Differential responses of transplanted stem cells to the diseased environment unveiled by a single molecular NIR II cell tracker

Abstract

designed and conducted the probe synthesis, in vitro experiments, in vivo experiments, analyzed and interpreted data, wrote the manuscript; C.Z. M.Z. and Z.W. contributed to the manuscript writing; S.C. performed the ALI and MCAO model experiments; X.Z. carried out the MI model experiments; H.T.W. differentiated the iPSC-ECs; Z.C. provided experimental design and advice, manuscript writing, and funding support. All authors reviewed the manuscript. AbstractStem cell therapy holds high promises in regenerative medicine. The major challenge of clinical translation is to precisely and quantitatively evaluate the in vivo cell distribution, migration, and engraftment, which cannot be easily achieved by current techniques. To address this issue, for the first time, we have developed a single molecular cell tracker with a strong fluorescence signal in the second near-infrared (NIR-II) window (1000-1700 nm) for real-time monitoring of in vivo cell behaviors in both healthy and diseased animal models. The NIR-II tracker (CelTrac1000) has shown complete cell labeling with low cytotoxicity and profound long-term tracking ability for 30 days in high temporospatial resolution for semi-quantification of the biodistribution of primary mesenchymal stem cell and induced pluripotent stem cell-derived endothelial cells. Taking advantage of the unique merits of CelTrac1000, the responses of transplanted stem cells to different diseased environments have been discriminated and unveiled. Furthermore, we also demonstrate CelTrac1000 as a universal and effective technique for ultrafast real-time tracking of the cellular migration and distribution in a single cell cluster resolution, along with the lung contraction and heart beating. As such, this single molecular NIR-II tracker will shift the optical cell tracking into a single cell cluster and millisecond temporospatial resolution for better evaluating and understanding stem cell therapy, affording optimal doses and efficacy. Significance StatementFor the first time, we synthesized a NIR-II tracker (CelTrac1000) for ultrafast real-time tracking of the migration trajectory of transplanted mesenchymal stem cells in the circulatory system with a single cell cluster resolution. Taking advantage of the merits of CelTrac1000, the responses of transplanted stem cells to different diseased environments, including acute lung injury, myocardial infarction, and middle cerebral artery occlusion, have been discriminated and unveiled in mice models. As such, our approach can help correlate critical biomedical information in stem cell therapies, such as stem cell dosing and engraftment and their relationships with efficacy, providing more accurate therapeutic treatment and outcomes in certain diseases during a long evaluation period (>30 days) in comparison with the commercial Qtracker (7-10 days). Main Text