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 cardio-pulmonary 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.
Progyaparamita Saha1,*, Sudhish Sharma1,*, Laxminarayana Korutla2,*, Srinivasa Raju Datla1, Farnaz Shoja-Taheri3, Rachana Mishra1, Grace E. Bigham1, Malini Sarkar1, David Morales1, Gregory Bittle1, Muthukumar Gunasekaran1, Chetan Ambastha1, Mir Yasir Arfat1, Deqiang Li1, Andreas Habertheuer2, Robert Hu2, Manu O. Platt3, Peixin Yang1, Michael E. Davis3, Prashanth Vallabhajosyula2,†, Sunjay Kaushal1,†1Division of Cardiovascular Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.2Division of Cardiovascular Surgery, University of Pennsylvania, Philadelphia, PA 19104, USA.3Wallace H. Coulter Department of Biomedical Engineering and Division of Cardiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Published in final edited form as:Sci Transl Med. 2019 May 22; 11(493): . doi:10.1126/scitranslmed.aau1168.