Abstract
Cell-based regenerative medicine therapies require robust preclinical safety, efficacy, biodistribution, and engraftment data prior to clinical testing. To address these challenges, we have developed an imaging toolbox comprising multispectral optoacoustic tomography and ultrasonography, which allows the degree of kidney, liver, and cardiac injury and the extent of functional recovery to be assessed noninvasively in a mouse model of multiorgan dysfunction. This toolbox allowed us to determine the therapeutic effects of adoptively transferred macrophages. Using bioluminescence imaging, we could then investigate the association between amelioration and biodistribution. Macrophage therapy provided limited improvement of kidney and liver function, although not significantly so, without amelioration of histological damage. No improvement in cardiac function was observed. Biodistribution analysis showed that macrophages homed and persisted in the injured kidneys and liver but did not populate the heart. Our data suggest that the limited improvement observed in kidney and liver function could be mediated by M2 macrophages. More importantly, we demonstrate here the utility of the imaging toolbox for assessing the efficacy of potential regenerative medicine therapies in multiple organs.
Highlights
Cell-based regenerative medicine therapies (RMTs), which include pluripotent stem cells, mesenchymal stromal cells, and macrophages, have the potential to treat a variety of human diseases
Issues which currently prevent the generation of such data include (i) the limitations associated with commonly used blood biomarkers of organ injury, such as serum creatinine (SCr) and blood urea nitrogen (BUN) for renal function [1,2,3,4,5] and alanine aminotransferase for liver function [6,7,8]; (ii) the technical limitations in repeated blood and urine sampling in small rodents; and (iii) the difficulties associated with monitoring organ function in small animal species longitudinally
For quantitative analysis of the changes observed in each individual animal, IRDye clearance data were expressed as the difference in the Cortex : Pelvis area under the clearance curve (AUC) between the measurements taken on days 1 and 4 (ΔAUC C : P)
Summary
Cell-based regenerative medicine therapies (RMTs), which include pluripotent stem cells, mesenchymal stromal cells, and macrophages, have the potential to treat a variety of human diseases. The assessment of organ injury in small rodents classically involves measurements of serum or urine biomarkers, or histopathological analysis. Since the latter is usually only undertaken at postmortem, it fails to allow the progression of injury to be monitored in the same animals longitudinally, requiring animals to be culled at multiple time points, which is not in keeping with the principles of the NC3Rs and reduces the power of the statistical tests.
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