir Arfat, University of Maryland; Deqiang Li, University of Maryland; Andreas Habertheuer, University of Pennsylvania; Robert Hu, University of Pennsylvania; Manu Platt, Emory University; Peixin Yang, University of Maryland; Michael Davis, Emory University; Prashanth Vallabhajosyula, University of Pennsylvania; Sunjay Kaushal, University of Maryland
• Language: English
• Date: 2019-05-22
• Publisher: AMER ASSOC ADVANCEMENT SCIENCE
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Copyright © 2019 The Authors, some rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1126/scitranslmed.aau1168
• Title of Journal or Parent Work: SCIENCE TRANSLATIONAL MEDICINE
• Volume: 11
• Issue: 493
• Grant/Funding Information: S.K. was supported by NIH grants 1R01HL118491, 1R01HL139060-02, and R01HL141922-02 and the Maryland Stem Research Fund. S.S. is supported by the Maryland Stem Cell Research Fund and AHA-CDA-18CDA34110282-2. S.R.D. was supported by the Maryland Stem Cell Research Fund. P.V and L.K. are supported by internal funds from the University of Pennsylvania.
• Keywords: EXTRACELLULAR VESICLES; Research & Experimental Medicine; THERAPY; METAANALYSIS; BIOLOGY; Science & Technology; Cell Biology; REGENERATION; CARDIAC STEM-CELLS; ACTIVATION; Life Sciences & Biomedicine; HEART; Medicine, Research & Experimental; PARACRINE MECHANISMS; INFARCTION
• Research Categories: Biology, Cell

Abstract

The stem cell field is hindered by its inability to noninvasively monitor transplanted cells within the target organ in a repeatable, time-sensitive, and condition-specific manner. We hypothesized that quantifying and characterizing transplanted cell-derived exosomes in the recipient plasma would enable reliable, noninvasive surveillance of the conditional activity of the transplanted cells. To test this hypothesis, we used a human-into-rat xenogeneic myocardial infarction model comparing two well-studied progenitor cell types: cardiosphere-derived cells (CDCs) and c-kit+ cardiac progenitor cells (CPCs), both derived from the right atrial appendage of adults undergoing cardiopulmonary bypass. CPCs outperformed the CDCs in cell-based and in vivo regenerative assays. To noninvasively monitor the activity of transplanted CDCs or CPCs in vivo, we purified progenitor cell-specific exosomes from recipient total plasma exosomes. Seven days after transplantation, the concentration of plasma CPC-specific exosomes increased about twofold compared to CDC-specific exosomes. Computational pathway analysis failed to link CPC or CDC cellular messenger RNA (mRNA) with observed myocardial recovery, although recovery was linked to the microRNA (miRNA) cargo of CPC exosomes purified from recipient plasma. We further identified mechanistic pathways governing specific outcomes related to myocardial recovery associated with transplanted CPCs. Collectively, these findings demonstrate the potential of circulating progenitor cell-specific exosomes as a liquid biopsy that provides a noninvasive window into the conditional state of the transplanted cells. These data implicate the surveillance potential of cell-specific exosomes for allogeneic cell therapies.