Significance: Obesity has reached pandemic levels, prompting the need for novel therapeutics. The immune system has been suggested to be critically linked to metabolic health, leading to the prospect of immune-directed therapies. We report that obese fat tissue contains multiple distinct populations of macrophages with unique tissue distributions, transcriptomes, chromatin landscapes, and functions. These results provide a higher resolution of the cellular and functional heterogeneity within adipose macrophages and provide a framework within which to develop new immune-directed therapies for the treatment of obesity and related inflammatory comorbidities.

In transplantation, there is a critical need for noninvasive biomarker platforms for monitoring immunologic rejection. We hypothesized that transplanted tissues release donor-specific exosomes into recipient circulation and that the quantitation and profiling of donor intra-exosomal cargoes may constitute a biomarker platform for monitoring rejection. Here, we have tested this hypothesis in a human-into-mouse xenogeneic islet transplant model and validated the concept in clinical settings of islet and renal transplantation. In the xenogeneic model, we quantified islet transplant exosomes in recipient blood over long-term follow-up using anti-HLA antibody, which was detectable only in xenoislet recipients of human islets. Transplant islet exosomes were purified using anti-HLA antibody–conjugated beads, and their cargoes contained the islet endocrine hormone markers insulin, glucagon, and somatostatin. Rejection led to a marked decrease in transplant islet exosome signal along with distinct changes in exosomal microRNA and proteomic profiles prior to appearance of hyperglycemia. In the clinical settings of islet and renal transplantation, donor exosomes with respective tissue specificity for islet β cells and renal epithelial cells were reliably characterized in recipient plasma over follow-up periods of up to 5 years. Collectively, these findings demonstrate the biomarker potential of transplant exosome characterization for providing a noninvasive window into the conditional state of transplant tissue.

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.

Extracorporeal membrane oxygenation (ECMO) is considered a life-saving treatment option for patients in cardiogenic shock or cardiac arrest undergoing cardiopulmonary resuscitation (CPR) due to acute pulmonary embolism (PE). We sought to analyze use and outcome of ECMO with or without adjunctive treatment strategies in patients with acute PE. We retrospectively analyzed data on patient characteristics, treatments, and in-hospital outcomes for all PE patients (ICD-code I26) undergoing ECMO in Germany between 2005 and 2018. At total of 1,172,354 patients were hospitalized with PE; of those, 2,197 (0.2%) were treated with ECMO support. Cardiac arrest requiring cardiopulmonary resuscitation was present in 77,196 (6.5%) patients. While more than one fourth of those patients were treated with systemic thrombolysis alone (n = 20,839 patients; 27.0%), a minority of patients received thrombolysis and VA-ECMO (n = 165; 0.2%), embolectomy and VA-ECMO (n = 385; 0.5%) or VA-ECMOalone (n = 588; 0.8%). A multivariable logistic regression analysis indicated the lowest risk for in-hospital death in patients who received embolectomy in combination with VA-ECMO (OR, 0.50 [95% CI, 0.41-0.61], p < 0.001), thrombolysis and VA-ECMO (0.60 [0.43-0.85], p = 0.003) or VA-ECMO alone (0.68 [0.57-0.82], p < 0.001) compared to thrombolysis alone (1.04 [0.99-1.01], p = 0.116). Our findings suggest that the use of VA-ECMO alone or as part of a multi-pronged reperfusion approach including embolectomy or thrombolysis might offer survival advantages compared to thrombolysis alone in patients with PE deteriorating to cardiac arrest.